MEDICINE

Psychiatric Symptoms Associated with Inborn Errors of Metabolism

Susan Beckwitt Turkel1 & Derek Wong2& Linda Randolph3

Accepted: 8 July 2020# Springer Nature Switzerland AG 2020

AbstractInborn errors of metabolism (IEM) are individually rare but collectively common disorders, occurring in 1:800 to 1:1000 births.There are more than 1000 known inherited disorders characterized by disruption of metabolic pathways which may present withdiverse symptoms affecting any organ at any age, including with psychiatric symptomsmimicking primary psychiatric disorders.This review is intended to help psychiatrists and other physicians suspect an inborn error of metabolism in a patient presentingwith psychiatric symptoms. A comprehensive literature review was undertaken, using Index Medicus and resources at theUniversity of Southern California Norris Medical Library to identify specific information for each individual disorder described.Those inborn errors of metabolism most likely to present with psychiatric symptoms primarily impact the brain, acting eitherdirectly on biochemical pathways in the central nervous system or indirectly reflecting dysfunction in other organs. Symptomsmay occur episodically under stress when metabolic demands are highest or progressively evolve over time reflecting gradualneuropsychiatric deterioration. Cognitive impairment and psychosis appear to be the most frequently reported psychiatricproblems. Noting age of onset, patterns of psychiatric presentation, and associated symptoms in other organ systems can increasesuspicion and facilitate diagnosis of psychiatric symptoms due to an inborn error of metabolism. Psychiatric problems can be seenwith multiple inborn errors of metabolism with associated systemic dysfunction or as isolated symptoms. It is important forphysicians to be aware of clues that might increase suspicion of an underlying genetic disorder, and to recognize that consultationwith a medical geneticist is recommended for diagnosis and to provide the patient optimal care in either situation.

Keywords Psychiatric symptoms .Metabolic disorders . Genetics . Pediatrics

Introduction

The overall incidence of inborn errors of metabolism is estimatedto range from 1:800 to 1:1000 live births, although the incidenceis probably much higher given difficulties in clinical diagnosis

and limitations in diagnostic testing [1, 2]. Inborn errors of me-tabolism are a heterogeneous group of disorders that may presentwith psychiatric symptoms at any age [3] and their symptomscan be easily confused with primary psychiatric disorders [4, 5].There are more than 1000 known inherited disorders character-ized by disruption of metabolic pathways typically due to defi-cient enzymes, cofactors, or transporters [6]. They may presentwith diverse symptoms affecting any organ at any age, includingwith psychiatric symptoms easily confused with primary psychi-atric disorders [2, 7]. Perhaps as many as 0.5% of patients pre-senting with psychosis may have an underlying metabolic disor-der [8], and a variety of these disorders present first with psycho-sis [9, 10]. Newer methods of genetic analysis and increasedsuspicion make it likely that inborn metabolic errors will berecognized more often in psychiatric patients than previously[11]. A positive family history of early childhood death in sib-lings or other relatives can increase suspicion and be helpful fordiagnosis, but a negative family history does not exclude a ge-netic disorder which may have arisen de novo or may not havebeen recognized before [12]. A patient with a history of parentalconsanguini ty; unexplained episodic symptoms;

Previously presented at the American Neuropsychiatry Associationannual meeting March, 2016 in San Diego, California

This article is part of the Topical Collection onMedicine

* Susan Beckwitt Turkelsbturkel@usc.edu

1 Department of Psychiatry, University of Southern California KeckSchool of Medicine, Los Angeles, CA, USA

2 Department of Pediatrics, Mattel Children’s Hospital, Division ofMedical Genetics, University of California Los Angeles GeffenSchool of Medicine, Los Angeles, CA, USA

3 Department of Pediatrics, Children’s Hospital Los Angeles, Divisionof Medical Genetics, University of Southern California Keck Schoolof Medicine, Los Angeles, CA, USA

https://doi.org/10.1007/s42399-020-00403-z

/ Published online: 13 August 2020

SN Comprehensive Clinical Medicine (2020) 2:1646–1660

decompensation during stress or illness; failure to thrive; symp-toms in high-energy-utilizing organs such as the brain, heart,liver, or muscle; avoidance of certain foods; or atypical responseto psychotropic medication should all increase concern for anunderlying metabolic disorder [1, 13]. These observations mayhelp distinguish patients with an underlying inborn error of me-tabolism, but psychiatric symptomsmay occurwithout historical,familial, or systemic symptoms to assist in diagnosis.Psychiatrists and other physicians need to remain open to thepossibility that metabolic disorders may present with isolatedpsychiatric symptoms alone. This review is intended to increasesuspicionwhen a patient presents with psychiatric symptoms andto encourage consultation with a specialist for definitive diagno-sis and collaborative care.

A comprehensive literature review using Index Medicus andresources at theUniversity of SouthernCaliforniaNorrisMedicalLibrary was employed to identify specific information for eachdisorder described. Patient charts were not evaluated andInstitutional Review Board clearance was not required. This ar-ticle does not contain any studies with human participants per-formed by any of the authors.

Porphyria

The porphyrias are disorders that result from decreased activityof the enzymes in the heme synthetic pathway. The largestamounts of heme are produced in the bone marrow for makinghemoglobin, and in the liver for making cytochrome P450 en-zymes. The porphyrias lead to the accumulation and excess ex-cretion of metabolic intermediates and products of heme synthe-sis. Most porphyrias are autosomal dominant, so males and fe-males are equally affected, although females aremore likely to besymptomatic. Symptoms can be precipitated by factors that de-plete intracellular heme including alcohol or starvation. Affectedpatients have 50% or less of enzyme activity. Given that only10–20% patients with the gene defect may be symptomatic, fam-ily history is often negative [5].

Acute Intermittent Porphyria

Acute intermittent porphyria (AIP) is the most common formof porphyria. There are close to 400 different mutations of theporphobilinogen deaminase gene which result in AIP. It isinherited as an autosomal dominant condition, although mostpeople with AIP never develop symptoms. AIP occurs in 1–2/10000 Europeans, with the highest rate in Scandinavia andFrance, and rates 50–200 times higher in psychiatric inpatientscompared to the general population [5, 8].

AIP is associated with intermittent elevations inporphobilinogen and related prophyrins, and symptoms aretypically episodic. Acute attacks can be triggered by fasting,stress, steroid hormones, and certain drugs. Diagnosis is

usually made by finding increased porphobilinogen, porphy-rin, and δ-aminolevulinic acid in the urine. Porphyrins in urineoxidize on standing, which turns urine red or dark brownish incolor [14].

