Most organic acidemias are disorders of amino acid metabolism. They were first described in 1961 as a syn-drome of mental retardation, hyperglycinemia and epi-sodic ketoacidosis, neutropenia and thrombocytopenia induced by protein intake or infection. Ultimately, it was realized that this biochemical and clinical phenotype, which had become known as ketotic hyperglycinemia, was actually a manifestation of organic acidemias, and in particular, methylmalonic acidemia, propionic acidemia, and 2-methyl-3-hydroxybutyric acidemia.
Organic acidemias can present in many ways and the indications for organic acid screening are quite diverse. They include (i) features of ketotic hyperglycinemia (see previous discussion); (ii) an unusual body odor; (iii) acute disease in infancy, especially when associated with meta-bolic acidosis, hypoglycemia, or hyperammonemia; (iv) chronic or recurrent metabolic acidosis, with or without an anion gap; (v) static or progressive extrapyramidal move-ment disorder in childhood; (vi) Reye syndrome when recurrent, familial, or in infancy; (vii) the combination of ataxia, alopecia, and rash; and (viii) seizure disorder and/or developmental delay of unknown cause. Because most organic acids are effectively cleared from the bloodstream by the kidney, urine is the preferred fluid for analysis.
Diagnosis of these conditions depends on methods to separate and identify organic acids, and the most widely used of these is gas chromatography-mass spectrometry (GC-MS), in which organic acid derivatives are separated by gas chromatography and then passed into a mass spec-trometer for identification. Tandem mass spectrometry (MS-MS) is a related technology in which compounds are separated by molecular weight by one mass spectrom-eter, fragmented as they exit, and identified on the basis
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of their fragments by a second mass spectrometer. This technique is used to measure the acylcarnitine esters that accumulate in various fatty acid oxidations and organic acid disorders and serves the basis for effective newborn screening for many of these disorders. The convergence of many metabolic pathways especially onto the distil end of branched-chain amino acid catabolism has led to much confusion in diagnosis over the years. Diseases named for metabolites ultimately proved to be imprecise because of the accumulation of the same metabolites in more than one condition. Thus, it is best to discuss this group of disorders based on the enzymatic and/or molec-ular defect rather than metabolite accumulation.
Most described organic acidemias are inherited as autosomal recessive traits. Two are X-linked recessive. Prenatal diagnosis is typically accomplished through measurement of enzyme activity in cultured amniotic cells or a chorionic villus sample, or through measurement of diagnostic metabolites excreted by the affected fetus into the amniotic fluid. Molecular diagnosis is also possible when a proband’s genetic defect has been identified.
97.1.1 Branched-Chain Organic Acidemias
The largest group of organic acidemias derives from defects in the mitochondrial-based degradation of the branched-chain amino acids leucine, isoleucine and valine (Figure 97-1). The branched-chain amino acids enter mitochondria via a combined, reversible deami-nation and transport step performed by the vitamin B6-dependent branched-chain amino acid aminotrans-ferases. Subsequently, the branched-chain ketoacids undergo oxidative decarboxylation by a single branched-chain ketoacid dehydrogrenase active with all three sub-strates, another reversible reaction. Deficiency of this
2 CHAPTER 97 Organic Acidemias and Disorders of Fatty Acid Oxidation
Isoleucine
2-Oxo-3-methylvalerate
Aminotransferase
Valine
2-Oxo-isovalerate
Aminotransferase
Leucine
2-Oxo-isocaproate
Aminotransferase
2-Methylbutyryl-CoA
BCKDH
SBCAD
Isobutyryl-CoA
BCKDH
Isovaleryl-CoA
BCKDH
IVDIBD 1 3 4
Tiglyl-CoAHydratase
Methacrylyl-CoAHydratase
3-Methyl-crotonyl-CoA
MCC
Deacylase
2-Methyl-3-OH-butyryl-CoA
3-OH-isobutyryl-CoA3-Methyl-
5
8
76
HADH2
Deacylase
Hydratase
Thiolase
DH
glutaconyl-CoA
2-Methyl-acetoacetyl-CoA
3-OH-isobutyrate
3-OH-3-methyl-glutaryl-CoA
Methylmalonate
9
1012
8
11HMG-CoA lyase
Methylmalonatesemialdehyde
Propionyl-CoA Acetyl-CoA Acetoacetate
C
Carboxylase
DH13
15
14
Methylmalonyl-CoA
Succinyl-CoA
Krebscycle
Mutase 16
FIGURE 97-1 Pathways of branched-chain amino acid catabolism. The first two steps in the metabolism of branched-chain amino acids are reversible and their deficiency leads to amino acid rather than organic acid accumulation. BCKDH, branched-chain ketoacid dehydrogenase. Documented steps shown to cause disease in humans are numbered. 1, IBD, isobutyryl-CoA dehydrogenase; 2–4, isobutyryl, short branched-chain, and isovaleryl-CoA dehydrogenase; 5 and 6, methacrylyl-CoA and tiglygl-CoA hydratase, respectively; 7, MCC, methylcrotonyl-CoA car-boxylase; 8, 3-hydroxyisobutyryl-CoA deacylase; 9, 3-hydroxyisobytyrate dehydrogenase; 10, 2-methyl-3-hydroxybutyryl-CoA dehydrogenase; 11, mitochondrial acetoacetyl-CoA thiolase; 12, 3-methylglutaconyl-CoA hydratase, 13, 3-hydoxy, 3-methylglutaryl-CoA lyase; 14, methyl-malonate semialdehyde dehydrogenase; 15, propionyl-CoA carboxylase; 16, methylmalonyl-CoA mutase.
fall anywhere on the spectrum of acute to chronic presen-
dehydrogenase leads to maple syrup urine disease and is discussed elsewhere in the book (Chapter 92). The remaining steps of the pathway are unique to the metab-olites of each of the amino acids.97.1.1.1 Isovaleryl-CoA Dehydrogenase Deficiency. Isovaleric acidemia (IVA) was the first condition to be rec-ognized as an organic acidemia when the odor of sweaty feet that surrounded an infant with episodic encephalop-athy was shown to be due to isovaleric acid (1,2). The disorder in leucine degradation is due to deficiency of iso-valeryl-CoA dehydrogenase, the mitochondrial enzyme that oxidizes the first irreversible step in this pathway, isovaleryl-CoA to 3-methylcrotonyl-CoA (3).
97.1.1.1.1 Clinical Course. Early literature on IVA, an autosomal recessive disorder, emphasized two appar-ent phenotypes (4). The first was an acute, neonatal pre-sentation with patients becoming symptomatic within the first two weeks of life (1,5–9). Patients appeared initially well, then developed vomiting and lethargy, progress-ing to coma. The second group presented with relatively nonspecific failure to thrive and/or developmental delay (chronic intermittent presentation) (5,6,10–12). Patients who survived an early acute presentation subsequently were indistinguishable from those with the chronic phe-notype, and both groups of patients were prone to inter-mittent acute episodes of decompensation with minor illnesses (4). In reality, it is now apparent that patients can
tation and that there is probably little predictive value to the initial presentation. Moreover, with the application of MS-MS in newborn screening, potentially asymptomatic patients with one recurring IVD gene mutation and a mild biochemical phenotype are being identified in increasing numbers, representing an additional phenotype of IVA (13). This type may represent a biochemical phenotype only without the expression of any clinical symptoms (such as in benign hyperphenylalaninemia) and therefore needs to be differentiated from the classic forms of IVA.
97.1.1.1.2 Diagnosis. Diagnosis is most frequently made by newborn screening in countries where tandem MS-MS screening is performed. In symptomatic patients, the diagnosis is suggested by the clinical course and odor, and is confirmed by organic acid analysis or by demon-strating a deficiency of isovaleryl-CoA dehydrogenase in tissues. Odor may be mild or absent, however, and thus the clinical picture may be relatively nonspecific. The organic acids characteristic of the condition are iso-valerylglycine and 3-hydroxyisovaleric acid; however, a long list of isovaleryl-CoA derived metabolites has been reported in blood and urine from patients with IVA and can assist in the confirmation of the disorder. Isovale-ric acid itself, which is responsible for the odor, is not detected by most analytic methods. Most of the accumu-lated isovaleryl-CoA is excreted as the nontoxic glycine
CHAPTER 97 Organic Acidemias and Disorders of Fatty Acid Oxidation 3
and carnitine esters, but the amounts that accumulate during infection or after a protein load exceed the capac-ity of the liver to esterify it, and the carbon skeleton then appears in other compounds. The same clinical presenta-tion and odor can be seen in glutaric acidemia type II, but urine organic acid analysis will effectively differenti-ate the two conditions.
97.1.1.1.3 Treatment. There are three goals for therapy of almost any organic acidemia, including IVA (3). The first is prevention of metabolic decompensation by careful clinical observation of the patient. During times of metabolic stress (including illness and fasting) endogenous substrate (leucine in IVA) from protein catabolism adds significantly to the production of meta-bolic intermediates. Achieving or maintaining anabolism is the main therapeutic approach to counter this prob-lem. Reducing, but not eliminating, natural protein in the diet for 12–24 h may help in this regard, but only if additional other calories to promote anabolism can be given. The second goal is long-term reduction of the production of toxic metabolites from general catabolism through dietary manipulation. Total protein and caloric intake must be adequate to support normal growth in children and maintain an anabolic state, but this may require the use of an artificial protein source restricted to the appropriate amino acid for a portion of the pro-tein requirement. The third goal of therapy is to prevent the accumulation of toxic metabolites by enhancing alternative metabolic pathways that produce alternative nontoxic compounds that are readily excreted. Carni-tine is commonly used for this purpose in many of the organic acidemias. In IVA, glycine also effectively conju-gates isovaleryl-CoA but is usually not needed to main-tain homeostasis.
97.1.1.1.4 Genetics. IVA is inherited as an autoso-mal recessive trait. The gene encoding isovaleryl-CoA dehydrogenase has been cloned and localized to chromo-some 15 (15q14–15), and multiple disease-causing muta-tions have been identified. Nearly half the mutant IVD alleles sequenced from infants diagnosed by newborn screening have been found to contain a common recur-ring missense mutation (932C>T; A282V) (13). Prenatal diagnosis can be achieved through enzyme measurement in cultured amniocytes, quantitation of isovalerylglycine in amniotic fluid, and molecular analysis when the muta-tions in the family are known.
3-Methylcrotanyl-CoA carboxylase (3MCC) deficiency can be caused by a defect in the gene for this enzyme or as part of a multiple carboxylase deficiency (see later sections). Isolated deficiency, manifesting as isolated 3-methylcrotonylglycinemia was first described in 1970 in a female infant with feeding problems, developmental delay, severe hypotonia, and an odor like that of cat’s
urine. The disorder is due to deficiency of 3-methyl-crotonyl-CoA carboxylase, a biotin-containing enzyme that converts its substrate, an intermediate in leucine oxidation, to 3-methylglutaconyl-CoA (Figure 97-2).97.1.2.1 Clinical Course. Early reports on patients with this condition reported episodes of vomiting, hypoglyce-mia, hepatomegaly, hyperammonemic encephalopathy, metabolic stroke, and hypotonia with developmental delay. Numerous affected babies have now been identified through newborn screening, most, if not all, of whom have remained well (14). Elevated metabolites characteristic of 3MCC deficiency have been identified through newborn screening in infants born to asymtpomatic mothers with 3MCC deficiency (15). In conjunction with the identifica-tion of asymptomatic siblings of severely affected patients, the clinical relevance of the biochemical abnormalities related to this deficiency must be called into question.97.1.2.2 Diagnosis. Diagnosis is usually made by organic acid analysis, and can be confirmed by enzyme assay in leukocytes or cultured fibroblasts. The most characteristic organic acids are 3-methylcrotonyl-glycine and 3-hydroxyisovaleric acid, and increased 3-hydroxyisovalerylcarnitine can be demonstrated by MS-MS. Serum carnitine may be low, possibly because of the excretion of 3-hydroxyisovalerylcarnitine. The char-acteristic but not specific metabolite identified through expanded newborn screening MS-MS is “C5-OH” carnitine. A similar organic aciduria is seen in biotin deficiency and combined carboxylase deficiency, but in these conditions together with 3-hydroxypropionic and methylcitric acids. The relationship of the metabolites to the clinical features of the disease is not well understood.97.1.2.3 Treatment. Acute episodes of vomiting and hypoglycemia should be treated with fluids, glucose, and
3-Methylcrotonyl-CoAapocarboxylase
Biotin
BiotinidaseHolocarboxylase
synthase
Biocytin Gut
3-Methylcrotonyl-CoAholocarboxylase
FIGURE 97-2 Relation of carboxylation of 3-methylcrotonyl-CoA to the activities of biotinidase and HCS. HCS also links biotin to apocar-boxylases for propionyl-CoA, acetyl-CoA and pyruvate, and biotini-dase releases biotin from proteins and enzymes that contain it.
f Fatty Acid Oxidation
4 CHAPTER 97 Organic Acidemias and Disorders o
electrolytes. The need for long-term restriction of protein or leucine is not established. Biotin supplementation (10–30 mg/day) has been reported but is of unproven effect. Carnitine supplementation may be warranted if serum levels are significantly reduced.97.1.2.4 Genetics. 3-Methylcrotonyl-CoA carboxyl-ase deficiency is transmitted as an autosomal recessive trait. The genes encoding the α- and β-subunits are located on chromosomes 3 (3q25–27) and 5 (5q12–13), respectively, and disease-causing mutations have been identified in both (14). Prenatal diagnosis, although likely possible, has not been reported.
