Medium Chain Acyl-Coenzyme A Dehdrogenase

( MCAD ) Deficiency

Done by: Dina

Introduction:

Medium-chain acyl-coenzyme A dehydrogenase deficiency is the most common a fatty acid oxidation disorder associated with inborn errors of metabolism. It is due to defects in the enzyme complex known as medium-chain acyl dehydrogenase (MCAD) and reduced activity of this complex. MCAD is an enzyme found in the mitochondria that is responsible for the metabolism of medium chain fatty acids. When this enzyme is missing, the body is unable to convert these fatty acids to energy during times of decreased food intake. (1, 4)

It is recognized as one of the more rare causes of sudden infant death syndrome (SIDS), although it may be better described as a mimic, rather than a cause, of SIDS

Overview:

Two main types of fat are found in the body: triglycerides and waxes.

A triglyceride consists of a three-carbon compound known as glycerol to which three fatty acids (carboxylic acids) are attached by ester bonds. The length of the fatty acids chains can vary; they may be classified as very long-chain, long-chain, medium-chain or short-chain depending on the number of carbon atoms in the chain.

The fatty acids are broken down in stages by the successive removal of molecules of acetyl-coenzyme A, which contains 2 carbon atoms. Ultimately, under normal conditions, the fatty acids are converted into carbon dioxide and water with the liberation of energy during this process. Once a fatty acid molecule is "activated" (attached to coenzyme A), a series of four reactions, each catalyzed by a different enzyme, is required to remove each acetyl-coenzyme A molecule. As the first step involves removal of hydrogen atoms (i.e. an oxidation) from an acyl group, the enzyme complex is known as an acyl dehydrogenase. Different enzymes are required to hold fatty acids of different lengths, and the deficiencies connected with these various proteins are:

Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCAD deficiency)

Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCAD deficiency)

Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCAD deficiency)

Short-chain acyl-coenzyme A dehydrogenase deficiency (SCAD deficiency)

3-hydroxyacyl-coenzyme A dehydrogenase deficiency (M/SCHAD deficiency) (1)

Frequency:

United States approximately 1 in every 8500 live births.

International

The average incidence rate among more than 8 million babies was 1 per 14,600 live births, with a range of 1 per 13,500 to 1 per 15,900.(2)

Symptoms:

Clinical presentation is often triggered by a seemingly innocuous illness (like otitis media). The initiating event is probably due to prolonged fasting, which may lead to vomiting, lethargy, coma, cardiopulmonary arrest, or sudden unexplained death. Symptoms often precede the onset of profound hypoglycemia and are probably related to high free fatty acid levels. Hypoglycemia occurs from an inability to meet gluconeogenic requirements during fasting despite activation of an alternate pathway of substrate production, proteolysis. Physical examination of the acutely ill child is remarkable for mild to moderate hepatomegaly. Some patients may also have demonstrable muscle weakness. (3)

Diagnosis:

Initial laboratory examination of blood may reveal hypoglycemia, mild metabolic acidosis, mild lactic acidosis, hyperammonemia, elevated BUN, and high uric acid levels. Liver function studies are also usually elevated. Examination of the urine often shows inappropriately low or absent ketones.

Biochemical testing of blood and urine for carnitine, acylcarnitines, acylglycines, and organic acids is diagnostic for this disorder. Low serum and urine carnitines are consistently found in the untreated patient. A generalized dicarboxylic aciduria is noted characterized by elevation of suberylglycine and hexanoylglycine. Plasma or blood spot acylcarnitine profiles show elevations of medium chain length fatty acid derived acylcarnitines, especially octanoylcarnitine.(3)

The oxidation of fatty acids occurs within mitochondria. Fatty acids from the cytoplasm are attached to a molecule called carnitine to transport them across the mitochondrial membrane. The combination of carnitine with a fatty acid is known as acyl carnitine. In individuals with MCAD deficiency, there is an increase in the concentration of medium-chain acyl carnitines in the cytoplasm of their cells; these acyl carnitines leak into the

blood stream. The presence of these acyl carnitines, especially octanoyl-carnitine, is a major diagnostic characteristic of MCAD deficiency. (1)

Without prior indication of metabolic disease, 20-25 percent of patients with this disease will die with their first episode of illness. Cerebral edema, and fatty liver, heart and kidneys are noted at autopsy, often leading to a misdiagnosis of Reye's syndrome or Sudden Infant Death Syndrome (SIDS). This disorder accounts for about one of 100 SIDS deaths. (3)

Testing should be initiated in individuals with the following indications:

Prenatal diagnosis for carrier couples Carrier screening in families of affected individuals Intermittent hypoglycemia Carnitine deficiency Urinary excretion of medium chain fatty acids and decreased ketones Vomiting, lethargy, and/or coma following fasting

Risk factors include finding fatty infiltration of the liver, family history of sudden death, Reye's Syndrome, myopathy, and decreased caloric intake before death. All siblings of individuals with MCAD should be tested even if they are without symptoms. (4)

Treatment:

Fundamental to the medical management of MCAD is to avoid fasting, particularly during periods of high metabolic stress, such as illness. Overnight fasts should last no longer than twelve hours, and infants should continue to receive nighttime or late evening feedings to reduce this period even further. High carbohydrate intake should be encouraged during illness, with initiation of intravenous glucose supplementation if the child is unsuccessful in keeping down fluids, or unable to take adequate oral feedings. The preventative efficiency of a low fat diet versus a normal fat diet is unclear, but high intake of long and medium chain fatty acids should be avoided.

Supplementation with oral L-carnitine at 100 mg/kg/day has been associated with a reduction in the frequency and severity of episodes in many patients. We recommend that the dose be increased to 200 mg/kg/day during acute illness. The continued need for carnitine supplementation post puberty is uncertain, and has not been adequately studied. The addition of 1-3 tablespoons of food grade cornstarch mixed in liquid at bedtime to some infants has also helped to decrease the frequency of morning hypoglycemia.(3)

References:

(1)Wikipedia.http://en.wikipedia.org/wiki/Medium_chain_acyl_dehydrogenase_deficiency

(2) Emedicine. http://emedicine.medscape.com/article/946755-overview

(3)MCAD: Medium Chain acyl CoA Dehydrogenase - Information for Clinicians

Charles R. Roe, MD. http://www.fodsupport.org/mcad.htm

(4)Public Health and Genetics Information Series.

http://www.hgen.pitt.edu/counseling/public_health/mcad.htm