Patients with AIP classically present with abdominal pain,psychiatric symptoms, and peripheral neuropathies. Abdominalpain may suggest pancreatitis, and is typically accompanied bynausea, vomiting, and constipation. AIPmay also present acutelywith tachycardia, hypertension, renal disease, pain,muscle weak-ness, agitation, confusion, depression, hallucinations, or convul-sions [15]. Patients can present with delirium, psychosis, depres-sion, or anxiety, and psychiatric symptoms may be the onlymanifestation of AIP [5, 16]. Acute attacks are rare before pu-berty, and the onset of symptoms typically occurs after puberty.Most patients present in the second to fourth decade. Whensuspected, AIP is confirmed by finding excess α-aminolevulinic acid (ALA) and porphobilinogen (PBG) in urineat the same time that porphobilinogen deaminase activity(PBGD) is decreased in the patient’s erythrocytes [5].

Psychotropic medications are generally effective in man-aging psychiatric symptoms in patients with AIP, but cautionis needed because some agents can precipitate or exacerbatean acute episode. Sedative-hypnotics (secobarbital, butalbital,phenobarbital, meprobamate, chlordiazepoxide) can exacer-bate AIP. Antipsychotics (trifluoperazine, chlorpromazine,olanzapine, clozapine, risperidone), lithium, and some benzo-diazepines (lorazepam, and clonazepam) have no impact onAIP. The effects of other psychotropic drugs (amitriptyline,nortriptyline, imipramine, clonazepam, diazepam, oxazepam)remain controversial [17].

Specific treatments for AIP are available. Hematin is effec-tive during an acute attack and for the prevention of an attack,while hemin acts faster by suppressing the overproduction ofporphyrin precursors and is currently used more often [18].

Disorders of Copper Metabolism

Copper is essential for cellular metabolism, but excess copper istoxic, and acts as a pro-oxidant for formation of free radicals andoxidation of lipids and proteins. Copper causes hepatocellulardamage and high intracellular levels of copper lead to hepaticcell death. The liver is the main organ that regulates copperhomeostasis, and excretion into bile is the only method of copperelimination. Over 90% of copper in the body is bound to ceru-loplasmin which transports copper in the blood [19].

Wilson’s Disease

Wilson’s disease is an autosomal recessive disorder of coppermetabolism. Its worldwide prevalence is 1/20000 to 1/100000and its carrier rate is about 1:90. Wilson’s disease results fromimpaired excretion of copper from hepatocytes to bile canaliculi

1647SN Compr. Clin. Med. (2020) 2:1646–1660

due to a defective gene for P-type adenosine triphosphatase B(ATP7B). ATP7B is large transmembrane protein expressedmostly in the liver. The gene for ATP7B is found on chromo-some 13q.14.3 and mutations of ATP7B are closely linked toimpaired copper excretion [20].

There is considerable allelic heterogeneity in Wilson’s dis-ease. Almost 500 mutations of ATP7B have been identifiedand more than 300 have been associated with clinical Wilson’sdisease. Different patterns ofmutation are found in different partsof the world and environmental factors can influence clinicalphenotypic expression [19].

The storage capacity for copper in the liver is limited.Excessive copper deposition is found mostly in the liver andbrain. Copper is deposited in the cornea as Kayser-Fleischerrings, in the kidneys disrupting renal function, in joints, and incardiacmuscle resulting in cardiomyopathy [19]. The commonlyobserved increase in serum ceruloplasmin in Wilson’s disease isan epiphenomenon. Ceruloplasmin levels increase to accommo-date increased amounts of copper in the blood, but as liver dam-age increases and hepatocellular production of ceruloplasmin iscompromised, ceruloplasmin levels decline. Hepatic symptomsare usually recognized first as copper accumulates in the liver,typically at 10 to 13 years. Deposition in the central nervoussystem follows and leads to neuropsychiatric symptoms usually5 to 10 years later [21].

It takes longer for the diagnosis of Wilson’s disease if psychi-atric symptoms present first, which occurs in 20–30%of patients,and 30–40%of patients have psychiatric symptoms at the time ofdiagnosis [22]. Abnormal behavior and mood symptoms aremost common when Wilson’s disease presents psychiatrically,but psychosis, anxiety, obsessive-compulsive disorder, anorexia,cognitive impairment, and isolated irritability have all been re-ported. Neuroimaging typically shows T2 hyperintensity signalsin the basal ganglia, thalamus, brainstem, and cerebellum; andSPECT shows hypoperfusion in the cerebral cortex, putamen,and caudate [23].

Treatment for Wilson’s disease begins with chelating agents(D-penicillamine or trientine) to decrease copper levels, and thenmaintenance with penicillamine or zinc [24, 25]. With progres-sive disease, liver transplant is recommended. Hepatic and usu-ally neurologic symptoms improve significantly after transplant,but improvement in psychiatric symptoms is usually modest[26]. Anxiety ismore persistent than other psychiatric symptoms.Antipsychotics, mood stabilizers, and anxiolytics may be neededin addition to chelating agents to control psychiatric symptoms[27, 28]. Screening first degree relatives of patientswithWilson’sdisease is recommended to identify those affected early, as zinctherapy appears effective in preventing significant copper accu-mulation and end-organ damage in asymptomatic relatives [24].

Aminoacidopathies

Phenylketonuria

Phenylketonuria (PKU) is the most common and probably thebest-known disorder of amino acid metabolism. It was the firstinborn error of metabolism to be screened in newborns. PKUwas initially recognized in 1934 in intellectually disabled chil-dren with decreased activity of phenylalanine hydroxylase lead-ing to increased levels of phenylalanine in the blood and excre-tion of urinary phenylpyruvic acid. There are more than 550mutations resulting in PKU. The overall global prevalence is1:12000, and the carrier rate is 1:55 [29].

Untreated, PKU presents with severe mental retardation,hyperactivity, seizures, light complexion, eczema, and a“mousy odor.” Excessive phenylalanine is thought to interferewith brain growth, myelination, and neurotransmitter synthe-sis, which results in intellectual impairment, epilepsy, motordeficits, microcephaly, and behavioral disturbances. Childrenand adolescents frequently have psychiatric symptoms andsignificant problems with attention, achievement, motivation,social competence, autonomy, and self-esteem despite earlytreatment. Generalized anxiety, depression, social isolation,and behavioral immaturity are common in early-treated adults,and psychosocial factors and the burden of living with achronic illness may contribute to psychological difficulties atany age [29].

A phenylalanine restricted diet is the main treatment forPKU, but strict adherence to it is onerous and compliancedecreases as patients get older. High phenylalanine levels areassociated with mood, anxiety, and attention problems [30],and with dopamine and serotonin deficits which may explainbrain damage and progressive neuropsychiatric impairment inadult PKU patients [31]. Psychotherapy can improve compli-ance with treatment, which is important in limiting cognitiveimpairment and psychiatric symptoms [32].