97.1.3 Multiple Carboxylase Deficiency (Biotinidase or Holocarboxylase Synthetase Deficiency)
Multiple carboxylase deficiency is caused by defects in the incorporation of the water-soluble B-complex vitamin biotin into or its release from four apocarboxylases acting on 3-methylcrotonyl-CoA, propionyl-CoA, acetyl-CoA, and pyruvate. Holocarboxylase synthetase (HCS) cova-lently binds biotin to the apocarboxylases, while biotini-dase catalyzes its release from biotinyl-ε-lysine (biocytin) or biotin-containing peptides (Figure 97-2). Both these conditions are inherited as autosomal recessive traits, and frequently cause a syndrome of alopecia, skin rash, and encephalopathy.97.1.3.1 Clinical Course. Biotinidase deficiency usually presents in infancy with a perioral dermatitis that resem-bles acrodermatitis enteropathica, patchy alopecia, and neurologic features such as ataxia, neurosensory defects, developmental delay, and convulsions, though later pre-sentation with predominantly neurologic symptoms is possible (16). Biotinidase assay is now a part of many newborn screening programs and frequently identifies infants with partial deficiencies. These infants are likely to remain well, but late onset symptoms have been reported. HCS deficiency usually causes earlier and more severe disease, with ketoacidosis, alopecia, and a red and scaly total body eruption (17). Coma, apnea, and death often ensue if therapy is not begun promptly. In both conditions the rash may be complicated by superinfec-tion with Monilia. There is sufficient overlap in time and severity of onset; however, accurate differentiation between the two can only be made by enzyme assay.97.1.3.2 Diagnosis. Urine organic acid analysis shows increased 3-methylcrotonylglycine and 3-hydroxyisovaleric acid, together with methylcitric and 3-hydroxypropionic, and acylcarnitine analysis shows 3-hydroxyisovaleryl- and propionylcarnitine. HCS can be assayed in fibroblasts or leukocytes, and biotinidase can be assayed in serum. Dietary biotin deficiency, especially during parenteral hyperalimentation, can be biochemically indistinguish-able from biotinidase deficiency (18).97.1.3.3 Treatment. Large doses of biotin (10–30 mg/day) usually produce rapid clinical improvement and
almost complete disappearance of abnormal urine organic acids. The frequency of biotinidase deficiency, the ease with which it can be treated, and the irreversibil-ity of the neurologic sequelae have led to its inclusion in several newborn screening programs, and many affected patients have now been detected and treated success-fully before the onset of symptoms (16,19). The need for treatment of partial biotinidase deficiency remains controversial.97.1.3.4 Genetics. Both conditions are transmitted as autosomal recessive traits. The genes that encode bio-tinidase and HCS have been localized to chromosomes 3 (3p25) and 21 (21q22.1), respectively. Numerous disease-causing mutations have been delineated in each gene (16,17,19,20). Both conditions can be diagnosed in utero by enzyme assay on cultured amniocytes or chorionic villus samples, and by mutation analysis, but prenatal diagnosis of an affected fetus has thus far been reported only in HCS deficiency (21).
97.1.4 3-Methylglutaconic Aciduria
Elevation of 3-methylglutaconic aciduria is seen in a heterogenous group of disorders: 3-methylglutaconyl-CoA hydratase deficiency (Figure 97-1), Barth syn-drome (cardiomyopathy due to tafazzin gene defects), mutations in the OPA3 gene (optic atrophy plus or Costoff syndrome), and cardiomyopathy with ataxia (due to mutations in the DNAJC19 gene) (Table 97-1) (22). Occasional patients with significant 3-methylglutaconic aciduria of unknown cause continue to be identified and are referred to as having the type 4 phenotype (23). While all these disorders share a similar biochemical phenotype, they are quite different disorders clinically.97.1.4.1 Clinical Course. Patients with 3-methylglu-taconyl-CoA hydratase deficiency have been reported to have a variable phenotype ranging from mild delay (including isolated speech delay) to more severe delay, cerebellar ataxia, and movement abnormalities and even quadraplegia. Older reports are likely to have confused hydratase deficiency with other causes of 3-methylgluta-conic aciduria, but the variability persists even in newer reports with documented enzymatic or molecular diag-noses. Thus the full spectrum of this disorder remains to be determined. Barth syndrome is an X-linked disorder
TABLE 97-1 Classification of Disorders Exhibiting Increased Excretion of 3-Methylglutaconic Acid
CHAPTER 97 Organic Acidemias and Disorders of Fatty Acid Oxidation 5
characterized by cardiomyopathy, neutropenia and skel-etal myopathy (24). Mitochondria are abnormal with tightly packed cristae and inclusion bodies. The cardio-myopathy may be congenital but can also be absent. In the latter setting, infections due to neutropenia sug-gest the diagnosis. In one report, the age distribution in 54 living patients was 0–49 years (24). Female carriers are usually healthy. Mutations in the tafazzin gene that encodes a mitochondrial cardiolipin transacylase are responsible for Barth syndrome (25). Secondary effects on the respiratory chain function and increased oxida-tive stress presumably lead to the pathophysiology in this disease. OPA3 deficiency presents with early-onset bilateral optic atrophy and late development of spastic-ity, extrapyramidal dysfunction and occasionally cogni-tive deficit (26). Cardiomyopathy and neutropenia are not present. An Iraqi-Jewish isolate has accounted for most reported cases. The function of the OPA3 gene is unknown, but it encodes at least two transcripts that are targeted to mitochondria (27). Mutations in DNAJC19 cause an autosomal recessive Barth-like syndrome (28). Described in 11 consanguineous Canadian Hutterite families, affected individuals had severe, early onset- cardiomyopathy that tended to be progressive. They sub-sequently exhibited growth failure and cerebellar ataxia. Mild normochromic, microcytic anemia and hepatoste-atosis may be present. DNAJC19 is a homolog of a yeast inner mitochondrial cochaperonin.97.1.4.2 Diagnosis. 3-Methylglutaconic acid is identi-fied in urine by standard GC-MS techniques. 3-Methyl-glutaric acid is also usually present. Levels are the highest in the hydratase deficiency and more modest in the other disorders. The hydratase activity can be measured in fibroblasts, but in practice molecular testing is probably easier clinically. Functional tests for the other disorders are not available, and so molecular testing is the only diagnostic option. In theory, prenatal diagnosis through metabolite analysis of amniotic fluid should be feasible,
but has not been reported yet. Molecular diagnosis can be applied prenatally.97.1.4.3 Treatment. Unfortunately, therapeutic advances for 3-methylglutaconic acidemias have lagged far beyond the growing understanding of their molecular causes. Currently, no effective therapy exists for any of the rec-ognized defects. Leucine restriction has not been shown to affect outcome.97.1.4.4 Genetics. The genes for 3-methylglutaconyl-CoA hydratase, tafazzin, OPA3 and DNAJC19 are on chromosomes 9, X, 19, and 3, respectively. Mutations in all the genes related to disease have been identified. No ethnic predilection has been reported for hydratase or tafazzin deficiencies. OPA3 and DNAJC19 defects have been identified in Iraqi-Jews and Canadian Hutterites, respectively.
Hydroxymethylglutaric acidemia is typically an early-onset disease. It is due to a deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase, an enzyme involved in leucine oxidation and in ketone body biosynthesis (Figure 97-3). Identification by newborn screening with MS-MS offers the opportunity to intervene before symptoms appear.97.1.5.1 Clinical Course. The condition most fre-quently presents in early infancy with hypoglycemia, metabolic acidosis, and hyperammonemia. In 30% of cases onset is between birth and day 5 of life or between 3 and 11 months of age and is frequently lethal (29). Older children present with episodic hypoketotic hypo-glycemia, hepatomegaly, and encephalopathy after intercurrent infections. The latter form of the condition is frequently mistaken for Reye syndrome. Neurologic signs, mental retardation, and cerebral atrophy may follow if the condition is not recognized and treated. Rare first presentations in adulthood have been reported.
97.1.5.2 Diagnosis. This condition, and disorders of fatty acid oxidation, should be excluded in any infant or child with hypoketotic hypoglycemia. Organic acid analysis shows large increases in 3-hydroxy-3-methylglu-taric, 3-methylglutaconic and 3-hydroxyisovaleric acids, especially after protein intake or in situations that favor the synthesis and utilization of ketone bodies. Note that the same pattern of metabolites is sometimes seen as a nonspecific marker of mitochondrial dysfunction and so follow up testing is mandatory. The diagnosis can be confirmed by demonstrating deficiency of hydroxymeth-ylglutaryl-CoA lyase activity in leukocytes or cultured fibroblasts. Molecular testing is available. 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency can be identified by newborn screening with MS-MS, but the metabolite identified (“C5 hydroxycarnitine”) is not specific, so urgent follow-up testing (urine organic acids) is required (30–32).97.1.5.3 Treatment. Episodes of hypoketotic hypo-glycemia should be treated with intravenous fluids, electrolytes, and glucose to reestablish an anabolic state. Long-term management is directed at avoiding fast-ing and the resulting hypoglycemia. Leucine restriction has been suggested but probably has limited effect (29). Carnitine supplementation may be helpful. The possible life-threatening consequences of acute attacks make it critical that parents bring the child to hospital as soon as possible whenever oral intake is reduced.97.1.5.4 Genetics. Hydroxymethylglutaric acidemia is inherited as an autosomal recessive trait, and heterozy-gote detection is possible by demonstrating intermediate lyase activity in leukocytes. The gene encoding HMG-CoA lyase has been cloned and localized to chromosome 1 (1pter-p33) and multiple disease-causing mutations
have been identified (29,33). Prenatal diagnosis has been established by enzyme assay in cultured amniocytes, by metabolite analysis of maternal urine and amni-otic fluid, and by mutation analysis on chorionic villus samples.
This enzyme was originally named 2-methyl branched-chain acyl-CoA dehydrogenase based on the substrate specificity of an enzyme purified from rat liver. At that time, it was not clear whether the same enzyme was active in both isoleucine and valine metabolism. Sub-sequently, cloning of the human genes showed the two pathways to use distinct enzymes and based on substrate specificity of the expressed human enzymes, the enzymes were designated short branched-chain- and isobutyryl-CoA dehydrogenase (SBCAD and IBD, for the isoleucine and valine enzymes, respectively) (Figure 97-4) (34). Deficiencies of both have now been described.97.1.6.1 Clinical Course. SBCAD deficiency was first described in two patients with rather significant neuro-logic symptoms (35,36). However, it was soon noted to be present in high frequency in the Hmong population in the United States due to a common founder muta-tion (37). These individuals, largely identified through newborn screening and family studies, appear to be asymptomatic. Other studies on affected, non-Hmong individuals, again largely identified through newborn screening, corroborate the lack of symptoms (38). Cur-rently, it seems appropriate to consider SBCAD deficiency a biochemical phenotype rather than a clinical disease, although long-term follow-up studies are necessary to
FIGURE 97-4 Branched-chain acyl-CoA dehydrogenases. The third step in the pathway of all three branched-chain acyl-CoA dehydrogenases is mechanistically shared but performed by three distinct enzymes for each amino acid (3). A common amino transferase (1) and NAD-dependent dehydrogenase (2) generate branched-chain acyl-CoAs unique to each amino acid. Individual defects of the FAD-dependent branched-chain acyl-CoA dehydrogenases are known, and a secondary deficiency of all three is seen in multiple acyl-CoA dehydrogenase deficiency (glutaric aciduria type 2) because of inability to reoxidize FADH2.
anic Acidemias and Disorders of Fatty Acid Oxidation 7
CHAPTER 97 Org
define any risks later in life. The major clinical concern is related to the characteristic metabolite (“C5 carnitine”) identified in babies by newborn screening with MS-MS. Identification of 2-methylbutyrylcarnitine and isovaler-ylcarnitine, isobaric 5 carbon species by MS-MS can be due to either SBCAD or IVD deficiency. Urine organic acid analysis can readily distinguish the two disorders.97.1.6.2 Diagnosis. Most children will be identified through newborn screening with MS-MS. The character-istic metabolite (“C5 carnitine”) can be either 2-methylbu-tyrylcarnitine or isovalerylcarnitine since they are isobaric. Urine organic acid analysis can readily distinguish the two disorders and should be performed urgently because of the potential for a more severe phenotype due to IVA. Fibroblast or lymphocyte enzyme testing and molecular analysis are possible but of minimal clinical utility.97.1.6.3 Treatment. No treatment is needed based on extensive experience with the Hmong population. In theory, there could be a risk for increased organic acide-mia with intercurrent illnesses, so caution by parents at these times seems prudent, and they should seek medical attention if an affected child has protracted vomiting or dehydration.97.1.6.4 Genetics. The SBCAD gene is located on chromosome 10q25–q26. A common c1165A>G muta-tion in the Hmong population leads both to protein inactivating amino acid substitution and exon skipping due to activation of a cryptic RNA splice site (37). Mul-tiple other private mutations have been described (38).
This enzyme in isoleucine metabolism has received sev-eral functional and genetic names since its discovery, which has led to some confusion in the literature. Based on one of the documented activities of the enzyme as a hydroxysteroid (17-beta) dehydrogenase, it has offi-cially been assigned a gene symbol HSD17B10, replac-ing the HADH2 designation more frequently seen in the inborn errors literature (Figure 97-1) (39). Two clinical phenotypes have been proposed to be the result of two different molecular mechanisms (40).97.1.7.1 Clinical Course. The first patient identi-fied with this deficiency, a male, exhibited a picture of progressive infantile neurodegeneration. He had unexplained metabolic acidosis with hypoglycemia in the newborn period. Modest psychomotor delay was reported in the first year of life, after which he devel-oped choreoathetotic movements and neurointellectual deterioration (41). Metabolic acidosis has not been consistently seen in subsequent patients, but neurode-generative symptoms have been uniform. Additional reported features in only a handful of patients include myoclonic or other seizures, hypotonia, optic atrophy, pigmentary or nonpigmentary retinopathy, sensorineu-ral deafness, ataxia, dystonia, choreoathetosis, spastic
di-/tetraplegia, cardiomyopathy and mild dysmorphism (42). Cerebral magnetic resonance imaging (MRI) may be normal or exhibit characteristic findings includ-ing frontotemporal or frontoparietal atrophy, parieto-occipital periventricular white matter changes, and basal ganglia lesions. These patients have had severe or complete enzyme deficiency. Female patients are typi-cally milder in keeping with X-linked inheritance, but severe disease can occur. X-linked mental retardation associated with choreoathetosis, and abnormal behav-ior in a four-generation pedigree has been linked to the HSD17B10 gene but affected patients had near-normal enzyme activity, so an alternative mechanism of patho-genesis was postulated.97.1.7.2 Diagnosis. Urine organic acids are notable for the accumulation of 2-methyl-3-hydroxybutyrate and tiglylglycine but not 2-methylacetoacetic acid. 2-Ethylhydracrylic and 3-hydroxyisobutyric acids have reported to be elevated. Enzyme and molecular testing are available. Prenatal testing has not been reported but should be possible.97.1.7.3 Therapy. No specific therapies are available. Isoleucine restriction is probably not useful. Carnitine supplementation may provide nonspecific benefit related to organic acid conjugation.97.1.7.4 Genetics. The HSD17B10 gene is located at Xp11.2. Rare, private mutations inactivating enzyme activity have been reported in males with the full clinical picture (42). In the extended family with normal enzyme activity, a c.574C>A mutation in the codon for R192 does not alter the amino acid at this position but leads to an altered balance of RNA splicing products of unknown significance (40).
