MCAD Deficiency Health Article

Definition

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is a rare genetic disorder characterized by a deficiency of the MCAD enzyme. This enzyme is responsible for the breakdown of certain fatty acids into chemical forms that are useable by the human body. MCAD deficiency accounts for approximately one to three of every 100 cases of sudden infant death syndrome (SIDS). MCAD deficiency is transmitted through a nonsex linked (autosomal) recessive trait. The first recognized cases of MCAD deficiency were reported in 1982.

Description

Medium chain acyl-CoA dehydrogenase (MCAD) is one of four enzymes in the mitochondria of the cells that is responsible for the breakdown of medium chain fatty acids into acetyl-CoA. Medium chain fatty acids are defined as fatty acids containing between four and 14 carbon atoms. Acetyl-CoA, the desired product of the breakdown of these fatty acids, is a two-carbon molecule. MCAD is the enzyme responsible for the breakdown of straight-chain fatty acids with four to 14 carbons. There are two other enzymes that are responsible for the breakdown of short straight-chain chain (less than four carbons) fatty acids, and long straight-chain (more than 14 carbons) fatty acids. These other two enzymes are not able to take over the function of MCAD when MCAD is deficient.

Individuals affected with MCAD deficiency produce a form of the MCAD enzyme that is not nearly as efficient as the normal form of MCAD. This lack of efficiency results in a greatly diminished, but still functional, capability to break down medium chain fatty acids.

Genetic profile

The gene that is responsible for the production of MCAD is located on chromosome 1 at 1p31. Twenty-six different mutations of this gene have been identified as causing MCAD deficiency; however, 95–98% of all cases are the result of a single point mutation. In this mutation, adenosine is substituted for guanine in base 985 (G985A), which causes a substitution of lysine (AAA) by glutamic acid (GAA) in residue 329 of the MCAD protein.

MCAD deficiency is a recessive disorder. This means that in order for a person to be affected with MCAD deficiency, he or she must carry two abnormal copies of the MCAD gene. In a population of individuals known to be affected with the G985A mutation, 81% were found to be homozygous for this mutation (two chromosomes, each with the same mutation). The remaining 19% were found to be heterozygous for the G985A mutation (only one chromosome carried the G985A mutation), but their other chromosomes carried one of the other MCAD gene mutations.

Demographics

MCAD deficiency is estimated to occur in approximately one out of every 13,000 to 20,000 live births. This estimate is confounded to a certain degree by the fact that up to 25% of all individuals affected with MCAD deficiency die the first time they exhibit any symptoms of the disease. Many of these children are often misdiagnosed with either sudden infant death syndrome (SIDS) or Reye syndrome. Unless an autopsy is performed, MCAD generally goes undetected in these individuals; and, even then, unless the physician performing the autopsy is familiar with MCAD deficiency, the cause of death may still be misreported.

MCAD deficiency is seen almost exclusively in Caucasians of Northern European descent (this includes people from every European country not bordering the Mediterranean Sea). Approximately 80% of the Caucasian population of the United States can be considered to be a part of this subpopulation. In this subpopulation, it is estimated that one in every 40 to 100 people is a carrier of the G985A mutation, and one in every 6,500 to 20,000 people is homozygous in this mutation. Homozygous individuals (carriers of two sets of the G985A mutation) should be affected with MCAD deficiency; however, the incidence rate of MCAD deficiency is lower than that predicted from the carrier populations. There are two possible reasons for the lower number of observed cases of MCAD deficiency than the carrier data suggests should occur. First, many individuals with MCAD deficiency may be misdiagnosed. Secondly,

there may be a significant number of homozygous people who for unknown reasons remain unaffected (asymptomatic).

As a comparison, one in every 29 Caucasians is a carrier for cystic fibrosis, but only one in every 3,300 people in this subpopulation develop the disease.

The high frequency of a single mutation leading to MCAD deficiency, combined with the extreme similarity of the other known mutations to this mutation, and the high concentration of MCAD deficiency within a single subpopulation, suggests a founder effect from a single person in a Germanic tribe.

Because MCAD deficiency is a recessive disease, both parents must be carriers of this trait in order for their children to be affected. If both parents carry a copy of the mutated gene, there is a 25% likelihood that their child will be homozygous for MCAD deficiency. Genetically, the probability that an affected person will have a sibling who is also affected is also 25%. In population studies of known MCAD deficient individuals, it has been observed that an average of 32% of these individuals have at least one sibling either known to be affected with MCAD deficiency or to have died with a misdiagnosis of SIDS.