Even when well treated early, there may be subtle deficits inexecutive functioning, mild reduction in mental processingspeed, social difficulties, and emotional problems, which in turnare related to problems in relationships, maintaining compliance,and job performance [33]. Psychiatric disorders are noted in25.7%patients even after early treatment, withmore internalizingdisorders and more women affected. Lack of adherence is direct-ly related to associated cognitive and executive functional declineand psychiatric problems [34].

Sapropterin is a synthetic form of tetrahydrobiopterin, thecofactor for phenylalanine hydroxylase. It can stabilize andincrease residual enzyme activity and about one-third ofPKU patients respond to oral sapropterin. Additional noveltherapies to reduce phenylalanine levels are under investiga-tion [34].

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Sulfur Amino Acids: Methionine, Cysteine,Homocysteine

Methionine, homocysteine, and cysteine are sulfur-containingamino acids connected by a methylation cycle. Methionine isan essential amino acid from diet, and it is converted to ho-mocysteine in the methylation cycle. The metabolism of ho-mocysteine is linked to folate, cobalamin (vitamin B12), andpyridoxine (vitamin B6) [35, 36].

Homocysteine is required for the synthesis of neurotrans-mitters and DNA, and in excess can be directly toxic to neu-rons and blood vessels. Elevated levels of homocysteine occurwith homocystinuria, MTHRF deficiency, and cobalamin dis-orders, and are associated with megaloblastic anemia, com-bined degeneration of the spinal cord, dementia, and psycho-sis [37]. Elevated homocysteine alters the release of mono-amines, affects neurotoxicity via N-methyl-D-aspartate(NMDA) receptors, causes leukodystrophy due to disruptedmyelination, and can present as a psychiatric disorder, includ-ing personality disorders, behavioral disturbances, depression,mood disorders, obsessive-compulsive disorder, and psycho-sis resembling schizophrenia [10, 38].

Homocystinuria

Homocystinuria is commonly attributed to cystathionine β-synthetase (CBS) deficiency, which leads to accumulation ofmethionine and homocysteine in blood, CSF, and urine. It isan autosomal recessive trait found in 1:150000 in the USA.About half the patients will respond to dietary therapy withpyridoxine and have a milder course. Psychiatric symptomscan be recognized in about two-thirds of adult patients [39]and may be the presenting symptom in 3%; adolescents mayrarely present with acute psychosis [40].

Methylene Tetrahydrofolate Reductase

Methylene tetrahydrofolate reductase (MTHFR) is a key en-zyme in folate/homocysteine metabolism, and its dysfunctionmimics folate deficiency. The MTHFR gene is polymorphicand associated with a spectrum of disorders [41]. Deficiencyof the enzyme 5,10-methylene tetrahydrofolate reductase(MTHFR) leads to impaired production of 5-methylenetetra-hydrofolate, resulting in decreased methionine synthetase.Deficiency of MTHFR has been reported with psychiatricdisorders, schizophrenia-like symptoms [10], malignancies,paraplegia, developmental delay, decreased levels of mono-amine neurotransmitters, seizures, atherosclerotic cerebrovas-cular disease, infantile apnea, and neonatal death [42]. Betainetreatment improves outcome and can prevent symptoms ifgiven early, while parenteral cobalamin has no proven benefit,and folic acid should be avoided [43].

Psychiatric symptoms are common in patients withMTHFR deficiency, but they do not fit a consistent pattern.The role of MTHFR in psychiatric disorders has been contro-versial. A recent meta-analysis of available case studies sug-gestedMTHFRC677T polymorphismmay be a risk factor forschizophrenia, but a definitive relationship between MTHFRand specific psychiatric disorders has not been established andmeta-analyses have been inconsistent [44].

Cobalamin

Cobalamin, or vitamin B12, is an organometallic compoundcontaining cobalt found in food of animal origin and synthe-sized by bacteria. Dietary deficiency of cobalamin is rare inWestern diets with the exception of strictly vegan diets orbreast-fed babies. The absorption of cobalamin involvescobalamin-binding proteins and receptors, so disorders relatedto the absorption and transport of B12 are considered inbornerrors of metabolism.

Methylmalonic acid and homocysteine accumulate inblood and urine with dietary B12 deficiency, impaired B12absorption, or impaired conversion of dietary B12 into meta-bolically active forms. Errors in the cobalamin pathway canresult in methylmalonic aciduria, homocystinuria, or both[45].

Cobalamin C

Cobalamin C disease is an inborn metabolic error with im-paired intracellular synthesis of the 2 active forms of cobala-min, adenosylcobalamin and methylcobalamin. It is related tomutations in the methylmalonic aciduria and homocystinuriatype C protein (MMACHC) gene [46]. Cobalamin C defect isthe most common inborn error involving B12 metabolismwith at least 40 mutations reported, and it results in increasedlevels of methylmalonic acid and homocysteine in blood andurine [45].

Presenting symptoms vary by age, with severe multi-systemic symptoms in the first year; hemolytic uremic syn-drome and pulmonary hypertension in preschool children;psychiatric symptoms, cognitive impairment, ataxia, and my-elopathy in older children and adolescents; and thromboem-bolic events and glomerulopathy almost exclusively in adults[47]. Later onset is less common and is associated with amilder phenotype, longer survival, and psychiatric symptomsof psychosis, confusion, dementia, and delirium are reported[45].

Urea Cycle Defects

The urea cycle is the primary nitrogen-disposal pathway andrequires the coordinated function of enzymes in the cytosol

1649SN Compr. Clin. Med. (2020) 2:1646–1660

and mitochondrial matrix. The liver is the only organ in whichall the urea cycle enzymes are found. Urea cycle defects areautosomal recessive, with the exception of ornithinetranscarbamyl transferase deficiency, which is X-linked. Thephenotypic spectrum of urea cycle defects varies consider-ably, and their overall prevalence is between 1:8000 and1:35000 [48, 49]. Two-thirds of patients will have their initialsymptoms after the newborn period, and postnatalhyperammonemic episodes are typically precipitated by anintercurrent infection. Mortality varies from 11% with lateonset, to 24% with neonatal onset, to 42% with carbamoylphosphate synthetase 1 (CPS1) deficiency [49] (Table 1).