Mitochondrial acetoacetyl-CoA thiolase deficiency, also called β-ketothiolase, is a mixed disorder of isoleucine catabolism and ketone body production (Figure 97-5) (43). It presents with episodes of acidosis and encepha-lopathy most frequently occurring in conjunction with upper respiratory tract infections and other minor illness. Accumulation of 2-methyl-3-hydroxybutyric acid in urine is characteristic.97.1.8.1 Clinical Course. The disease can present in the newborn period with hyperammonemia, metabolic aci-dosis, and severe ketosis, but more often presents beyond the first year of life with fasting or protein-induced epi-sodes of vomiting, hepatomegaly, ketoacidosis, and encephalopathy (44). Mental retardation or death during an episode of ketoacidosis is common, but some patients are relatively free of symptoms. Intrafamilial variation has been reported (45).97.1.8.2 Diagnosis. Organic acid analysis shows increased 2-methyl-3-hydroxybutyric acid, 2-methylaceto-acetic acid, and tiglylglycine, but large amounts of normal
8 CHAPTER 97 Organic Acidemias and Disorders of Fatty Acid Oxidation
Isoleucine
Tiglyl-CoA ValineThreonineMethionineOdd h i f tt id
2-Methyl, 3-hydroxy-butyryl-CoA
chain fatty acidsCholesterol side chains
1 2 3 4CO2
2-Methylaceto-acetyl-CoA Propionyl-CoA
D-Methyl-malonyl-CoA Succinyl-CoA
L-Methyl-malonyl-CoA
ATP ADP
FIGURE 97-5 Formation and metabolism of propionyl-CoA. (1) Acetoacetyl-CoA thiolase. (2) Propionyl-CoA carboxylase. (3) Methylmalonyl CoA racemase. (4) Methylmalonyl-CoA mutase. Adenosylcobalamin is the specific coenzyme for methylmalonyl-CoA mutase.
ketone bodies (3-hydroxybutyric and acetoacetic acids) will often obscure these increases when the patient is acutely ill. Indeed, it may only be possible to detect the diagnostic metabolites when the patient is free of symptoms, or after an oral load (100 mg/kg) of isoleucine. As in propionic and methylmalonic acidemia, glycine is frequently elevated in blood and urine. Enzyme assays to confirm the diagnosis, if necessary, can be performed on fibroblasts or lymphocytes. Mutation analysis is available, but genotype/phenotype correlations have been poor.97.1.8.3 Treatment. Acute episodes should be treated with intravenous glucose and sodium bicarbonate. Long-term treatment with a low-protein diet, combined with the avoidance of fasting, decreases the frequency and severity of episodes of acidosis and permits normal growth and development if irreversible neurologic dam-age has not already occurred.97.1.8.4 Genetics. The disease is inherited as an auto-somal recessive trait. The mitochondrial acetoacetyl-CoA (ACAT1) gene is on chromosome 11, and multiple mutations in patients have been described (44). Prenatal diagnosis should be possible by enzyme assay in cultured amniocytes or chorionic villus samples, or by mutation analysis, but has not yet been reported.
97.1.9 Isobutyryl-CoA Dehydrogenase Deficiency
Of the three mitochondrial dehydrogenases involved in the third step of leucine, isoleucine, and valine metab-olism, isobutyryl-CoA dehydrogenase (IBDH) in the valine pathway was the last to be definitively identified (Figure 97-2) (46). As with deficiency in its companion
enzymes in leucine and isoleucine catabolism, IBDH deficiency is largely identified through newborn screen-ing by MS-MS. While an original symptomatic patient was described, those identified through newborn screen-ing have been mostly well (47).97.1.9.1 Clinical Course. The first patient with IBDH deficiency presented with carnitine and cardiomyopathy at 1 year of age (48). The child responded to carnitine supplementation and has no recurrence of cardiac dis-ease or episodes of metabolic decompensation. Since the identification of the disorder, at least 15 additional patients have been reported, all identified through new-born screening (47,49,50). All but one have remained without symptoms. One patient had recurrent episodes of vomiting and dehydration with intercurrent illnesses (47). Of note, in keeping with observations in the original patient, this infant had significant decreases in plasma free carnitine (to <10 μM) during these episodes, suggesting decreased muscle stores or excess renal loss of carnitine. She showed no signs of cardiomyopathy and had normal development at age 5 years.97.1.9.2 Diagnosis. Isobutyrylcarnitine elevation in blood can be documented by tandem mass spectroscopy including newborn screening. Since MS-MS does not distinguish between butyryl- and isobutyryl carnitine, follow-up testing is necessary. Identification of isobutyr-ylglycine (as opposed to butyrylglycine) in urine differ-entiates the two disorders, and the diagnosis is then best confirmed by molecular analysis. Enzyme assay on fibro-blasts or lymphocytes is possible but not readily avail-able in many clinics.97.1.9.3 Treatment. The need for treatment in IBDH deficiency is unproven. Carnitine losses in two patients
ic Acidemias and Disorders of Fatty Acid Oxidation 9
CHAPTER 97 Organ
may indicate the need for carnitine supplementation at least when ill, but this remains conjecture. Valine restric-tion is not warranted.97.1.9.4 Genetics. The gene for IBDH is the ACAD8 gene located on chromosome 11q25. Multiple private mutations have been identified in patients (47).
The next step in the valine catabolic pathway associ-ated with a clinical disease is 3-hydroxyisobutyryl-CoA deacylase (Figure 97-1). (Methacrylyl-CoA hydratase deficiency has not been described.) Only two patients have been described with molecularly confirmed diagno-ses (51,52). Accumulation of 3-hydroxybutyric acid in urine is not seen. Part of the pathology of this disorder is likely due to the highly reactive chemical nature of accu-mulated methacrylyl-CoA (51). Patients reported with 3-hydroxyisobutyric acid in urine likely have a different disorder.97.1.10.1 Clinical Course. The first patient with 3-hydroxyisobutyryl-CoA deacylase deficiency pre-sented with vertebral malformations and tetrology of Fallot along with dysmorphic features (51). There was little growth or development and he died at age 3 months. Agenesis of the cigulate gyrus and corpus callo-sum was found on autopsy. Enzyme assay confirmed the diagnosis. The second patient appeared well at birth but exhibited neurodegeneration beginning at age 4 months. He had an episode of acute metabolic acidosis at age 14 months during which 3-hydroxyisobutyric acid was not identified in urine. MRI of the brain at that time dem-onstrated abnormalities in the globus pallidus and the midbrain, with asymmetrical involvement of the cere-bral peduncles, although no structural abnormalities were noted. A number of patients have been reported with 3-hydroxyisobutyric acid in urine but no consis-tent clinical picture suggesting that they have a different disorder(s).97.1.10.2 Diagnosis. 3-Hydroxyisobutyric acid does not accumulate in this disorder, probably because it is in equilibrium with methacrylyl-CoA, which is highly reactive. In the first patient, the alternative metabolites S-(2-carboxypropyl)cysteamine and S-(2-carboxypropyl)cysteine were seen. These compounds were not reported in the second patient but a hydroxy-C4-carnitine species was elevated. Since mass spectrometry cannot distinguish between hydroxybutyryl- and hydroxyisobutyrylcarni-tine, this finding can also be consistent with a disorder of short-chain 3-hydroxyacyl-CoA deficiency. Both patients were shown to have enzymatic deficiency of 3-hydroxy-isobutyryl-CoA deacylase on fibroblast assay, but the second patient also had partial deficiencies of respiratory chain complexes I and IV in muscle. Because of the com-plicated metabolite picture in these patients, it is likely that 3-hydroxybutyryl-CoA deacylase is underdiagnosed
and the full clinical spectrum remains to be described. Patients with 3-hydroxyisobutyric aciduria without deacylase deficiency also have had an inconsistent array of branched-chain organic acids in urine, again pointing to possible heterogeneity in diagnosis (53).97.1.10.3 Treatment. No effective treatment has been reported for the deacylase defect. Experience with other distal disorders in the branched-chain amino acid degradative pathways suggests that valine supplemen-tation is unlikely to be effective. Supplementation with cysteamine to increase conjugation of the accumulating methacrylyl-CoA is an attractive consideration but has not been tested. Carnitine supplementation may provide additional nonspecific conjugation of abnormal interme-diates.97.1.10.4 Genetics. The gene for 3-hydroxyiso-butyryl-CoA deacylase is designated HIBCH and is located on chromosome 2q32.2. Mutation analysis has only been reported on one patient (52). Sequencing of the 3-hydroxyisobutyryl-CoA dehydrogenase gene in one patient with 3-hyroxyisobutyric aciduria failed to identify a mutation and thus the cause for this biochemi-cal phenotype remains unclear (53).
Several reports in the literature describe patients with metabolite accumulation thought to be consistent with methylmalonate semialdehyde dehydrogenase deficiency but only one has subsequently been shown to have muta-tions in the gene for this enzyme (Figure 97-1) (54).97.1.11.1 Clinical Course. The single patient with this disorder was identified on newborn screening for the unrelated finding of hypermethioninemia (54). Addi-tional metabolic evaluation revealed high levels of uri-nary 3-hydroxyisobutyric acid and lesser elevations of 2-ethylhydracrylic acid, 3-aminoisobutyric acid, and β-alanine. Valine loading studies induced increased excre-tion of 3-hydroxyisobutyric acid in urine. A mutation in the MMSDH gene was ultimately identified (55). In the same study, three other patients previously suspected as having methylmalonate semialdehyde dehydrogenase deficiency were shown not to have MMSDH gene mutations, pointing to the lack of specificity of the met-abolic findings. The patient was last reported at age 4 years to be well, so the clinical relevance of the biochemi-cal phenotype is unknown.97.1.11.2 Diagnosis. Based on the single bona fide patient, metabolite detection is unreliable. Patients with significant elevation of 3-hydroxyisobutyric acid in urine of otherwise unknown cause should have sequencing of the MMSDH gene.97.1.11.3 Treatment. No treatment is warranted based on the single patient.97.1.11.4 Genetics. The MMSDH gene is on chro-mosome 14q24.3. The single patient described was
10 CHAPTER 97 Organic Acidemias and Disorders of Fatty Acid Oxidation
homozygous for a single mutation, for which his parents were heterozygous, confirming recessive inheritance.
97.2 OTHER ORGANIC ACIDEMIAS
97.2.1 Ethylmalonic Encephalopathy
Deficiency of a mitochondrial sulfur dioxygenase leads to a characteristic phenotype known as ethylmalonic encephalopathy. Previously thought to be a disorder in branched-chain amino acid metabolism, the defect rather leads to the accumulation of sulfides within mito-chondria, which in turn impairs mitochondrial energy metabolism.97.2.1.1 Clinical Course. Ethylmalonic encephalopa-thy is characterized by neurodevelopmental delay and regression, prominent pyramidal and extrapyramidal signs, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea (56,57). Pyramidal signs, hypotonia, microcephaly, failure to thrive, seizures, and episodic encephalopathy are common. Death usually occurs before age two; however, heterogeneity and longer sur-vival has been reported (58,59). Symmetrical necrotic lesions in the deep gray matter structures are consis-tent neuropathological features of the disease. Most patients have been of Mediterranean origin. Ethylmalo-nic encephalopathy is caused by homozygous mutations in the ETHE1 gene that encodes a mitochondrial sulfur dioxygenase (58). The resultant enzymatic deficiency leads to impaired catabolism of inorganic sulfur (sulfite), accumulation of H2S in tissues, and inhibition of the mitochondrial respiratory chain complex IV (60).97.2.1.2 Diagnosis. Ethylmalonic acid accumulation in urine is the hallmark of ethylmalonic encephalopa-thy, but is nonspecific and can be intermittent in milder cases (58). The compound is likely the product of α-carboxylation of butyrate elevated secondary to the inhibition of mitochondrial fatty acid oxidation. How-ever, ethylmalonic aciduria is also seen in short-chain acyl-CoA dehydrogenase (SCAD) deficiency and pri-mary respiratory chain deficiencies. Elevation of C4 and C5 carnitines in blood and isobutyrylglycine and 2-methylbutyrylglycine can also be seen in all these dis-orders. Urinary thiosulfate accumulation may be a more specific marker (60). Ultimately, in the correct clinical
setting, diagnosis by molecular testing should be pur-sued (61,62).97.2.1.3 Treatment. Identification of the enzymatic cause of ethylmalonic encephalopathy has led to new therapeutic options in this previously untreatable disor-der. In a single study, metronidazole, or N-acetylcysteine (a precursor of sulfide-buffering glutathione) substan-tially prolonged the lifespan of ETH1-deficient mice, with the combined treatment being additive. The same dual treatment caused marked clinical improvement in five affected children, with no reported adverse side effects (63). Additional studies will be needed to confirm the efficacy of this promising regimen.97.2.1.4 Genetics. The molecular cause of ethylmalo-nic encephalopathy was first localized to chromosome 19q13 in a genetic mapping study and multiple muta-tions were ultimately identified in the ETHE1 gene. All patients have mutations of both alleles, confirming autosomal recessive inheritance. No common mutations have been identified.
97.2.2 l-2-Hydroxyglutaric Acidemia
l- and d-2-Hydroxyglutaric acids are chiral enantiomers and require special separation techniques to be differen-tiated (64). Patients with l-2-hydroxyglutaric acidemia have a defect in the mitochondrial flavoenzyme l-2- hydroxyglurate dehydrogenase that catalyzes the conver-sion of l-2-hydroxyglutarate to 2-ketoglutarate (Figure 97-6) (65). They exhibit a variable leukodystrophy. Of note, l-2-hydroxyglutarate does not seem to have a physiologic function in human metabolism (66). Rather it appears to be the product of mitochondrial l-malate dehydrogenase illic-itly acting on 2-ketoglutarate. Thus, l-2-hydroxyglurate dehydrogenase has been called a metabolic repair enzyme, preventing the accumulation of its extremely toxic substrate.97.2.2.1 Clinical Course. The first patient described with this disorder had relatively nonspecific mental retardation (67). Additional patients were subsequently identified with mental retardation, cerebellar symptoms, and movement abnormalities with onset of symptoms in childhood (2). MRI revealed a consistent pattern includ-ing subcortical leukoencephalopathy, cerebellar atrophy, and signal changes in the putamina and dentate nuclei.