When the diagnosis of a urea cycle defect is suspected,confirmation is necessary by documenting elevated blood am-monia levels. Ammonia is present in serum as NH4+ and istoxic. Hyperammonemia will alter neurotransmission and canresult in irreversible cerebral edema, causing neurologic dam-age, intracranial hypertension, herniation, and death. Milderforms of urea cycle defects may be difficult to differentiateclinically from drug abuse, psychosis and psychiatric disor-ders, or hepatic encephalopathy [50]. Adult onset urea cycledisorders may present with psychiatric symptoms, which oc-casionally can be the initial presentation [51]. Agitation andhallucinations can occur, and associated neurologic symptomsmay provide the clue to an underlyingmetabolic disorder [51].

Ornithine Carbamoyl Transferase Deficiency

Ornithine carbamoyl transferase deficiency (ornithinetranscarbamylase deficiency, OCT) is X-linked and is themost common urea cycle defect. It is found in more than halfthe cases and is associated with a 57% risk for liver dysfunc-tion. It results from deficiency of the mitochondrial enzyme,ornithine transcarbamylase, which catalyzes the conversion ofornithine and carbamoyl phosphate to citrulline [52].

OCT usually presents in males in the newborn period withacute hyperammonemia, feeding problems, vomiting, respira-tory distress, convulsions, coma, and death. Male patientswith later onset, from 15 months to 5 years, present withheadache, vomiting, lethargy, hyperventilation, episodes ofabnormal behavior, disorientation, confusion, ataxia, hypoto-nia, and rarely focal neurologic signs. Associated CNS dam-age is probably related to accumulation of glutamine, andcystic changes with degenerated neurons and eosinophilicgranular material may be seen in the CNS at autopsy. Olderpatients often voluntarily avoid high protein foods and adopt avegetarian diet. Adults may occasionally present with psychi-atric symptoms initially, with hallucinations, agitation, anddelirium [51]. Females heterogeneous for the defect havemilder symptoms, and usually only become symptomatic inassociation with a very high protein intake, intercurrent infec-tion, trauma, anesthesia, surgery, childbirth, and post-partumpsychosis [48, 49, 53]. A chronic low protein diet can result in

normal weight and linear growth. Nitrogen-scavenger therapywith phenylbutyrate can result in low levels of branched-chainamino acids, requiring patients to be monitored for amino aciddeficiencies [54].

Citrullinemia

Deficiency of argininosuccinate synthetase results incitrullinemia, an autosomal recessive disorder. Psychosismay be the first manifestation of citrullinemia, leading to di-agnostic confusion with schizophrenia for many years [55].Additional symptoms of memory loss, drowsiness, liver dys-function, and hyperactivity increase suspicion of a metabolicdisorder, and elevated ammonia and citrulline levels indicatethe high likelihood of a urea cycle defect. Nocturnal delirium,aggression, irritability, hyperactivity, restlessness, delusionalthinking, disorientation, memory loss, drowsiness, seizures,and coma are also consistent with citrul l inemia.Citrullinemia can be treated with sodium pyruvate and argi-nine, or by liver transplant [55].

Lysosomal Storage Diseases

Lysosomes are membrane-bound intracytoplasmic bodieswhich contain hydrolytic enzymes, store material to be metab-olized, and sequester material that cannot be adequatelydigested [56]. There are at least 50 known lysosomal storagedisorders, with an overall frequency of 1:5000 live births.Genes associated with lysosomal storage disorders code forlysosomal enzymes and lysosomal membrane proteins [57].Most lysosomal storage disorders are autosomal recessive anda few are X-linked. Those with severe systemic features typ-ically present in the first years of life, and less severe present inlater childhood, adolescence, or adulthood. Psychiatric symp-toms are usually associated with later presentation, and caninclude depression or mania, psychosis with hallucinations orparanoia, or aggressive behavior [58]. Dementia is common inthe late stages of lysosomal disorders [].

Metachromatic Leukodystrophy

Metachromatic leukodystrophy (MLD) is an autosomal reces-sive disorder related to deficiency of arylsulfatase A. It occursrarely in the general population (1/40000–1/130000 livebirths), but more frequently in Western Navaho Nation(1/2520 live births) [57, 59]. Deficiency of arylsulfatase Aresults in sulfatide accumulation in lysosomes in the centraland peripheral nervous system, which can be seen microscop-ically as metachromatic staining in myelin sheaths. The term“metachromatic” refers to variable staining of the sulfatidecontaining lysosomes. Sulfatide accumulation leads to demy-elination of axons and peripheral nerves, leaving cell bodies

1650 SN Compr. Clin. Med. (2020) 2:1646–1660

Table1

Sum

maryof

pattern

ofinheritance,frequency,chromosom

allocatio

nof

genetic

defect,disorderedmetabolism,typicalageof

onset,psychiatricandsystem

icsymptom

s,andavailabletreatm

ent

ofinborn

errorsdescribed

Disorder

Genetics

Frequency

Chrom

osom

eMetabolicdefect

Age

onset

Symptom

sTreatment

Acuteinterm

ittent

porphyria

AD

1–2/10000

11q23

Porphobilinogendeam

inase

defectleadsto

porphobilin

ogen

and

α-aminolevulinicacid

inurine

Lateadolescence

Abdom

inalpain,

anxiety,neuropathy

Hem

in,hem

atin;

psychotropic

medications

may

precipitatesymptom

s

Wilson’sdisease

AR

1/20000–1/100000

13q14.3

P-typeATP7

Bdefectleadsto

accumulationof

copper

intissue,

firstliver,thenCNS;later

liver

failu

re,psychosis,coagulopathy

8–20

years

Psychosis,liver

failu

reChelatin

gagentsfirst,

then

liver

transplant

Ureacycledefects

AR

1/8000–1/35000

Abnormallevelsof

differentamino

acids:glutam

ine,alanine,citrullin

e,arginine,argininosuccinate,

ornithine,homocitrullin

e

Mostafternewborn

period

Phenotypicspectrum

;may

resemble

prim

arypsychotic

disorder

ordrug

abuse

Low

-protein

diet

Ornith

ine

transcarbamylase

deficiency

(OCT)

XR

Xp21.1

Deficiencyof

ornithine

transcarbamylase

New

born

males

but

laterin

females

oroldermales

HighNH3,seizures,

vomiting

Low

-protein

diet,

phenylbutyrateand

monito

rforam

inoacid

deficiencies

Citrullin

emia

AR

Infant

9q34

Adult7q2

Deficiencyof

argininosuccinate

synthetase

Deficiencyof

citrin

Infant:T

ype1

Adult:

Type2

Presentswith

psychosis

inadultslik

eschizophrenia

Sodium

pyruvateand

arginine;liver

transplant

Phenylketonuria(PKU)

AR

1/12000carrier1:55

12q22

Increasedphenylalaninedueto

defect

inphenylalaninehydroxylase

New

born

Severemental

retardationseizures

eczemabehavior

problems

Phenylalanine

free

diet,

sapropterin,vitamin

supplements

Hom

ocystin

uria

AR

21q22.3

Cystathionine

β-synthetase

Adolescent

Psychosis

Increaseddietary

pyridoxine

Cobalam

in(B12):

cobalamin

Cdefect

(MMACHC)

AR

1p23.2

Accum

ulatemethylm

alonicacid

and

homocysteinein

urineandblood

Varies

Psychiatricsymptom

sin

olderchild

including

psychosis

Methylene

tetrahydrofolate

reductasedeficiency

(MTHFR

)

AR

1p36.22and

14q23.3

Failu

reof

remethylatio

nfrom

absence

ofmethylg

roup

providingenzyme

substrate

Varies

Mim

icsfolate

deficiency,large

varietyof

disorders

with

nospecific

psychiatricsymptom

s

Betaine

avoidfolate

cobalamin

ineffective

Tay-Sachs

disease

AR

1/200000,1:250

carrierin

general,

1:27

inAskenazi

Jews

15q23

β-G

alactosidase

deficiency

leadsto

storageof

GM2ganglio

side

inneuronsasmem

branouscytoplasmic

bodies

Infant (4–6

months)

Lateonset

(adolescento

radult)

Infants:rapiddecline,

hypotonia,weakness,

loss

ofmilestones,

cherry

redspot

inmacula

Lateonset:psychosis

Supportiv

eSo

mebenefitfrom

bone

marrowtransplant

and

enzymereplacem

ent

Gaucher’sdisease

AR

Carrier

1/100

1q22

Deficiencyin

glucocerebrosidase

and

storageof

glycolipid

Psychiatricsymptom

sin

type

3

1651SN Compr. Clin. Med. (2020) 2:1646–1660

Tab

le1

(contin

ued)

Disorder

Genetics

Frequency

Chrom

osom

eMetabolicdefect

Age

onset

Symptom

sTreatment

Neuronalceroid

lipofuscinosis

Usually

AR,few

adulto

nsetAD

1/25000inUSA

and

Scandinavia

1/100000

worldwide

1p34 15

q23;

160

mutations

in8genes

Accum

ulationof

ceroid

lipopigments,

notspecificbutm

arkerof

abnorm

alcellmetabolism

Classifiedby

ageof

onset

Blin

dnessinfants,

psychiatricsymptom

sin

75%

olderpatients

Intraventricular

cerliponasealfa

for

CLN2

Fabry’sdisease

XR

1/40000–1/60000

males

About

600

mutations

reported

Deficiencyof

α-galactosidase

AMultip

leorgans,pain,

risk

ofsuicide,

psychosis;symptom

sin

carriers

Enzym

ereplacem

entw

ithagalsidase

alfa;o

rMigalastat

“chaperone”forsome

variants

Metachrom

atic

Leukodystrophy

AR

1/40000–1/130000;

1/2520

inwestern

Navajo

22q13

Arylsulfatase

deficiency,accum

ulation

ofsulfatideinlysosomes

inCNSand

PNS

Onsetrelatedto

degree

ofdeficiency

Behaviorandcognitive

problemsearlier;

psychosis,catatonia

inolder

Earlycord

bloodstem

cell

transplant

Hurler

MPS

IAR

1/100000

4p16.3

Deficiencyα-L-iduronidase;

accumulationderm

atan

andheparan

sulfate

Abnormalfacial,

skeletalstructure;

anxiety,learning

problems

Laronidaseenzyme

replacem

ent

HunterMPSII

XR

1/111000

males

Xq27

Deficiencyof

iduronate-2-sulfatase

Languagedelay,

ADHD,seizures

Idursulfaseenzyme

replacem

ent

SanfilippoMPS

III

AR

0.28–4.1/100,000

12q14

4typeswith

defectin

catabolism

ofheparinsulfate

Disruptivebehavior,

disordered

sleep,

psychiatricproblems

after10

yearsold

Niemann-Pick

disease

AR

1/100000

TypeC1:

18q11;

TypeC2:

14q24

TypeC1:largemem

braneglycoprotein

TypeC2:

smallm

embrane

glycoprotein

Errorsin

cellu

lartraffickingof

cholesterol

Progressivefatal

neonataltype

toadulto

nset

neurodegenera-

tion

Cognitiv

edeclineto

dementia,psychosis,

ADHD,depression,

aggressive

and

disorganized

behavior

Adrenoleukodystrophy

(ALD)

XR

1/8000–1/20000

males

Xq21

Peroxisomaldisorder

with

defective

VLCFA

synthetase,decreased

beta

oxidation,andincreasedVLCFA

2–10

yearsmost

common

ADHD,abnormal

behavior,neurologic

symptom

s;psychiatricsymptom

swith

adolescent

onset;may

present

with

psychosisor

mania

“Lorenzo’soil”and

decreaseddietaryfat

may

slow

deterioration

ifgivenearly;

neurolepticsmay

cause

severe

dystonicside

effects;bone

marrow

transplant;g

ene

therapypossible

MELAS:

mito

chondrial

encephalopathy,

lacticacidosis,and

stroke-likeepisodes

Polygenicmutations

inmaternal

mito

chondriaDNA

Childhood

tolate

adolescence

Seizures,diabetes,

depression,psychosis

1652 SN Compr. Clin. Med. (2020) 2:1646–1660

unaffected. Age of presentation is related to the degree ofenzyme deficiency. The infantile form presents by 30 months,and the juvenile form presents with behavioral and cognitiveproblems between 3 and 16 years and occasionally in patientsolder than 16 years [60].

Psychiatric symptoms can be the first signs of the diseaseand are a prominent feature of the disorder, often leadingpatients to be initially diagnosed with schizophrenia. Morethan half of patients diagnosed from late childhood to earlyadulthood present with psychosis, complex auditory halluci-nations, bizarre delusions, catatonic posturing, personalitychanges, disinhibition, and behavioral disorganization [61].

MRI in metachromatic leukodystrophy shows characteris-tic white matter demyelination extending from periventricularareas in the cerebrum and white matter loss in the cerebellum.Psychotic symptoms are related to demyelination ofsubfrontal white matter and disruption of corticocortical andcorticosubcortical connections [61]. The degree of demyelin-ation correlates with motor and cognitive symptoms, and thecentral demyelination at onset of symptoms can predict dis-ease progression [62].

Newborn screening is not yet available for MLD. Cordblood stem cell transplant may improve the course and slowthe progression of MLD, and transplant would have the mostbenefit if done before symptoms occur [63]. It is still better totransplant before symptoms are advanced since it takes 6 to12 months after transplant for the donor cells to be effective[60]. Although children with MLD have a significantly betteroutcome after transplant, they will still need support servicesin school and long-term follow-up [64].