L-Malate dehydrogenase
(Mitochondrial)
L—2-OH-Glutarate
dehydrogenase
- -- -2 Ketoglutarate 2 KetoglutarateL 2 HydroxyglutarateFIGURE 97-6 Physiological role of l-2-Hydroxyglutarate metabolism. l-2-hydroxyglutarate dehydrogenase serves to oxidize its highly toxicsubstrate produced as a secondary reaction product of l-malate dehydrogenase in mitochondria.
CHAPTER 97 Organic Acidemias and Disorders of Fatty Acid Oxidation 11
Later onset patients have exhibited milder and relatively nonspecific symptoms including autism (68). Intrigu-ingly, patients are at increased risk to develop CNS tumors, although the percentage so affected is still small (~5%) (69). Riboflavin (100 mg daily) and flavin adenine dinucleotide (FAD) (30 mg daily) supplementation have been reported to improve symptoms in separate patients (70,71). Successful pregnancy in an affected woman has been reported (72).97.2.2.2 Diagnosis. 2-Hydroxyglutaric acid is iden-tifiable in urine by routine organic acid analysis, but additional separation techniques are required to differ-entiate the l and d enantiomers (64). The metabolite is also elevated in brain. l-2-hydroxyglutaric acid is often elevated in glutaric academia type II, but other metabo-lites permit unequivocal differentiation of these disor-ders. Lysine is consistently elevated in blood and should not be confused with hyperlysinemia. Characteristic findings on MRI of the brain include a combination of predominantly subcortical cerebral white matter abnormalities and abnormalities of the dentate nucleus, globus pallidus, putamen, and caudate nucleus (73). Enzymatic assay is difficult and thus molecular analy-sis is probably the definitive diagnostic test of choice (74,75).97.2.2.3 Treatment. Riboflavin (100 mg daily) and FAD (30 mg daily) supplementation have been reported to improve symptoms in separate patients but larger
trials have not been performed (70,71). Carnitine may increase organic acid excretion nonspecifically.97.2.2.4 Genetics. The l-2-hydroxyglutaric dehy-drogenase (L2GHDH) gene is located on chromo-some14q22.1. Multiple private mutations have been reported. Turkish and Iraqi isolates exist (76,77).
97.2.3 d-2-Hydroxyglutaric Acidemia
d-2-Hydroxyglutaric acidemia is less frequent than its l-counterpart and has two genetic causes with variable symptoms. d-2-Hydroxyglutaric acid is generated from 2-ketoglutarate by the enzymatic action of hydroxy-acid-oxoacid transhydrogenase but the role of d-2-hydroxyglutaric acid in normal metabolism remains undefined (Figure 97-7) (78).97.2.3.1 Clinical Course. Variable clinical symptoms have been described in patients with d-2-hydroxyglutaric aciduria. In one large survey of 17 patients, 10 had a severe early-infantile-onset encephalopathy characterized by dysmorphic features, epilepsy, hypotonia, cerebral visual failure, and little development. In addition, five of these patients had cardiomyopathy (79). Dysmorphic features described include coarse facial appearance, flat face, broad nasal bridge, upturned nose, and simple and anteverted ears (80). Seven patients had a much milder and variable clinical picture, most often characterized by mental retardation, hypotonia, and macrocephaly.
FIGURE 97-7 d-2-Hydroxyglutarate metabolism. d-2-Hydroxyglutarate is formed as a product of the enzyme hydroxyacid-oxoacid transhy-drogenase, but the physiologic role of this metabolite remains unknown.
12 CHAPTER 97 Organic Acidemias and Disorders of Fatty Acid Oxidation
Asymptomatic patients have been reported (81). Defects in two enzymes have now been reported in patients with d-2-hydroxyglutaric acidemia but clinical correla-tions have not yet been possible. Both mild and severely affected patients have been shown to have mutations in the gene for d-2-hydroxyglutaric acid dehydrogenase, while others have mutations in the mitochondrial isoci-trate dehydrogenase 2 gene (74,82,83).97.2.3.2 Diagnosis. Biochemical findings include elevations of d-2-hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid (CSF). γ-Aminobutyric acid is also elevated in CSF. Urinary citric acid cycle intermedi-ates are variably elevated. Brain MRI in severely affected patients shows mild ventriculomegaly with enlarged frontal subarachnoid spaces and subdural effusions similar to those seen in glutaric aciduria (79). Cerebral maturation is delayed. Subependymal cysts over the head or corpus of the caudate nucleus are seen in patients <6 months of age. Elevated d-2-hydroxyglutaric acid in urine has been reported in patients with proven succinic semialdehyde dehydrogenase deficiency (84).97.2.3.3 Treatment. No specific therapy is currently available for the disorder. Seizures and movement abnor-malities should be treated symptomatically.97.2.3.4 Genetics. The D2HGA gene for d-2-hydroxy- glutaric acid dehydrogenase is on chromosome 2q37.3. The gene for the mitochondrial isocitrate dehydrogenase (IDH2) is on chromosome 15q26.1. Mutations in patients are nearly evenly divided between the two loci (74,82,83). D2HGA gene mutations are recessive, but IDH2 muta-tions appear to be dominant.
97.2.4 Propionic Acidemia
Propionic acidemia, one of the more common organic acidemias, was first described in 1968 in an infant with severe metabolic acidosis, and many additional patients have since been reported. Propionyl-CoA is an interme-diate in the oxidation of four amino acids (threonine, valine, methionine and isoleucine) as well as odd-chain fatty acids. Propionic acid is also absorbed from the large intestine where it is produced by propiogenic bacteria. Propionic acidemia is due to deficiency of propionyl-CoA carboxylase, a mitochondrial biotin-containing enzyme that catalyzes conversion of propionyl-CoA to d-methylmalonyl-CoA (Figure 97-5). The disorder is extremely variable and identification through newborn screening is possible.97.2.4.1 Clinical Course. The disorder may present in the first week of life with feeding difficulties, lethargy, vomiting, and life-threatening acidosis, hypoglyce-mia, hyperammonemia, and bone marrow suppression (85,86). Severe hyperammonemia probably contributes appreciably to the encephalopathy of the acutely ill neo-nate, possibly because propionyl-CoA inhibits the synthe-sis of N-acetylglutamate, the major allosteric activator of carbamyl phosphate synthetase. Mortality in early-onset
disease is high (87). Equally common is a more chronic course, which presents in the first months of life with poor feeding and episodes of vomiting, infection-induced ketoacidosis, failure to thrive, and osteoporosis severe enough to cause pathologic fractures. Developmental retardation, which is probably due to neonatal hyperam-monemia or chronic illness, is common, and metabolic strokes due to acute degeneration of the basal ganglia may occur during or between episodes of ketoacido-sis (88). Cardiomyopathy, which may be rapidly fatal, occurs frequently and does not respond to carnitine (89). Pancreatitis is an increasingly recognized complication of the disease (90). Before expanded newborn screen-ing, most patients did not survive beyond the first decade of life, with death often occurring during an episode of ketoacidosis in a chronically malnourished child. New-born screening via tandem mass spectroscopy reliably can identify propionic acidemia before symptoms occur and a much milder clinical spectrum results. However, the specificity of moderately elevated C3 carnitine levels in newborns remains controversial.97.2.4.2 Diagnosis. Urine organic acids at diagnosis show large amounts of 3-hydroxypropionic and methyl-citric acids, often with propionylglycine and tiglylglycine, and abnormal ketone bodies such as 3-hydroxy-n-valeric and 3-keto-n-valeric acids. Acylcarnitine analysis by MS-MS shows increased C3 carnitine, and glycine levels are often elevated in blood and urine. Although usually not necessary, the enzyme defect can be demonstrated in many tissues, including leukocytes and cultured fibroblasts. Molecular testing is clinically available. Pre-natal diagnosis has been accomplished with metabolite, enzymatic, and molecular techniques (91).97.2.4.3 Treatment. Acute therapy is directed to treating shock, acidosis, hypoglycemia, and hyperam-monemia with fluids, bicarbonate, glucose, and dialysis. Restriction of dietary natural protein (or of propiogenic amino acids) to amounts necessary to support normal growth and development is indicated, and usually results in natural protein intake less than 1 g/kg/day. Special-ized formula restricted in isoleucine, valine, methionine, and threonine is used to provide additional protein for growth. Biotin supplementation is not clinically useful, but oral carnitine may be helpful to increase excretion of nontoxic metabolites. N-carbamylglutamate may help resolve hyperammonemia more quickly during episodes of acute metabolic decompensation (92,93). Metronida-zole given on an intermittant basis decreases the load of propiogenic bacteria in the bowel. Liver transplant elimi-nates the risk for episodes of metabolic decompensation and can reverse cardiomyopathy (94,95).97.2.4.4 Genetics. Propionic acidemia is inherited as an autosomal recessive trait. The genes encoding the α- and β-subunits have been localized to chromosomes 13 (13q32) and 3 (3q13.3–22), respectively, and several disease-causing mutations have been identified in both genes (96–98). No one prominent α-gene mutation has
nic Acidemias and Disorders of Fatty Acid Oxidation 13
CHAPTER 97 Orga
been identified, but only a few mutations account for the majority of β-gene mutations identified to date (96).
97.2.5 Methylmalonic Acidemias
Methylmalonic acidemia can be caused by an inher-ited deficiency of methylmalonyl-CoA mutase, an adenosylcobalamin-requiring enzyme that converts l-methylmalonyl-CoA to succinyl-CoA (Figure 97-5), or in the metabolic pathway that catalyzes the biosynthe-sis of adenosylcobalamin from vitamin B12 (Figure 97-8 and Table 97-2). When the latter defect occurs in a proximal step that also impairs the synthesis of methyl-cobalamin, homocysteine accumulates behind a block in N5-methyltetrahydrofolate: homocysteine methyltransfer-ase. Recently, a defect in the methylmalonyl-CoA epimer-ase has been described (Figure 97-5).97.2.5.1 Clinical Course. Not surprisingly, the clini-cal course of the disorders leading to methylmalonic acidemia varies considerably depending on the precise metabolic defect (99). The clinical presentation, course, and postmortem findings of complete methylmalonyl- CoA mutase deficiency mimic those of propionic
acidemia. Many present with severe ketoacidosis, hyper-ammonemia, and thrombocytopenia in the first days or weeks of life. Acute striatal degeneration is a frequent complication of the disease, and late-developing inter-stitial nephritis and renal failure are common. Patients with later onset forms due to some residual mutase activity manifest a variety of symptoms including inter-mittent ataxia, recurrent vomiting, failure to thrive, and developmental delay. In either setting, life-threat-ening episodes of decompensation are typically due to minor intercurrent illnesses. Patients with cblA and cblB defects usually have isolated methylmalonic aci-demia but somewhat milder disease. Secondary respira-tory chain deficiencies have been reported with several of the disorders of methylmalonyl-CoA metabolism (100,101). Methylmalonyl-CoA epimerase catalyzes the interconversion of d- and l-methylmalonyl-CoA and its deficiency results in a mild phenotype with iso-lated methylmalonic acidemia (102). Mutations in the SUCLA gene, which encodes an ATP-forming subunit of the Krebs cycle enzyme succinyl-CoA ligase, are a novel cause of methylmalonic acidemia. Affected patients have a severe phenotype including hypotonia, muscle
Methylmalonyl-CoA Succinyl-CoAAd l b l i
Mut
Adenosylcobalamin
CblB
Cell plasma membrane CblA
Lysosome
Mitochondrion
CblD (v2)
Transcobalamin-cobalamin
Transcobalamin-cobalamin Cblx Cblx Cblx
CblE
CblC CblD
CblD (v1)
CblF
CblGHomocysteine Methionine
Methylcobalamin
CblD (v1)
FIGURE 97-8 Defects in cobalamin metabolism leading to disorders of methylmalonate and/or homocysteine metabolism. To date, nine complementation-group defects of the cobalamin pathway have been described. Cobalamin bound to transcobalamin enters the cell by means of lysosome-mediated endocytosis and is released through proteolysis. Export from the lysosome into the cytoplasm is defective in patients with the cblF defect. The steps in the cytosol after lysosomal release are still unclear but are defined by the complementation groups cblC and cblD. In addition, the exact form of cobalamin at this stage is unclear (as indicated by “Cblx”). In the cytoplasm, cobalamin is reductively methylated by methionine synthase reductase (cblE) to methylcobalamin, the cofactor for methionine synthase (cblG). After its transport into the mitochondrion, cobalamin is converted to adenosylcobalamin, the cofactor for methylmalonyl-coenzyme A (CoA) mutase (mut), by cobala-min adenosyltransferase (cblB). The exact role of the protein associated with the cblA complementation group is unclear. The cblD protein constitutes a branch point between the cytosolic and mitochondrial pathways, controlled by the cblD-methylmalonic aciduria variant and the cblD-homocystinuria variant, respectively. Three groups of patients with CblD mutations have been described. They have isolated accumula-tion of MMA (v1) or HCY (v2), or can have both present (simply designated as CblD). The cblH complementation group is probably identical to the cblD (v2) group.
14 CHAPTER 97 Organic Acidemias and Disorders of Fatty Acid Oxidation
atrophy, hyperkinesia, mental retardation, growth fail-ure, central and cortical atrophy of the brain, and basal ganglia atrophy (103).
Mutations in the CblC gene cause combined methyl-malonic acidemia and homocystinemia. CblC deficiency most commonly presents in infancy with severe clinical manifestations including basal ganglia necrosis, micro-cephaly, failure to thrive, metal retardation, retinopathy, and megaloblastic anemia. Thromboembolic events can occur because of elevated homocystine in the blood. However, patients with milder, late-onset disease have been reported (104). CblD mutations can cause com-bined disease as seen in CblC-deficient patients, but variants with isolated methylmalonic acidemia as well as isolated homocystinemia have been identified (105). Patients with defects in the CblE and CblG groups are deficient only in methylcobalamin biosynthesis, and have homocystinuria without methylmalonic aciduria (106). CblF deficiency results in defective transport of B12 out of lysosomes and a combined methylmalonic acidemia and homocystinemia (107). The clinical picture can be severe or mild.
Methylmalonic acidemia is now often identified through newborn screening by MS-MS; however, reports of the clinical efficacy of early detection have been mixed (99,108,109).97.2.5.2 Diagnosis. Urine organic acids show increased methylmalonic acid and, especially in mutase-deficient patients, 3-hydroxypropionic and methylcitric acids, and tiglylglycine (99). The same abnormal ketone bodies noted in propionic acidemia are seen in this condition. Acylcarnitine analysis by MS-MS shows increased C3 carnitine, and glycine is usually elevated in blood and urine. Megaloblastosis is often observed in patients with the cblC, cblD, and cblF defects. The homocystinemia and homocystinuria seen in such patients is accompanied by low methionine and high cystathionine in serum and not, as in cystathionine synthetase deficiency, by high methionine and low cystathionine. Excretion of meth-ylmalonic acid can be seen in dietary B12 deficiency but is not as pronounced as in the inherited disorders unless the vitamin deficiency is very severe (110). Dif-ferentiation among the various enzyme deficiencies often requires a combination of fibroblast enzyme analysis,
complementation studies, and molecular sequencing of candidate genes.97.2.5.3 Treatment. As in propionic acidemia, treat-ment in episodes of acute metabolic decompensation is directed first to treating shock, acidosis, hypoglycemia, and hyperammonemia, followed by restriction of protein (specifically, propiogenic amino acids). Carnitine is used to treat secondary carnitine deficiency. Some patients treated in this manner do well, but many do not and die in early childhood, often during an episode of ketoacidosis (99). Patients with defects in cobalamin metabolism may respond partially or completely to supplementation with intramuscular hydroxycobalamin, but residual metabolic abnormalities are common. Betaine hydrochloride, which promotes conversion of homocysteine to methionine by betaine:homocysteine methyltransferase, can decrease homocystine levels in blood in patients with combined disorders. Liver transplantation in isolated mutase defi-ciency can reduce metabolic symptoms, and one patient with chronic real failure was treated successfully with combined liver–kidney transplantation (111,112).
Patients with defects in adenosyl–B12 biosynthesis often respond to large doses of B12. Even with treatment, however, many patients succumb to pancytopenia, renal involvement and neurologic impairment resembling hemolytic–uremic syndrome or to metabolic coma and cardiorespiratory arrest during childhood. Long-term survival does, however, occur, often with neurologic def-icits. Prenatal diagnosis by metabolite, enzyme, or molec-ular analysis should be possible for all of the disorders.97.2.5.4 Genetics. All forms of congenital methylma-lonic acidemia are transmitted as autosomal recessive traits (Table 97-2). Multiple mutations in patients with all the disorders have been reported.
97.2.6 Glutaryl-CoA Dehydrogenase Deficiency
Glutaric acidemia (type I) was first described in 1975 in two siblings with a progressive movement disorder beginning in early childhood (113). The condition is inherited as an autosomal recessive trait and is due to deficiency of glutaryl-CoA dehydrogenase, a mitochon-drial enzyme that converts glutaryl-CoA, an intermediate
TABLE 97-2 Complementation Groups in Cobalamin Metabolic Disorders
Metabolite Present Cbl Complementation Group
A B C D D (v1) D (v2) E F GMethylmalonic acid + + + + + +Homocystine + + + + + + +Enzyme activity ? Cob(1)alamin
nic Acidemias and Disorders of Fatty Acid Oxidation 15
CHAPTER 97 Orga
in the oxidation of lysine, tryptophan and hydroxylysine, to crotonyl-CoA (Figure 97-9).97.2.6.1 Clinical Course. Most patients with glutaric acidemia are born with relative macrocephaly, and sud-denly develop hypotonia and dystonia during or after a relatively minor infection between the ages of 6 months and 3 years (114). Seizures, abnormal movements, hypo-glycemia, hepatomegaly, and acidosis may be noted dur-ing the episode, and CT or MRI scans show acute striatal degeneration, with shrinkage of the caudate and puta-men. Less common is a more chronic course in which dystonia and athetosis develop gradually during the first years of life (115). Fatty changes in the viscera, and glio-sis and neuronal loss in the putamen and lateral aspects of the caudate, have been described at autopsy. Perhaps 5% of enzyme-deficient individuals remain asymptom-atic. Diagnosis through expanded newborn screening with MS-MS reduces the risk for acute metabolic epi-sodes and chronic neurologic damage (116,117).97.2.6.2 Diagnosis. Type 1 glutaric acidemia is caused by a deficiency of glutaryl-CoA dehydrogenase. In most instances glutaric and 3-hydroxyglutaric acids are increased in urine; acylcarnitine analysis by MS-MS shows increased glutarylcarnitine (C5 hydroxycarnitine). Serum carnitine may be low (116). Some patients have easily detectable abnormal organic aciduria only when they are ill, and a few have so little glutaric aciduria even when ill that they are very difficult to detect with organic acid and/or acylcar-nitine analysis. Diagnosis of such patients may require mea-surement of glutaric and 3-hydroxyglutaric acid in serum or urine by stable isotope dilution GC-MS, assay of enzyme activity in leukocytes or cultured fibroblasts, or mutation analysis. Molecular diagnosis is available. Glutaric aciduria type 2, also known as multiple acyl-CoA dehydrogenase, is a distinct disorder caused by the deficiency of either the electron transfer flavoprotein (the physiologic electron acceptor for glutaryl-CoA dehydrogenase) or its dehydro-genase and is discussed later in this chapter. Glutaric acid-uria type 3 appears to be a benign phenotype of no clinical relevance caused by a deficiency of a gene of still unknown function. These individuals do not accumulate 3-hydroxy-glutarate, glutarlycarnitine, or glutarylglycine in urine.97.2.6.3 Treatment. Treatment of neurologically impaired patients is not usually effective, but when begun
before the onset of symptoms appears to prevent dam-age in two-thirds of cases (115,116). Treatment involves preventing catabolism during fasting and/or infections with intravenous fluids, electrolytes, glucose and insulin if necessary, and oral carnitine, as well as symptomatic treatment. Natural protein (or lysine) restriction is less well established in preventing symptoms, but should probably be tried. Supplementation with carnitine, cre-atine, glutamine, riboflavin, coenzyme Q10, pantothenic acid and a-linolenic acid as a cocktail has been used extensively in the Amish population, but has not been standardized in other ethnic groups (117). Aggressive neurologic management of seizures and spasticity is nec-essary for patients with striatal damage.97.2.6.4 Genetics. Consistent with inheritance as an autosomal recessive trait, the gene encoding glutaryl- CoA dehydrogenase is located on chromosome 19 (19p13.2). Many disease-causing mutations have been identified, but none is common except in inbred popu-lations (118,119). A common Amish isolate has been described (117). Prenatal diagnosis is possible by enzyme assay in cultured amniocytes or chorionic villus samples, by mutation analysis, or by demonstrating large amounts of glutaric acid in amniotic fluid (118). Glutaric aciduria type 3 in the Amish population is caused by mutations in the C7orf10 gene on chromosome 7p14.
97.2.7 Mevalonate Kinase Deficiency
Mevalonic acidemia is caused by a deficiency of meval-onate kinase, an enzyme involved in the biosynthesis of cholesterol and nonsterol isoprenes from 3-hydroxy-3-methylglutaryl-CoA, and is inherited as an autosomal recessive trait (Figure 97-3) (120).97.2.7.1 Clinical Features. Mevalonate kinase defi-ciency is an extremely heterogeneous disorder (121). The most severely affected patients have had profound developmental delay, distinctive facial dysmorphism, cataracts, lymphadenopathy and hepatosplenomeg-aly, and have died in infancy. Less severely affected patients have had milder retardation and hypotonia, myopathy, and ataxia. All have had recurrent crises of fever, lymphadenopathy, arthralgia, subcutaneous edema, and a morbilliform rash. Neuroimaging shows
Lysine
hydroxy-L-lysine
tryptophan
Glutaryl-CoAdehydrogenase
FAD 2 CO2
2 Acetyl-CoA
Glutaryl-CoA Glutaconyl-CoA Crotonyl-CoA
FADH
FIGURE 97-9 Glutaryl-CoA dehydrogenase both dehydrogenates and decarboxylates the substrate. Electrons pass from the FAD of glutaryl-CoA dehydrogenase into the electron transport chain at coenzyme Q, through the ETF and ETF:QO.
f Fatty Acid Oxidation
16 CHAPTER 97 Organic Acidemias and Disorders o
progressive atrophy of the cerebellum (122). When less complete, the same enzyme defect causes hyper-immunoglobulinemia D and periodic fever syndrome, characterized by recurrent febrile episodes accompa-nied by lymphadenopathy, abdominal distress, joint involvement and skin lesions, but without mevalonic aciduria (121).97.2.7.2 Treatment. Treatment has largely been non-specific and ineffective (121). Cholesterol restriction and use of lovastatin can worsen symptoms. Corticosteroids (prednisone 2 mg/kg/day) may be helpful to reduce the duration of acute crises. Long-term administration of antioxidants such as vitamin C and ubiquinone has been proposed. A three-year-old boy with severe disease was free of symptoms for 15 months following allogeneic bone marrow transplant (123).97.2.7.3 Diagnosis. Organic acid analysis shows increased mevalonic acid lactone, and mevalonic acid can then be measured in blood and/or urine by stable isotope dilution GC-MS (120). If necessary, enzyme defi-ciency can be demonstrated in cultured fibroblasts or lymphocytes.97.2.7.4 Genetics. The gene encoding mevalonate kinase has been localized to chromosome 12 (12q24), and although several disease-causing mutations have been identified, none is common (124). Prenatal diag-nosis is possible by enzyme assay in chorionic villus samples or by showing increased mevalonic acid in amniotic fluid.
Pyridoxine-dependent seizures were first described in the medical literature in 1954, but only recently has the cause been identified as a deficiency of the enzyme l-α-aminoadipic semialdehyde dehydrogenase (ALDH7A1), also known as antiquinin (Figure 97-10) (125,126). Multiple mutations have now been described in this gene and the clinical phenotype has expanded beyond isolated seizures (127).97.2.8.1 Clinical Features. Pyridoxine-dependent sei-zures were originally defined as clonic seizures respon-sive to pyridoxine supplementation in the first month of life, but it is now clear that in atypical cases, they may begin as late as 2 years of life. The electroencephalo-graph (EEG) is usually abnormal and may show a burst suppression pattern. MRI of the brain may be normal or show a variety of nonspecific abnormalities (128). While seizures are usually isolated, they may occur in the context of electrolyte imbalances, infections, endo-crine disturbances (including hypothyroidism and diabe-tes insipidus), irritability, feeding intolerance, hypotonia, and respiratory distress (127). It should thus be consid-ered in all sick infants with seizures. l-α-aminoadipic semialdehyde is in equilibrium with l-Δ1-piperideine 6-carboxylate in cells and when the latter accumulates in
this defect, it reacts nonenzymatically with and depletes pyridoxine phosphate (127).97.2.8.2 Treatment. Rapid response of seizures to pyridoxine supplementation (50–100 mg intravenous (IV)) is usual but may take up to 7 days. Patients can then be maintained on 5–10 mg/kg/day per os (PO). Other antiepileptics are usually not effective and gener-ally not necessary to control seizures.97.2.8.3 Diagnosis. Pipecolic acid is elevated in the blood and CSF but is not specific to this disorder (129). Elevation of l-α-aminoadipic semialdehyde and its ratio to creatinine in urine is diagnostic and the level usually drops with treat-ment (127). CSF and blood levels of threonine, glycine, taurine, and 3-methoxytyrosine may be elevated, mimicking pyridoxine-5′-phosphate oxidase deficiency, while glycine, taurine, and glutamine are often elevated in blood. Defini-tive testing is through molecular analysis of the ALDH7A1 gene. Enzyme analysis is not readily available.97.2.8.4 Genetics. ALDH7A1 is on chromosome 5q31 and the disorder is inherited in an autosomal recessive manner. Sixty-four disease-causing mutations, mostly private, have been published. Genotype/phenotype cor-relations have been poor (127).
This disorder is a part of the degradation pathway of the neurotransmitter GABA but manifests with increased excretion of the organic acid 4-hydroxybutyrate in urine (Figure 97-7).
L- 1-Piperidine-6-carboxylate
2-Aminoadipic semialdehyde
dehydrogenase
2-Aminoadipate
2-Aminoadipic semialdehydeFIGURE 97-10 Pyridoxine-dependent seizures are caused by a deficiency in 2-aminoadipic semialdehyde dehydrogenase. Pyri-doxine is lost from cells after it reacts nonenzymatically with l-Δ1-piperidine-6-carboxylate, which is in chemical equilibrium with 2-aminoadipic semialdehyde.
CHAPTER 97 Organic Acidemias and Disorders of Fatty Acid Oxidation 17
97.2.9.1 Clinical Features. The most frequent clinical findings in this disorder include mild to moderate global developmental delay, expressive language delay, variable mental retardation, hypotonia, dystonia, seizures, hypo-reflexia, ataxia, and behavioral problems (130,131). Age of onset varies from <1 to 21 years of age. MRI of the brain typically reveals an increased T2-weighted signal of the globus pallidus, with variable involvement of white matter and the cerebellar dentate nucleus.97.2.9.2 Treatment. Vigabatrin may improve ataxia and dystonia. It probably does not affect intellectual development and has been reported to both help and aggravate seizures (132,133).97.2.9.3 Diagnosis. 4-Hydroxybutyrate is excreted in urine, but some extraction techniques may lead to loss of this volatile compound. If the diagnosis is suspected, additional specific metabolite analysis is warranted (134). 4-Hydroxybutyrate is also present in high concen-trations in CSF. 4-Aminobutyrate and homocarnosine are also elevated in urine and CSF, and glutamine may be low. Enzyme analysis is possible but not often clini-cally useful. With characteristic metabolites present, it is more expedient to proceed directly to molecular testing.97.2.9.4 Genetics. The gene for succinic semialdehyde dehydrogenase (ALDH5A1) is on chromosome 6p22. Multiple mutations have been described in patients with no common mutations (135).