Tay-Sachs Disease

Tay-Sachs disease is one of the disorders characterized asamaurotic familial idiocy when first described over a centuryago. Tay-Sachs disease is seen in 1/200000 live births. Thecarrier rate is markedly increased to 1/27 in a few groupsincluding Ashkenazi Jews of eastern European descent, non-Jewish French-Canadians from eastern Quebec, and Cajunfamilies in southwest Louisiana [65]. The carrier rate is1/250 for the general population, including Sephardic Jewsof North African or Middle Eastern origin. Tay-Sachs diseaseis an autosomal recessive disorder caused by a deficiency ofβ-hexosaminidase A which leads to ganglioside GM2 accu-mulation in neurons [66]. GM2 forms characteristic membra-nous cytoplasmic bodies when seen by electron microscopy,which can be observed first in fetal spinal cord, then cerebel-lum, and then cerebrum [67].

There are three clinical variants of Tay-Sachs disease dif-ferentiated by age of onset. The infantile variant is the mostcommon, and presents before 6 months with developmentalarrest, hypotonia, startling, and a typical cherry red spot in themacula. It is associated with rapid neurologic deterioration

and death before 5 years. The subacute variant typically pre-sents at about 5 years and is associated with a more protractedcourse, leading to a chronic vegetative state and death by thesecond decade. The late onset variant is characterized by awide spectrum of symptoms and a protracted course with pro-gressive neurologic deterioration, psychosis, catatonia, andmood symptoms in adolescence and thereafter [68].

Management of Tay-Sachs disease is essentially support-ive, although bone marrow transplant and enzyme replace-ment therapy have been done with some benefit. Gene therapyusing viral vectors is under investigation [66].

Niemann-Pick Disease

Niemann-Pick disease type C is an autosomal recessivelipidosis that results from an error in cellular trafficking ofexogenous cholesterol, which leads to the lysosomal accumu-lation of unesterified cholesterol. It occurs in 1/100000 livebirths and presents with significant phenotypic heterogeneity,even in twins. There is a broad spectrum of presentation ofNiemann-Pick disease from rapidly progressive, fatal neonataltype, to adult onset type with a chronic, neurodegenerativecourse [69].

Niemann-Pick disease type C1 is found in 95% of patients.Its gene has been mapped to chromosome 18q11 and codesfor a large membrane glycoprotein. The defect in Niemann-Pick type C2 has been mapped to 14q24.3 and instead codesfor a small soluble lysosomal protein [70].

Progressive cognitive decline appears to be inevitable inpatients with Niemann-Pick type C disease and ranges fromsubtle impairment in executive function to profound dementiawith apathy and mutism. Younger patients have school andbehavior problems, agitation, hyperactivity, sleep disorders,and depression. Almost half of all patients present with psy-chiatric problems including acute psychosis, paranoid delu-sions, hallucinations, disorganized behavior, aggressiveness,self-mutilation, major depressive episodes, bipolar disorder,and obsessive-compulsive disorder. Neurologic symptomsmay be absent when the patient is psychotic [71].

Gaucher Disease

Gaucher disease is a lysosomal glycolipid storage disorderdue to glucocerebrosidase deficiency. Glucocerebroside is abreakdown product of membrane glycosphingolipids, and itaccumulates in the reticuloendothelial system, whileglucosylceramide accumulates in the spleen, liver, and bonemarrow [72].

Gaucher disease is relatively common, and carriers arefound in 1:100 in the general population, and in 1:15Ashkenazi Jews. Type I is the most common form ofGaucher disease, and it is not associated with CNS involve-ment. Type 2 is the acute neuronopathic form which has an

1653SN Compr. Clin. Med. (2020) 2:1646–1660

early onset in infancy with severe CNS involvement, andleads to death by 2 years. Type 3 is primarily associated withvisceral involvement and has a later onset of cognitive prob-lems, mood, anxiety, and psychotic symptoms. Neurologicsymptoms including myoclonus, ataxia, seizures, and demen-tia have also been reported [72].

Neuronal Ceroid Lipofuscinoses

Neuronal ceroid lipofuscinoses (CLN) were previously char-acterized as Batten disease. The name neuronal ceroidlipofuscinoses refers to lysosomal autofluorescentlipopigments which can be seen microscopically in the brainand other tissue. This is a heterogeneous group of more than160 mutations in one of 14 genes that can result in this neu-rodegenerative disorder [73]. Most are autosomal recessive,but autosomal dominant forms also occur. They differ in theage of onset and appearance of the stored material on electronmicroscopy [74].

These are progressive neurodegenerative disorders whichmay initially present with psychiatric symptoms. CLN occur1:25000 in the USA and Scandinavia, and 1:100000 livebirths worldwide [73]. Patients are clinically classified intofour major groups by age. The juvenile form is the most com-mon, with onset between 4 and 10 years, and patients areusually diagnosed in childhood when prominent neurodegen-erative symptoms become apparent. Course is variable andloss of vision is characteristic. Visual loss is associated withseizures, motor and cognitive deterioration, behavioral disor-ganization, and psychiatric symptoms. Patients are usuallyinitially calm, but then become increasingly irritable; developsleeping problems, aggressiveness, restlessness, anxiety, rapidmood changes, and psychosis with visual hallucinations anddelusions; progressing to dementia and death usually in thethird or fourth decade. Adult onset patients lack visual prob-lems but have psychiatric symptoms, seizures, and motor ab-normalities [74].

The enzyme abnormality has been identified in some casesof CLN. Disease-specific treatment with enzyme replacementtherapy is only available for CLN2 with cerliponase alfa. Ithas been approved in the USA, and it is administered via animplanted intraventricular device. Long-term efficacy has yetto be determined [56].

Fabry Disease

Fabry disease is an X-linked recessive disorder ofglycosphingolipid catabolism which results from the deficien-cy of the lysosomal hydrolase, α-galactosidase A. It occurs in1:3100 to 1:117000 live male births. Female carriers are alsousually symptomatic [56]. Fabry’s disease is associated withsevere pain and paresthesias in the extremities, which increasethe risk for major depression, addiction, and suicide. Severe

ocular and skin problems, episodic abdominal pain and diar-rhea, and progressive renal and cardiac failure occur. Fabrydisease may also present with acute psychotic symptoms, de-lusions, and auditory hallucinations, and resemble a formalthought disorder [75]. Enzyme replacement therapy is avail-able with agalsidase alfa which has been shown to be effectiveand safe [76]. It is recommended to start enzyme replacementtherapy once a patient becomes symptomatic, regardless ofage [56]. Migalastat is a pharmacological chaperone that sta-bilizes and facilitates trafficking of α-galactosidase A enzymefrom endoplasmic reticulum to lysosomes and increases lyso-somal activity. It is given orally in adults with Fabry disease[77].