97.3 DISORDERS OF FATTY ACID OXIDATION: INTRODUCTION
Mitochondrial fatty acid oxidation is a complex process involving transport of activated acyl-CoA moieties into the mitochondria, and sequential removal of two car-bon acetyl-CoA units. It is the main source of energy for many tissues including heart and skeletal muscle and is critically important during times of fasting or physiologic stress. When the body’s glycogen stores are depleted, long-chain fatty acids are mobilized from adipose tissue and taken up by liver and muscle cells. While short- and medium-chain fatty acids (C4 to C12) diffuse freely across plasma and mitochondrial mem-branes, the transport of longer chain species (C14 to C20) depends at least in part on active transport, a high-affinity mechanism of major physiological importance in skeletal muscle, liver, and adipocytes (136,137). Two additional enzymatic steps are necessary for the com-plete oxidation of mono- and diunsaturated fatty acids, 2,4 dienoyl-CoA reductase and an enoyl-CoA isomer-ase, which allow for the complete oxidation of physi-ologically abundant fatty acids such as linoleate (C18:2) and oleate (C18:1) (138,139). Each cycle of the pathway produces a molecule of acetyl-CoA and a fatty acid with two fewer carbons. Under physiological conditions, the latter reenters the cycle until it is completely consumed. In peripheral tissues, the acetyl-CoA is terminally oxi-dized in the Krebs cycle for ATP production. In the liver,
the acetyl-CoA from fatty acid oxidation can instead be utilized for the synthesis of ketones, 3-hydroxybutyrate, and acetoacetate, which are then exported for final oxidation by brain and other tissues (140). At least 25 enzymes and specific transport proteins are responsible for carrying out the steps of mitochondrial fatty acid metabolism, some of which have only recently been rec-ognized (Figures 97-11 and 97-12) (141–143). Of these, defects in at least 22 have been shown to cause disease in humans (143).
Most patients with fatty acid oxidation defects are now identified through newborn screening by MS-MS of carnitine esters in blood spots. Unscreened patients can present throughout life. In the first week of life, cardiac arrhythmias, hypoglycemia, sudden death, and occa-sionally with facial dysmorphism and malformations, including renal cystic dysplasia are seen. Symptoms in later infancy and early childhood may relate to the liver or cardiac or skeletal muscle dysfunction, and include fasting or stress-related hypoketotic hypoglycemia or Reye-like syndrome, conduction abnormalities, arrhyth-mias or dilated or hypertrophic cardiomyopathy, and muscle weakness or fasting- and exercise-induced rhab-domyolysis. Adolescent- or adult-onset muscular symp-toms, including rhabdomyolysis, and cardiomyopathy predominate.
Diagnosis can usually be established even when the patient is asymptomatic, although analysis of samples during acute illness can uncover some mild cases. The most important single diagnostic test is analysis of acyl-carnitine esters in serum, plasma, or dried blood spots by tandem MS, which will identify characteristic com-pounds in many of these conditions. Other tests that may be useful include urine organic acids and acylglycines, free and total carnitine in serum and urine, and enzyme assays or flux studies in leukocytes or fibroblasts.
Treatment of the acute encephalopathy of hypo-ketotic hypoglycemia is by intravenous glucose and l-carnitine. Long-term therapy involves replenishing carnitine stores with l-carnitine, and preventing hypo-glycemia. In some cases this can be done by providing a snack or glucose polymers before bedtime, but in others requires continuous intragastric feeding. Supplemen-tation with medium-chain triglyceride (MCT) oil pro-vides a fat source that can be utilized by patients with long-chain defects.
97.3.1 Long-Chain Fatty Acid Transport Defect
Two patients affected with a defect of long-chain fatty acid transport at the plasma membrane level have been reported (Figure 97-11) (3). The first patient had a his-tory of recurrent acute liver failure and uninformative or nonspecific findings of biochemical investigations. In some of the episodes, hyperammonemia and encepha-lopathy were also present, but skeletal or cardiac
18 CHAPTER 97 Organic Acidemias and Disorders of Fatty Acid Oxidation
myopathy was never observed. Growth and develop-ment were normal and between episodes the patient was entirely well. At 5 years of age, however, he under-went orthotopic liver transplantation following a life- threatening episode that evolved into chronic hepatic insufficiency. The second patient presented with fulmi-nant liver failure at 4 years of age and also underwent
liver transplantation (3). Both patients are doing well several years posttransplant.
In cultured skin fibroblasts, the oxidation rates of C14 to C18 fatty acids were reduced with the severity of the defect correlating to the chain length of the substrate, but were normal in digitonin-permeabilized cells. The site of the defect was confirmed by reduced velocity of C14 to
Plasmamembrane
Outermitochondrialmembrane
CoASH
CoASH
CoASH
CoASH
Carnitine
4 1
23 3-Hydroxy Acyl-CoA
3-Keto acyl-CoA 2,3-Enoyl-CoA
Carnitine
Carnitine
Short-medium-chain fatty acids
Carnitinetransporter
Long-chainfatty acid
transporter
Translocase CPT II
CPT I
Acylcarnitine
Acylcarnitine
Acyl-CoA
Acetyl-CoAKetogenesis
TCA cycleSteroidogenesis
Acyl-CoA
Acyl-CoA
Carnitine
Innermitochondrialmembrane
FIGURE 97-11 Fatty acid transport and mitochondrial oxidation. Medium- and short-chain fatty acids do not require an active transport mechanism to reach the mitochondrial matrix. Long-chain fatty acids and carnitine are actively transported across the plasma membrane by tissue-specific transporters. Enzymes of the carnitine cycle (CPT I, translocase, and CPT II) shuttle long-chain fatty acids across the mitochon-drial membranes. The fatty acid β-oxidation spiral includes an FAD-dependent acyl-CoA dehydrogenase step (1) followed by a 2,3-enoyl-CoA hydratase reaction (2), the NAD-dependent 3-hydroxyacyl-CoA dehydrogenase step (3) and the thiolase cleavage reaction (4). CPT, carnitine palmitoyltransferase; CoASH, free coenzyme A; TCA, tricarboxylic acid cycle.
HDAFDAF 2
ETF + H– ETF
AoC-lyonEAoC-lycA Acyl-CoA dehydrogenase
2-Enoyl-CoA2-Ketoacyl-CoA
3-OH Acyl-CoA dehydrogenase
hydratasethiolase
3-Hydroxyacyl-CoA3-Ketoacyl-CoA NAD– NADHFIGURE 97-12 The fatty acid oxidation spiral. Multiple enzymes with chain-specific substrate utilization optima exist at each step.
CHAPTER 97 Organic Acidemias and Disorders of Fatty Acid Oxidation 19
C20 fatty acid uptake, while the uptake of 2-deoxy-d-glucose, carnitine, and palmityl-l-carnitine were nor-mal. The two index cases did not show correction of the uptake defect after complementation, providing addi-tional evidence that they are affected with the same pri-mary defect. However, any other combinations lead to normalization of oleate uptake, suggesting the possible existence of multiple defects manifesting with impaired long-chain fatty acid uptake in vitro. The gene encoding this transporter(s) has not yet been identified.
Before undergoing β-oxidation, free fatty acids must be activated to their corresponding acyl-CoA thioesters by long-chain specific acyl-CoA synthetases (Figure 97-11) (144). Short- and medium-chain carboxylic acids directly enter the mitochondrial matrix where they are activated. In contrast, long-chain fats are activated in the cyto-plasm and require active transport into mitochondria. Transport of long-chain acyl-CoAs requires at least two enzymes, a transporter protein and the use of carnitine as an intermediate carrier molecule. Carnitine is itself transported intracellularly by a specific transporter protein (145). Two carnitine transporters have been described, one specific to the liver and a second with a more ubiquitous distribution including kidney, muscle, and fibroblasts.
Primary carnitine deficiency is caused by a defect in the sodium-dependent high-affinity carnitine trans-porter in the plasma membrane of muscle and kidney (but not liver) cells, which ultimately limits β-oxidation by reducing the entry of acyl-CoA esters into mito-chondria (Figure 97-11). Free fatty acids are trans-ported through the blood after intestinal absorption or mobilization from endogenous stores by the use of albumin as a carrier protein or in the form of triacylglyc-erols in lipoprotein complexes (146). Transport of free fatty acids intracellularly and through the cytoplasm is probably accomplished by a specific transport process; however, the mechanism of this step is not well charac-terized (147). Before undergoing β-oxidation, free fatty acids must be activated to their corresponding acyl-CoA thioesters. Long chain-specific acyl-CoA synthetases can be found in various subcellular locations but are thought to arise from a single gene product (144). Short- and medium-chain carboxylic acids directly enter the mitochondrial matrix where they are activated. In con-trast, long-chain fats are activated in the cytoplasm and require active transport into mitochondria. Transport of long-chain acyl-CoAs requires at least two enzymes, a transporter protein and the use of carnitine as an inter-mediate carrier molecule. Carnitine is itself transported intracellularly by a specific transporter protein (145). Two carnitine transporters have been described, one spe-cific to the liver and a second with a more ubiquitous
distribution including kidney, muscle, and fibroblasts. Long-chain acyl-CoAs are conjugated to carnitine by car-nitine palmitoyl transferase I (CPT I) (148). This enzyme is located on the inner aspect of the outer mitochondrial membrane. Tissue-specific isoforms of this enzyme exist for muscle, liver and brain (145). Long-chain acylcarni-tines are then passed to carnitine palmitoyl transferase II (CPT II) in the inner mitochondrial membrane by a translocase (149). Carnitine is freely filtered by the kid-ney and must be reabsorbed from the proximal tubules to preserve plasma levels. Lack of carnitine uptake in the kidney and gut causes severe hypocarnitinemia, which responds dramatically to l-carnitine.97.3.2.1 Clinical Course. Patients with carnitine trans-porter deficiency can present with severe hypoglycemia and dilated cardiomyopathy in infancy or childhood. Alternatively, they may show onset of hypertrophic car-diomyopathy, progressive muscle weakness, and muscle lipid storage with mild elevations of creatine kinase. Car-riers of OCTN2 mutations are usually asymptomatic, but hypertrophic cardiomyopathy has been reported in middle-aged individuals. Fetal hydrops secondary to this disorder have been reported (150,151). Multiple reports of asymptomatic, affected mothers have been identified when newborn screening of their affected or carrier off-spring have been positive for severely low free carnitine levels (145).97.3.2.2 Diagnosis. Acylcarnitine and organic acid analysis are usually normal, and diagnosis is suggested by finding extremely low levels of carnitine in serum and tissues. In fact, serum carnitine may be 1μmol/L or unde-tectable (normal = 30–70). If necessary, deficient carni-tine uptake by tissues such as cultured fibroblasts can also be demonstrated. Molecular testing of the OCTN2 gene is clinically available.97.3.2.3 Treatment. The response to l-carnitine sup-plementation is dramatic and life saving; 100 mg/kg/day can be given intravenously in emergency situations, and then administered orally on a long-term basis.97.3.2.4 Genetics. The carnitine uptake defect is inher-ited as an autosomal recessive trait. The OCTN2 gene encoding the carnitine transporter is on chromosome 5q31, and numerous disease-causing mutations have been described (52,73). No single prominent mutation has been identified. Prenatal diagnosis can be accom-plished by showing deficient carnitine uptake in cultured amniocytes or molecular testing when mutations in the proband are known (10).
97.3.3 Defects of Fatty Acid Entry into Mitochondria (The Carnitine Cycle)
Short- and medium-chain fatty acids are thought to enter mitochondria directly, but mitochondrial uptake of fatty acids longer than C10–12 requires esterification to an acyl-CoA, and the concerted action of CPTs I and II, and carnitine–acylcarnitine translocase (Figure 97-11). CPT I
20 CHAPTER 97 Organic Acidemias and Disorders of Fatty Acid Oxidation
in the outer mitochondrial membrane first transfers the acyl moiety from CoA to carnitine, and the translocase moves the acylcarnitine ester across the inner membrane in exchange for free carnitine. CPT II in the inner mem-brane then reconstitutes the CoA esters, which enter the β-oxidation spiral.97.3.3.1 Clinical Course. Severe deficiency of liver CPT I is rare but more frequent milder variants have been identified in geographically restricted populations. Severe symptoms include episodic hypoketotic hypogly-cemia beginning in infancy and multiorgan system failure (152–154). Cardiac symptoms are not present. Creatine kinase levels in blood are elevated in acute episodes. Organic aciduria is not prominent in this disorder, but hyperammonemia may be present. Mild CPT1 deficiency is found in high frequency in first nation populations in Canada and Alaska where it is most frequently identified through newborn screening (155,156).
Deficiency of the carnitine-acylcarnitine translocase (CACT) was initially reported in newborns who had a nearly uniform poor outcome (157–159), presenting with severe hypoketotic hypoglycemia and cardiac arrhythmias and/or hypertrophy (157,158,160,161). All have had a grossly elevated acylcarnitine to free carnitine ratio, while dicarboxylic aciduria was reported in one. Patients with a more benign clinical course have since been identified, who have responded well to modest carnitine supplemen-tation and dietary therapy (145,162). Two affected sibs have been reported, where the younger sib was prospec-tively treated and has not developed any sequelae 2 years later (163). It appears that these patients have a higher level of residual enzyme activity than the more severely affected patients. Specific diagnosis of this disorder can be made via direct enzyme or molecular analysis.
CPT II deficiency is the most common of this group of disorders. It classically presents in late childhood or early adulthood as episodes of recurrent exercise- or stress-induced myoglobinuria (145,164,165). Episodes can be severe enough to lead to acute renal failure. Patients are typically well between episodes. There is no tendency to develop hypoglycemia. Weakness and muscle pain are reported. The characteristic diagnostic finding in these patients is a low total plasma carnitine level with an increased acylcarnitine fraction and no dicarboxylic acid-uria. Long-chain acylcarnitines may be elevated (145). A more severe variant of CPT II deficiency presenting with symptoms similar to severe CACT deficiency has been described (166,167). In these patients, the presenting symptoms were neonatal hypoglycemia, hepatomegaly, and cardiomyopathy. Several polymorphic variants in the CPT gene have been associated with an adverse neu-rologic outcome in influenza encephalitis in Japan.97.3.3.2 Diagnosis. The serum acylcarnitine profile is usually normal in CPT I deficiency, but acylcarnitine levels are low. CPT II and translocase deficiency can be identified but not distinguished from each other by
biochemical testing, both showing elevated C16 esters. The acylcarnitine profile may be normal in milder dis-ease. Urine organic acids either are normal or show mild dicarboxylic aciduria. Blood amino acids are usually normal. Free carnitine in serum is two to three times nor-mal in CPT I deficiency, and is very low in CPT II and translocase deficiency. All three enzymes can be assayed in fibroblasts and leukocytes.97.3.3.3 Treatment. Acute episodes of hypoketotic hypoglycemia should be treated with intravenous glucose-containing fluids to provide at least 8–10 mg/kg/min of glucose. Treatment of hyperammonemia may require dialysis. Ammonia conjugating agents are usually not needed as the hyperammonemia reverses with cor-rection of the underlying metabolic process. Prevention of fasting is the mainstay of therapy in all three disorders and continuous intragastric feeding may be necessary in severe disease. Carnitine supplementation is not usually effective but should be considered when free carnitine is extremely low. Bezafibrate has been shown to induce fatty acid oxidation in cells and improve flux through fatty acid oxidation in cells from patients with resid-ual CPT2 activity (168). A subsequent small trial (six patients) indicated improvement over a 3-year period of treatment (169). Expansion of this therapy to other long-chain fatty acid oxidation disorders may be possible.97.3.3.4 Genetics. All three enzyme defects are inher-ited as autosomal recessive traits, and the genes CPTIA, CPT2, and SLC25A20 (the gene for the translocase) have been localized to chromosomes 11 (11q13), 1 (1p32), and 3 (3p31.21), respectively. Disease-causing mutations have been identified in all three genes, with a relatively common mutation present in the late-onset muscular form of CPT II deficiency (170), and mild CPT1 defi-ciency in the Hutterite population (155). Numerous cod-ing polymorphisms of unknown significance have been identified in the CPTII gene. Prenatal diagnosis by muta-tion analysis or enzyme assay on amniocytes is possible in all three conditions.
97.3.4 Defects of the β-Oxidation Spiral
Once in the mitochondrial matrix, acyl-CoA esters enter the β-oxidation spiral in which a series of four reactions successively removes two-carbon fragments of acetyl-CoA (Figure 97-12). FAD-dependent acyl-CoA dehy-drogenases first oxidize the acyl-CoA to 2,3-unsaturated (enoyl-) derivatives, and these are hydrated to 3-hydroxy esters by hydratases. Oxidation to 3-ketoacyl-CoAs by NAD-requiring hydroxyacyl-CoA dehydrogenases and removal of acetyl-CoA by 3-ketothiolases follow, and the acyl-CoA, now two carbons shorter, reenters the spi-ral. The acyl-CoA dehydrogenases differ from most other dehydrogenases because they utilize electron transfer fla-voprotein (ETF) as a final electron acceptor, and thus can channel electrons directly into the ubiquinone pool of the
anic Acidemias and Disorders of Fatty Acid Oxidation 21
CHAPTER 97 Org
electron transport machinery by way of ETF:ubiquinone oxidoreductase (ETF dehydrogenase, ETF:QO) (171).
All the enzymes of β-oxidation have distinct (and often overlapping) substrate chain-length specifici-ties. For instance, different FAD-containing dehydro-genases oxidize very-long-chain (C12-24), long-chain (C6-20), medium-chain (C4-14), and short-chain (C4-6) acyl-CoAs, and similar specificities exist for the hydra-tases, hydroxyacyl-CoA dehydrogenases, and thio-lases. Inherited defects in almost all these enzymes have been described. As a rule, defects in long chain-specific enzymes block β-oxidation more completely and cause more severe clinical diseases than do deficits in the medium- and short chain-specific enzymes. Although most of these conditions were originally thought to be rare, defects in very-long-chain acyl-CoA dehydroge-nase (VLCAD), medium-chain acyl-CoA dehydrogenase (MCAD), and long-chain hydroxyacyl-CoA dehydro-genase (LCHAD) are among the most common meta-bolic defects identified though newborn screening with tandem MS. Patients who were originally reported with long-chain acyl-CoA dehydrogenase (LCAD) deficiency have all in fact been subsequently shown to have defects of VLCAD (172). Thus no bona fide patients with LCAD deficiency are known to exist.
97.3.5 Very-Long-Chain Acyl-CoA Dehydrogenase and ACAD9 Deficiency
97.3.5.1 Clinical Findings. VLCAD deficiency can present in the newborn period with arrhythmias and sudden death, or with hepatic, cardiac, or muscle presentations later in infancy or childhood (173–177). The hepatic presen-tation is characterized by fasting-induced hypoketotic hypoglycemia, encephalopathy, and mild hepatomegaly, often with mild acidosis, hyperammonemia, and elevated liver transaminases. Some present with arrhythmias or dilated or hypertrophic cardiomyopathy in infancy or childhood, and some with adolescence onset of exercise- or fasting-induced muscle pain, rhabdomyolysis, elevated creatine phosphokinase, and myoglobinuria. The disorder is inherited as an autosomal recessive trait. Tendency to develop hypoglycemia decreases with age, but low-grade, chronic rhabdomyolysis with acute exacerbations is common.
ACAD9 deficiency has been reported with two dis-tinct phenotypes. In the first publication, patients had severe recurrent hypoglycemia with hepatocellular fail-ure reversible with administration of intravenous glu-cose. One set of sibs also had cardiomyopathy (178). All reported patients appeared to have null mutations as indicated by lack of enzyme antigen. The deficiency has also been reported in patients with a deficiency of complex I of the respiratory chain apparently because of a second function for ACAD9 as a complex I assem-bly or stability factor (179,180). All these patients have
had point mutations, a finding that may be integral to determining the clinical picture. In fact, both phenotypes can be explained by the existence of a multifunctional protein complex within mitochondria that contains both the respiratory chain and fatty acid oxidation enzymes providing close physical and functional relationships between the two pathways (181).97.3.5.2 Diagnosis. Analysis of serum acylcarnitines by tandem MS usually shows elevations of saturated and unsaturated C14–18 esters in VLCAD deficiency, even between episodes. Organic acid analysis during acute episodes often shows C6, C8, and C10 dicarboxylic aciduria, but because these acids can also be seen when physiological ketosis is resolving, or following the intake of MCTs, this will not raise suspicion of disease unless C12 and C14 dicarboxylic acids are also present. Free carnitine in serum is usually low. If necessary, enzyme deficiency can be demonstrated in fibroblasts or leuko-cytes. Molecular testing is readily available. VLCAD deficiency is now most frequently diagnosed by newborn screening with tandem MS. No consistent specific bio-chemcial markers in blood or urine have been identified in patients with ACAD9 deficiency. Liver acylcarnitine profile has been reported to be abnormal with an excess of unsaturated compared to saturated species.97.3.5.3 Treatment. Acute management of VLCAD deficiency involves administration of high infusion of high rates of glucose-containing intravenous fluids to give 8–10 mg/kg/min of glucose. Chronic management is somewhat controversial (182,183). Avoiding fasting and maintaining a high carbohydrate intake are clearly indicated, and continuous intragastric feeding may be necessary to achieve this goal, especially overnight. MCTs, whose oxidation does not involve VLCAD, can be administered to provide calories but should not be used until a diagnosis of MCAD deficiency has been excluded. However, safe fasting intervals, the use of oral carnitine, and substitution in the diet of the experimental medium-chain oil triheptanoin are more controversial. As with CPT2 deficiency, bezafibrate has been suggested as a possible means of increasing activity in patients with partially stable mutations and residual enzyme activity (168). Treatment of ACAD9 deficiency remains uncer-tain because of its infrequency. Institution of high glu-cose infusion is warranted if hypoglycemia or elevated liver enzymes are elevated, but the need for chronic man-agement when well has not been demonstrated.97.3.5.4 Genetics. The ACADVL gene has been cloned and localized to chromosome 17 (17p13), and although several disease-causing mutations are known, there is no single prominent mutation. In general, the more severe defects cause the most severe and early presenting clini-cal disease (5). Prenatal diagnosis is possible through enzyme assay in cultured amniocytes, by demonstrating abnormal metabolism of stable isotopically labeled pal-mitate by amniocytes (51), and by mutation analysis (4).
Fatty Acid Oxidation
22 CHAPTER 97 Organic Acidemias and Disorders of
The ACAD9 gene is on chromosome 3q21.3. There have been no reported cases of prenatal diagnosis.
97.3.6.1 Clinical Findings. The most common of the fatty acid oxidation disorders, MCAD deficiency, historically most frequently presented during the first 2 years of life with episodes of fasting-induced vomiting, hepatomegaly, hypoketotic hypoglycemia, and lethargy progressing to coma and seizures (184). Blood levels of ammonia, uric acid, liver transaminases, and creatine phosphokinase may be elevated during acute episodes, and liver biopsy shows microvesicular steatosis. Autopsy shows fatty infiltration of the liver, renal tubules, and heart and skeletal muscle (185,186). The disorder was often misdiagnosed as Reye syndrome or sudden infant death syndrome, because the initial episode was fatal in about 25% of cases. Diagnosis through clinical symptoms is now rare as the disorder is readily identified through newborn screening by tandem MS. Patients thus identified are typically well, although at risk for hypoglycemia with intercurrent illness, and fatalities are a rarity. A few enzyme-deficient individuals born prior to newborn screening have had their first presentation in adolescence or adult life and some have remained asymptomatic (187).97.3.6.2 Diagnosis. Analysis of serum acylcarnitines by tandem MS shows elevations of C8, C8:1, and C10:1 esters even between episodes (188). The same abnormali-ties are identified through newborn screening. The C6, C8, and C10 dicarboxylic aciduria that occurs during acute episodes often should raise suspicion of the dis-ease and biochemical confirmation can be obtained by measurement of hexanoylglycine and suberylglycine in urine. Phenylpropionylglycine in urine will be elevated if the gut has been colonized by adult-type flora (189), but can be missed by all but the most sensitive techniques. Free carnitine in serum is usually low. Enzyme deficiency can be shown in fibroblasts or leukocytes, but molecular diagnosis is more readily available and often faster.97.3.6.3 Treatment. Treatment of acute episodes in MCAD deficiency is primarily supportive and aimed at quickly reversing the catabolic state that is responsible for stimulating the pathways of lipolysis and fatty acid oxida-tion (183,190). Hypoglycemia should be corrected with bolus administration of intravenous dextrose. Continuous infusion of dextrose should then be given at a rate that maintains plasma glucose levels at, or slightly above, the normal range in order to stimulate insulin secretion and suppress adipose tissue lipolysis. Specific therapy for the mild hyperammonemia that may be present during acute illness has not usually been required. Cerebral edema has occurred during treatment in some patients with severe coma, possibly as a late reflection of acute brain injury from hypoglycemia, toxic effects of fatty acids, or
ischemia. Recovery from the acute metabolic derange-ments associated with coma may require more than a few hours, but is usually complete within 12–24 h, except where serious injury to the brain has occurred. Long-term management consists of dietary therapy to prevent exces-sive periods of fasting that can lead to coma. Overnight fasting in infants should be limited to no more than 8 h. A duration of 12 h is probably safe in children >1 year of age (191). Home blood glucose monitoring is not useful because symptomatic illness can begin before hypoglyce-mia has occurred. Although it is reasonable to modestly reduce dietary fat, because this fuel cannot be used effi-ciently in MCAD deficiency, patients appear to tolerate normal diets without difficulty, and severe restriction of fat intake may be unnecessary. Formulas containing MCT oil should be avoided. Although patients with MCAD deficiency and other acyl-CoA oxidation defects have sec-ondary carnitine deficiency, the use of carnitine supple-mentation in these disorders is controversial (183,190). Some investigators suggest 50–100 mg/day of oral carni-tine but its utility is unproven.97.3.6.4 Genetics. The ACADM gene is on chromo-some 1 (1p31), and MCAD deficiency is inherited as a recessive trait. The vast majority of patients with MCAD deficiency have a single common missense mutation: an A-to-G transition at cDNA position 985, which changes a lysine residue to glutamate at amino acid 329 of the MCAD precursor protein (192). The mutated amino acid is far removed from the catalytic site of the enzyme but appears to make the protein unstable by interfer-ing with intramitochondrial folding and assembly of the nascent peptide (193). Preventing this misfolding offers an opportunity for development of new therapeutic agents for MCAD deficiency (194). The A985G muta-tion accounts for approximately 90% of the mutant alleles in MCAD deficiency (192). Approximately 70% of patients are homozygous for the A985G mutation. Most of the remaining patients are compound heterozy-gotes for the A985G allele in combination with one of several rarer mutations. Thus, only a small percentage of MCAD patients do not have at least one A985G allele. The unusually high frequency of a single common muta-tion has made molecular diagnosis especially valuable in MCAD deficiency. As more information accumulates from patients identified through newborn screening, cor-relation of phenotype with genotype is becoming clearer. Patients with the common mutation accumulate the high-est levels of metabolites in the newborn period and are probably at risk for more severe disease than are many other mutations (195).
97.3.7.1 Clinical Findings. A number of patients with SCAD deficiency have been reported (196,197). Reported clinical findings have included episodes of intermittent
anic Acidemias and Disorders of Fatty Acid Oxidation 23
CHAPTER 97 Org
metabolic acidosis, neonatal hyperammonemic coma, neonatal acidosis with hyperreflexia, multicore myopathy, and infantile-onset lipid storage myopathy with failure to thrive, and hypotonia. Hypoglycemia is a rare finding in this disorder. The characteristic metabolites of ethylmalonic and methylsuccinic acids of SCAD deficiency were also detected in individuals with normal SCAD activity in fibroblasts (198,199). Subsequently, it was demonstrated that the presence of one of two relatively common variants of SCAD (625 G>A and 511 C>T) predisposes to excessive ethylmalonic acid production. In general, it is clear that the vast majority of patients with complete SCAD deficiency identified through newborn screening have been well, while a variety of symptoms continue to be ascribed to the deficiency in patients identified through clinical testing later in life (197,200). The full clinical spectrum of this deficiency, and the clinical relevance of the common polymorphisms, remains to be defined (201,202).97.3.7.2 Diagnosis. Butyrylcarnitine in blood is ele-vated in complete SCAD deficiency and less reliably so in the presence of the common polymorphism. Urine ethylmalonic acid can be elevated in both clinical set-tings but is not specific for SCAD deficiency. Fibroblast enzyme analysis and acylcarnitine profile will identify the deficiency but may be normal in the presence of just the common polymorphisms. Molecular testing is clinically available.97.3.7.3 Treatment. The need for specific dietary or supplement therapy is not supported by current literature (196). Since ethylmalonic and butyric acids are organic acids, it seems prudent to caution parents to be alert for the development of signs of acidosis during intercurrent illness and seek emergency care if they develop.97.3.7.4 Genetics. The ACADS gene is located at chromosome 12q24.31. The two common variants (625 G>A and 511 C>T) can be present in as many as 35% of Caucasians. A common inactivating mutation has been described in the Ashkenazi Jewish population. Multiple other private inactivating mutations have been reported, as have combinations of an inactivating mutation with one of the polymorphisms in trans.