Mucopolysaccharidoses

Mucopolysaccharidoses (MPS) are genetic disorders causedby a deficient activity of one of the lysosomal enzymes neededto break down glycosaminoglycans, which are long un-branched polysaccharides consisting of repeating disaccha-rides [78]. Glycosaminoglycans (GAGs) then accumulate invarious tissues and result in a multisystem clinical presenta-tion and a cascade of interrelated metabolic, inflammatory,and immunologic responses [79]. Mucopolysaccharidosesare mostly autosomal recessive and a few are X-linked reces-sive disorders. There are 11 known enzyme deficienciesresulting in 7 distinct forms of MPS, with a collective inci-dence of 1:25000 live births [78].

Infants are usually normal at birth, and the diagnosis of amucopolysaccharidosis is suspected as the phenotype evolvesover time. The classic presentation occurs in the preschool-aged child with developmental delay, short stature, recurrentear and respiratory infections, hepatosplenomegaly, andcoarsening facial features, then multiorgan involvement withadditional clinical features evolves over time [56]. Themucopolysaccharidoses are chronic disorders which presentafter infancy as either severe bone dysplasia or dysmorphicfeatures with learning difficulties, behavior problems, andeventual cognitive decline. They are occasionally associatedwith other psychiatric symptoms, including sleep and behav-ior problems, autistic symptoms, and hyperactivity [78, 80].Psychosis occurs with adult onset forms in a variety ofmucopolysaccharidoses [].

Early diagnosis and intervention improve outcome, whichhas led to newborn screening, so far only for MPS I.Combined multiple assay of GAGs for screening is underdevelopment []. Enzyme replacement therapy is available forMPS I, MPS II, MPS IV, MPS VI, and MPS VII. Diagnosisprenatally or in the perinatal period allows for treatment beforethe onset of clinical symptoms. The beneficial effects of en-zyme replacement are soon lost if treatment is discontinued,

1654 SN Compr. Clin. Med. (2020) 2:1646–1660

and stopping replacement leads to significant worsening of thepatient’s clinical status and increased risk of death [81].

Hurler (MPS I)

Mucopolysaccharidosis I (Hurler disease, MPS I) is related toa deficiency of α-1-iduronidase which leads to accumulationof dermatan sulfate and heparan sulfate. MPS I typically pre-sents with dysmorphic facial features and skeletal deformities,and anxiety, learning problems, and restlessness are noted at ayoung age. Treatment with laronidase before 5 years can leadto symptomatic improvement. Untreated, patients with severeMPS I usually die before 10 years old from cardiac and respi-ratory disease [81].

Hunter (MPS II)

Mucopolysaccharidosis II (Hunter disease, MPS II) is themost common of the mucopolysaccharidoses. It is related toa deficiency of iduronate sulfatase, and results in the decreasedbreakdown of dermatan sulfate and heparan sulfate. Hunterdisease is the only mucopolysaccharidosis that is X-linked,with an incidence 1:111000 male births. Symptomatic femalecarriers are very rare. MPS II is associated with dysmorphicfeatures, hyperactivity, delayed language, seizures, fearful-ness, and neurodegeneration. Treatment with idursulfase be-fore age 5 years is effective in improving clinical status [81].

Sanfilippo (MPS III)

Mucopolysaccharidosis III (Sanfilippo syndrome, MPS III)is found in 0.28 to 4.1 per 100,000 births. It results from adeficiency in one of the four enzymes needed to breakdown heparan sulfate, which is found in the extracellularmatrix and cell surface glycoproteins. Heparan sulfate thenaccumulates and can be found in urine. This disorder pri-marily affects the nervous system, and presents early withdevelopmental and speech delay, progressing to severe dis-ruptive behavior, hyperactivity, and profound sleep prob-lems by 3 to 4 years. After age 10, neurologic and psychi-atric problems develop, with hyperactivity, chaotic behav-ior, aggression, restlessness, biting/mouthing, autistic be-haviors, and hypersensitivity [80]. Loss of skills continueswith slow deterioration into a vegetative state, usuallyleading to death in the third decade [82].

Peroxisomal Disorders

Adrenoleukodystrophy

Peroxisomes are small intracytoplasmic membrane-boundorganelles which contain catalase and oxidases. X-linked

adrenoleukodystrophy (ALD) is a peroxisomal disorderthat is found in all ethnicities with an overall incidenceof 1:18000 to 1:20000 male births in the USA [83, 84].ALD is caused by mutations in the ABCD1 gene whichleads to the accumulation of very-long-chain fatty acids(VLCFAs) in plasma and tissue [85]. The defect in X-linked ALD codes for a peroxisomal membrane protein[86].

VLCFAs are a major component of CNS membranesand can be toxic when not effectively metabolized. Theaccumulation of VLCFA leads to degenerative changesand cerebral demyelination, loss of axons, and myelin inlong tracts of the spinal cord, and an inflammatory reac-tion in white matter. “Lorenzo’s oil,” a 4:1 mixture ofglyceryl trioleate and glyceryl trierucate, may have someeffect in delaying symptoms of the disease when given inasymptomatic patients. When combined with at leastmoderate reduction of dietary fat, it may normalize orsignificantly lower plasma VLCFA within 4 weeks, butbenefits do not last and the clinical efficacy for Lorenzo’soil remains controversial [87].

The most common age of onset of cerebral ALD is 2 to10 years with rapidly progressive neurodegeneration andcerebral and spinal cord demyelination. One-third of boyswith ALD will develop small inflammatory brain lesionsthat insidiously grow before symptoms manifest [88].Attention-deficit hyperactivity symptoms and other be-havior changes occur early, and are followed by progres-sive cognitive and neurologic deficits, clumsiness, visualdisturbances, seizures, and adrenal dysfunction, then neu-rologic deterioration leads to a vegetative state and deathsoon after [89].

There can be extreme variability in presentation ofALD, and onset and symptoms may differ in membersof the same family, even between twins. ALD may beless severe when it first presents in adolescence (10%patients) with adrenal insufficiency, neurologic dysfunc-tion, and psychiatric symptoms. The adult form of ALDmay present with adrenomyeloneuropathy and slowly pro-gressive spinal disease (25%), at a slightly older age in anolivo-ponto-cerebellar form (8%), or in still older maleswho had unrecognized symptoms earlier and then presentin an adult cerebral form (21%) with gonadal insufficien-cy, cognitive decline, and neurologic and psychiatricsymptoms. ALD may rarely present with adrenal symp-toms alone [89], and the lifetime prevalence of adrenalsymptoms in ALD is about 80%, which warrants regularadrenal assessment in ALD patients [90].