97.3.8 Trifunctional Protein and Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency
Several chain length-specific NAD-dependent 3- hydroxyacyl-CoA dehydrogenases catalyze the oxida-tion of 3-hydroxyacyl-CoA esters to 3-ketoacyl esters. LCHAD acts on hydroxyacyl-CoAs longer than C8. LCHAD and long-chain enoyl-CoA hydratase activities are carried out on the α-subunit of the mitochondrial tri-functional protein, and long-chain β-ketothiolase activity is carried out on the β-subunit. LCHAD deficiency can exist alone, or together with deficiency of the other two enzymes.
97.3.8.1 Clinical Findings. Patients with a deficiency of this enzyme tend to fall into two clinical subclasses (203–207). One group presents primarily with symp-toms of cardiomyopathy, myopathy, and hypoglycemia. Peripheral neuropathy and recurrent myoglobinuria may be present. These patients are deficient in all three enzy-matic activities of the trifunctional protein. The other group, deficient only in LCHAD activity, has hepato-cellular disease with hypoglycemia with or without pig-mentary retinopathy. Cholestasis and fibrosis may also be present (208). Considerable overlap in these groups has been described, however, and LCHAD deficiency has also been reported in patients with recurrent Reye syndrome-like symptoms and in sudden infant death (209). Milder cases with adolescent onset of recurrent rhabdomyolysis have been reported (210). Fetal LCHAD deficiency frequently causes acute fatty liver or HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) in the (heterozygous) mother during preg-nancy, especially when one or both mutant alleles in the fetus is E474Q (211).97.3.8.2 Diagnosis. Acylcarnitine analysis by tandem MS is usually diagnostic including in the newborn period, and shows elevated saturated and unsaturated C16 and C18 hydroxyacylcarnitines. Organic acid analysis often shows elevated C6–14 3-hydroxydicarboxylic acids, but the same abnormalities have been seen in patients with respiratory chain defects and glycogenoses, and are not specific. The enzyme defect can be demonstrated in fibroblasts and leukocytes and, for prenatal diagnosis, in amniocytes.97.3.8.3 Treatment. Therapeutic options and controver-sies parallel those for VLCAD deficiency (143,182,183,212). In addition, docosahexaenoic acid, a polyunsatu-rated C20 acid, has been proposed to slow down the devel-opment of retinitis but remains under investigation (213).97.3.8.4 Genetics. LCHAD deficiency, whether isolated or part of trifunctional protein deficiency, is inherited as an autosomal recessive trait, as the genes for both sub-units (HADHA and HADHB) are located on chromo-some 2 (2p24.1–23.3). Several disease-causing mutations have been identified, and most affect the α-subunit. One of these, E510Q (E474Q in the mature subunit), accounts for nearly 90% of mutant alleles in patients of European extraction with isolated LCHAD deficiency (214). Defects in the β-subunit tend to destabilize the trifunctional protein resulting in the multiple enzymatic deficiencies seen in some patients (207,215–217). Prenatal diagnosis can be made by enzyme assay in amniocytes or chorionic villus samples or, when appropriate, by mutation analysis, and on occasion will be indicated to avoid the complications of pregnancy.
Short-chain l-3-hydroxyacyl-CoA dehydrogenase (SCHAD) catalyzes the NAD-dependent oxidation of
24 CHAPTER 97 Organic Acidemias and Disorders of Fatty Acid Oxidation
3-hydroxyacyl-CoA for C4 to C10 substrates. Deficient patients present with hypoketotic hypoglycemia associ-ated with hyperinsulinism, reduced SCHAD activity in fibroblast mitochondria, and mutations in the HADHSC gene (218–220). Several other patients with abnormal metabolite or enzymatic studies suggestive of SCHAD deficiency have been reported, but as SCHAD gene sequencing was normal, the nature of their disorders remains unclear.97.3.9.1 Diagnosis. A biochemical diagnosis is based on the findings of marked ketotic C8 to C14 3-hydroxy dicarboxylic aciduria. SCHAD activity in cultured skin fibroblasts may or may not be abnormal. Characteris-tic metabolic findings in patients with hyperinsulinemic hypoglycemia should trigger gene sequencing studies (218–220).97.3.9.2 Treatment. Patients with hyperinsulinism may exhibit improved glucose homeostasis with diazox-ide therapy. No specific metabolic interventions beyond avoidance of fasting and IV hydration with glucose con-taining solutions during illness have been reported.97.3.9.3 Genetics. The genetic nomenclature for SCHAD is somewhat confusing. The gene defective in patients with hyperinsulinism is referred to as HADHSC in the literature but is designated as HADH in Gen-Bank. It is located on chromosome 4q22–q26 and mutations in patients have been described. An enzyme designated MSCHAD in the literature is likely different than the one defective in hyperinsulinism patients, but also is identified as HADH in GenBank. No gene muta-tions have yet been identified in patients with metabolic findings of SCHAD deficiency but without hyperinsu-linism, suggesting these individuals in fact have a dif-ferent disorder.
The first confirmed case to be reported was a Japanese male neonate who died shortly after presenting at 2 days of age with vomiting, dehydration, metabolic aci-dosis, liver dysfunction, and terminal rhabdomyolysis with myoglobinuria (221). Urine organic acid analysis revealed ketotic lactic aciduria and significant C6 to C12 dicarboxylic aciduria, with strikingly elevated C10 and C12 species. In skin fibroblasts, palmitate oxida-tion was normal, octanoate oxidation was reduced to 31% of controls, and there was an isolated deficiency of medium-chain 3-ketoacyl-CoA thiolase activity, a result supported by the finding of a reduced protein signal by immunoprecipitation. Additional patients presented with variable but nevertheless typical symptoms of a fatty acid oxidation disorder (fasting intolerance, cardiomyopathy, and sudden death in one case) (222,223). Unfortunately, in vitro functional or molecular confirmation is not read-ily available.
97.3.11 Multiple Acyl-CoA Dehydrogenase Deficiency/Glutaric Acidemia Type II
Electrons from the acyl-CoA dehydrogenases involved in mitochondrial fatty acid and amino acid oxidation are transferred from their FAD coenzymes to coenzyme Q in the respiratory chain via ETF and ETF:QO. Defects in ETF and ETF:QO cause multiple acyl-CoA dehydro-genase deficiency, often called glutaric acidemia type II because of one of the characteristic metabolites that accumulates.97.3.11.1 Clinical Findings. Glutaric acidemia type II was first described in 1976 in a baby who died at 3 days of age with severe hypoglycemia, metabolic acidosis, and the smell of sweaty feet, and many additional patients have since been described. Clinical manifestations are extremely heterogeneous (224); Frerman, 1988 #9910. A neonatal form can be seen with severe hypotonia, dys-morphic features, and cystic kidneys. These infants also exhibit metabolic acidosis and hypoglycemia. Milder variants are common, presenting with nonspecific neu-rological signs, lipid storage myopathy, fasting hypo-ketotic hypoglycemia, and/or intermittent acidosis. In some patients, only fasting hypoketotic hypoglycemia and/or intermittent acidosis is seen and can be of late onset (202,224). In these cases, the organic acid profile in times of illness is usually dominated by ethylmalonic and adipic acids, leading to an alternate name of eth-ylmalonic-adipic aciduria for this disorder. Structural brain abnormalities are common including agenesis of the cerebellar vermis, hypoplastic temporal lobes, and focal dysplasia of the cerebral cortex (225). Neuronal migration abnormalities may be present. Riboflavin-responsive mutations in the ETFDH gene have been reported (226).97.3.11.2 Diagnosis. Organic acid analysis usually shows increased ethylmalonic, glutaric, 2-hydroxyglu-taric, and 3-hydroxyisovaleric acids, together with C6, C8, and C10 dicarboxylic acids and isovalerylglycine, and acylcarnitine analysis by MS-MS shows glutarylcar-nitine, isovalerylcarnitine, and straight-chain esters of chain length C4, C8, C10, C10:1, and C12. Serum carni-tine is usually low, and serum sarcosine is often increased in patients with mild disease. Enzyme or immunoblot analyses, if necessary, will show that some patients are deficient in ETF, and that others are deficient in ETF:QO. Molecular testing is typically more readily available.97.3.11.3 Treatment. Patients with complete defects often die during the first weeks of life, usually of conduc-tion defects or arrhythmias, but those with incomplete defects can survive well into adult life. As in other fatty acid oxidation disorders, treatment relies on the avoid-ance of fasting, sometimes with continuous intragastric feeding, and carnitine to replenish lost stores. Ribofla-vin is usually given, and appears to have helped some
Acidemias and Disorders of Fatty Acid Oxidation 25
CHAPTER 97 Organic
patients. Carnitine supplementation (100 mg/kg/day) will increase metabolite excretion and should be used.97.3.11.4 Genetics. ETF and ETF:QO deficiencies are both inherited as autosomal recessive traits, and the genes encoding ETF:QO and the α- and β-subunits of ETF have been mapped to chromosome 4 (4q32>ter), 15 (15q23–25), and 19 (19q13.3), respectively. Disease-causing mutations have been identified in all three genes, but only in the EFTA gene is there a common mutant allele (T266M) (227). Severe forms of the disease have been diagnosed in utero by demonstrating increased amounts of glutaric acid in amniotic fluid (228,229), and in some cases renal cysts have been seen in the fetus on ultrasound examination (230).
97.3.12 Disorders of Ketone Body Metabolism
97.3.12.1 Clinical Findings. Deficiency of the mitochondrial acetoacetyl-CoA thiolase (also known as β-ketoacyl-CoA thiolase) and 3-hydroxy- and 3-methylglutaryl-CoA lyase are shared disorders between ketone body metabolism and isoleucine degradation. They are discussed with the organic acidemias. Succinyl-CoA: 3-ketoacid CoA transferase (SCOT) functions in conjunction with mitochondrial acetoacetyl-CoA thiolase to generate ketones in extrahepatic tissues. SCOT deficiency presents as persistent ketonuria in the first 1–2 years of life, while acetoacetyl-CoA thiolase deficiency presents with variable clinical symptoms and exaggerated ketoacidosis in response to minor physiologic stress (231–233). HMG-CoA synthase deficiency has been reported in eight patients who presented with coma, hypoglycemia and dicarboxylic aciduria with very low ketones (234–236). Their acylcarnitine profiles were reported as normal.97.3.12.2 Treatment. Treatment for most of the ketone body synthesis disorders is essentially supportive. Maintaining adequate hydration during intercurrent ill-ness minimizes symptoms. HMG-CoA lyase deficiency can present with life-threatening hypoglycemia and hyperammonemia and must be treated aggressively (see Organic Acidemias in this chapter).97.3.12.3 Genetics. Multiple mutations in the succi-nyl-CoA: 3-ketoacid CoA transferase gene (also called 3-oxoacid CoA transferase; OXCT1; chromosome 5) have also been described in patients with enzymatic defi-ciency. The HMG-CoA synthase gene (HMGCS2) is on chromosome 1 and gene mutations in patients have been identified (234–236).
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FURTHER READING
http://www.ommbid.com/.Zschocke, J., Hoffmann, G. F., Eds. Vademecum Metabolicum,
Dr Vockley is Professor of Pediatrics, School of Medicine; Professor of Human Genetics, Grad-uate School of Public Health; and Chief of Medical Genetics, Children’s Hospital of Pittsburgh. He received his undergraduate degree at Carnegie-Mellon University in Pittsburgh, Pennsylva-nia, and received his degree in Medicine and Genetics from the University of Pennsylvania School of Medicine in Philadelphia, Pennsylvania. He completed his pediatric residency at the University of Colorado Health Science Center, and his postdoctoral fellowship in Human Genetic and Pediatrics at Yale University School of Medicine in New Haven, Connecticut. Before assuming his current position in Pittsburgh, Dr Vockley was Chair of Medical Genetics in the Mayo Clinic School of Medicine.
Dr Vockley is internationally recognized as a leader in the field of inborn errors of metabo-lism. His laboratory has been responsible for identifying multiple new disorders, many of them defects in mitochondrial energy and amino acid metabolisms, and he has published over 140 scientific articles in peer review journals. His current research focuses on the molecular archi-tecture of mitochondrial energy metabolism, in which he is breaking new ground in describing the role of dysfunction of mitochondrial energy metabolism in such common conditions as diabetes, obesity, and Alzheimer disease. Dr Vockley serves on numerous national and inter-national scientific boards including the Advisory Committee (to the Secretary of Health and Human Services) on Heritable Disorders in Newborns and Children where he is chair of the technology committee. He also serves as chair of the Pennsylvania State Newborn Screening Advisory Committee and the American College of Medical Genetics Therapeutics Committee. He is a past president of the International Organizing Committee for the International Congress on Inborn Errors of Metabolism and the Society for the Inherited Metabolic Disorders (SIMD).
Dr Vockley is the cofounder and editor of the North American Metabolic Academy estab-lished by the SIMD to help educate the next generation of metabolic physicians in the United States, and serves as associate editor for the journals Molecular Genetics and Metabolism and The Journal of Inherited Metabolic Disorders. Dr Vockley was recognized in 2002 as the Research Educator of the Year while at the Mayo Clinic. At the University of Pittsburgh, Dr Vockley teaches in both the Medical School and Graduate School of Public Health. Dr Vock-ley has mentored numerous PhD candidates, postdoctoral fellows, and undergraduate in their research.