Female carriers of ALD are typically asymptomatic un-til over 30 years of age, and half have symptoms after age40 years, usually with mild myelopathy, increased deeptendon reflexes, and sensory changes in their legs [5, 91].Many symptomatic females are initially diagnosed with

1655SN Compr. Clin. Med. (2020) 2:1646–1660

multiple sclerosis until diagnosis is made in a male in thefamily [92]. A milder and later onset adrenomyeloneuropathyis described in a minority of carriers. Cerebral involvementcan rarely occur in carriers in middle age or later, and clinicaladrenal insufficiency and psychosis are very rare in carriers ofany age [5, 83].

Approximately 40% patients present with psychiatricsymptoms and 20% present with a psychiatric problemexclusively, resembling bipolar disorder or schizophrenia[93].

Psychiatric symptoms with psychosis resemblingschizophrenia may be found in up to 25% of adolescentsand adults with ALD. The diagnosis of ALD becomesmore likely when psychosis is associated with cognitiveimpairment, visual hallucinations, and resistance to anti-psychotic treatment. Catatonia, depression, mania, andobsessive-compulsive disorder are also reported, and cat-aplexy triggered by emotions may rarely occur [91].

Patients with ALD may not respond to antipsychoticsin expected ways, and they may be particularly vulnerableto adverse side effects which may worsen the disease pro-cess. Dystonic side effects from neuroleptics may worsenfunctional impairment by adding rigidity and bradykinesiato spasticity seen with ALD. Akathisia is especially

troublesome if the ALD patient cannot move. Atypicalantipsychotics are generally preferred, but anticholinergicside effects may exacerbate cognitive impairment, dys-phagia from dryness, and hypotension. Manic symptomsare frequent with ALD, and mood stabilizers can be help-ful, although lithium may be a problem because of ALDcan potentially be associated with electrolyte abnormali-ties from adrenal involvement. Benzodiazepines may helpspasticity and agitation with mania but may worsen ataxia[94].

Bone marrow or cord blood stem cell transplant can haltthe progression of ADL and currently offer the best out-come for patients with ALD [88]. Patients younger than4 years with no or only mild gross motor defects and min-imal if any MRI changes when transplanted are likely tohave the most benefit and the mildest course [95]. Patientswith larger cerebral lesions at the time of transplant haveworse clinical outcomes [96], and nontransplanted patientsare most likely to die of disease progression [95]. Genetherapy for ADL using elivaldogene tavalentivec viral vec-tor may provide an alternative to bone marrow transplant[97]. Ultimately, newborn screening for ADL will allowfor early diagnosis and intervention and yield the bestprognosis [98] (Table 2).

Table 2 Checklist of psychiatric symptoms associated with inborn errors

Psychosis Depression Agitation Mania Anxiety Obsessive-compulsivebehavior

Inattention Hyperactivity Disorganizedbehavior,confusion

Autisticbehavior

Porphyria X X X X X X

Wilson’s X X X X X

Phenylketonuria X X X

Homocysteinemia X X X X

MTHFR X

Cobalamin C X X

Urea cycle defects X X X

OCT deficiency X X X

Citrullinemia X X X

Tay-Sachs disease,adult

X X

Niemann-Pick C X X X X X

Gaucher’s disease X X

Neuronal ceroidlipofuscinosis

X X X X

Fabry’s disease X

Metachromaticleukodystrophy

X X

MPS I X

MPS II X

MPS III X X X

Adrenoleukodystrophy X X X X X X X

MELAS X X X X

1656 SN Compr. Clin. Med. (2020) 2:1646–1660

Mitochondrial Disorders

Mitochondrial Encephalopathy, Lactic Acidosis, andStroke-Like Episodes

Mitochondrial encephalopathy, lactic acidosis, and stroke-likeepisodes (MELAS) is a progressive neurodegenerative disor-der associated with polygenetic, maternally inherited mito-chondrial DNA mutations [99]. MELAS usually presents inchildhood and late adolescence, between 2 and 20 years in70% of patients. MELAS is characterized by seizures, enceph-alopathy, stroke, short stature, cognitive impairment, mi-graines, depression, cardiomyopathy, cardiac conduction de-fects, and diabetes mellitus [100]. The stroke-like lesions aretypically in the posterior of the brain, and focal cerebellarinfarction can be the initial sign of MELAS [101].Psychiatric features may predate the diagnosis of MELASand include depressed mood, anxiety, psychosis, cognitivedecline, behavioral disturbance, and aggression [105].Course and prognosis are variable, but progressive cognitive

decline typically leads to dementia, increasing disability, andpremature death [99].

Conclusion

While cognitive problems are probably the most commonneuropsychiatric symptoms overall, symptoms of psychosis,attention problems, anxiety, mood disturbance, confusion, anddisorganized behavior can be seen with multiple IEMs, espe-cially those affecting the central nervous system. It is impor-tant for physicians to be aware that genetic disorders maypresent with only psychiatric symptoms or with systemicsymptoms in addition. The definitive diagnosis of an IEMcan only be made when the physician’s suspicions lead tofurther investigation [3].

Consultation with a specialist is recommended when a pa-tient presents with psychiatric symptoms and an inborn errorof metabolism is suspected.

Psychosis

Neuronal Ceroid Lipofuscinosis (AR, AD)

Metachroma�c leukodystrophy (AR, few AD)

Fabry’s Disease (XR)

Homocysteinemia Cobalamin disorders

MTHFR

Homocys�nuria (AR)

Lysosomaldisorders

Niemann-Pick Type C (AR)

Adrenoleuko-dystrophy (XR)

Citrullinemia (AR)

Porphyria (AD)

Wilson’s Disease (AR)

Late onsetTay-Sachs (AR)

Late onset Gaucher’s (AR)

OCT deficiency (XR)

Urea Cycle Defects:Increased serum ammonia

Variable presenta�on within same family

Liver dysfunc�on,abnormal MRI

Abdominal pain, Red-brown urine

2 forms

Stored material in mul�ple �ssues

Severe extremity pain

Megaloblas�c anemia

Decision tree to facilitate differential diagnosis of psychosis occurring in association with inborn errors of metabolism

1657SN Compr. Clin. Med. (2020) 2:1646–1660

Compliance with Ethical Standards

Conflict of Interest The authors declare that they have no conflicts ofinterest.

Ethical Statement This manuscript is based on literature review.

Ethical Approval Patient charts were not reviewed. This article does notcontain any data from a new study with human participants performed byany of the authors. Institutional ReviewBoard clearance was not required.

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