MCAD deficiency

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 non-sex 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 carbon) fatty acids, and long straight-chain (more than 14 carbon) 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, an adenosine is substituted for a 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 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.

Signs and symptoms

There is no classic set of symptoms that characterize MCAD deficiency. The severity of symptoms observed in individuals affected with MCAD deficiency ranges from no symptoms at all (asymptomatic) to the occurrence of death upon the first onset of symptoms. The first symptoms of MCAD deficiency generally occur within the first three years of life. The average age of onset of the first symptoms is one year of age. Some individuals become symptomatic prior to birth. The onset of symptoms in adults is extremely rare.

Lethargy and persistent vomiting are the most typical symptoms of MCAD deficiency. The first episode of symptoms is generally preceded by a 12 to 16 hour period of stress. Most affected individuals show intermittent periods of low blood sugar (hypoglycemia) and higher than normal amounts of ammonia in the blood (hyperammonemia). An abnormally large liver (hepatomegaly) is also associated with MCAD deficiency.

Approximately half of all individuals showing symptoms of MCAD deficiency for the first time experience respiratory arrest, cardiac arrest, and/or sudden infant death. Between 20% and 25% of all MCAD deficiency affected infants die during their first episodes of symptoms.

Some individuals affected with MCAD deficiency also are affected with a degenerative disease of the brain and central nervous system (encephalopathy). Seizures, coma, and periods of halted breathing (apnea) have also been seen in people with MCAD deficiencies.

Long-term symptoms of MCAD deficiency may include: attention deficit disorder (ADD), cerebral palsy , mental retardation, and/or developmental delays.

The severity of the symptoms associated this MCAD deficiency is linked to the age of the person when the symptoms first happen. The risk of dying from an onset of the disease is slightly higher in individuals who show the first symptoms after the age of one year. The highest risk ages are the ages of 15 to 26 months. Seizures and encephalopathy are most frequently seen in affected individuals between the ages of 12 and 18 months. Seizures at these ages are often associated with future death during a symptomatic episode, recurrent seizures throughout life, the development of cerebral palsy, and/or the development of speech disabilities.

Diagnosis

The Departments of Health in Massachusetts and North Carolina require mandatory newborn screening for MCAD deficiency. California has a voluntary newborn screening policy. Additionally, Neo Gen Screening offers voluntary newborn screening at birthing centers throughout the Northeastern United States. In September 2000, Iowa also began a pilot program to screen all newborns in that state. It is expected that MCAD deficiency screening will become mandatory statewide in Iowa sometime in 2001.

These newborn screening methods employ either a recently developed (1999) tandem mass spectrometry (MS/MS) blood test method or a PCR/FRET analysis. The MS/MS test discovers the presence of the G985A mutation in the MCAD gene by the difference in molecular weight in this gene versus the molecular weight of the normal MCAD gene.

In the PCR/FRET test, a sample of blood is drawn and the DNA is extracted. This DNA is then reproduced multiple times by the polymerase chain reaction (PCR amplification). Once enough sample has been made, the sample is labeled with a fluorescent chemical that binds specifically to the region of chromosome 1 that contains the MCAD gene. How this fluorescent chemical binds to the MCAD gene region containing the G985A mutation allows the identification of homozygous G985A, heterozygous G985A, and normal (no G985A mutations) MCAD genes (FRET analysis).

An older method for the detection of MCAD deficiency is a urine test that checks for elevated levels of the chemicals hexanoylgylcine and phenylpropionylgylcine.

Prenatal testing for MCAD deficiency is also available using a test similar to the PCR/FRET blood test. In this case, however, the DNA to be studied is extracted from the amniotic fluid rather than from blood. Another prenatal test involves studying the ability of cultured amniotic cells to breakdown added octanoate, an 8-carbon molecule that requires MCAD to break it down.

Because MCAD deficiency is generally treatable if it is recognized prior to the onset of symptoms, most parents of a potentially affected child choose to wait until birth to have their children tested.

Treatment and management

Because individuals affected with MCAD deficiency can still break down short chain and long chain fatty acids at a normal rate and most have a diminished, but functional, ability to break down medium chain fatty acids, a precipitating condition must be present in order for symptoms of MCAD deficiency to develop. The most common precipitators of MCAD deficiency symptoms are stress caused by fasting or by infection. At these times, the body requires a higher than normal breakdown of medium chain fatty acids. MCAD deficient individuals often cannot meet these increased metabolic demands.

The main treatments for MCAD deficiency are designed to control or avoid precipitating factors. Persons affected with MCAD deficiency should never fast for more than 10 to 12 hours and they should strictly adhere to a low-fat diet. Blood sugar monitoring should be undertaken to control episodes of hypoglycemia. During acute episodes, it is usually necessary to administer glucose and supplement the diet with carbohydrates and high calorie supplements.

Many individuals affected with MCAD deficiency benefit from daily doses of vitamin B7 (L-carnitine). This vitamin is responsible for transporting long chain fatty acids across the inner mitchondrial membrane. Elevated levels of L-carnitine ensure that these individuals breakdown long chain fatty acids in preference to medium chain fatty acids, which helps prevent acute symptomatic episodes of MCAD deficiency. Additionally, L-carnitine helps remove toxic wastes from the bloodstream to the urine, so it is also pivotal in controlling hyperammonemia.

Some individuals affected with MCAD deficiency present symptoms for the first time when they receive the diphtheria-pertussis-tetanus (DTP) vaccine. It is important that any person suspected to be affected with MCAD deficiency receive treatment for hypoglycemia in connection with the administration of this vaccine. Chicken pox and middle ear infections (otitis media) have also been shown to initiate symptoms of MCAD deficiency.

Prognosis

MCAD deficiency has a mortality rate of 20–25% during the first episode of symptoms. If an affected individual survives this first attack, the prognosis is excellent for this individual to have a normal quality of life as long as appropriate medical treatment is sought and followed.

Resources

PERIODICALS

Berberich, S. "New developments in Iowa's newborn screening program." The University of Iowa Hygienic Library Hotline (September 2000): 1-2.

Chace, D., Hillman, S., J. Van Hove, and E. Naylor. "Rapid diagnosis of MCAD deficiency: Quantitative analysis of octanoylcarnitine and other acylcarnitines in newborn blood spots by tandem mass spectrometry." Clinical Chemistry (November 1997): 2106-2113.

Yokota, I. et al. "Molecular survey of a prevalent mutation, 985A-to-G transition, and identification of five infrequent mutations in the medium-chain Acyl-CoA dehydrogenase (MCAD) gene in 55 patients with MCAD deficiency." American Journal of Human Genetics (December 1991): 1280-91.

ORGANIZATIONS

Fatty Oxidation Disorders (FOD) Family Support Group. 805 Montrose Dr., Greensboro, NC 24710. (336) 547-8682. [email protected]. <http://www.fodsupport.org/welcome.htm>.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

Organic Acidemia Association. 13210 35th Ave. North, Plymouth, MN 55441. (763) 559-1797. Fax: (863) 694-0017. <http://www.oaanews.org>.

Sudden Infant Death Syndrome Network. PO Box 520, Ledyard, CT 06339. <http://sids-network.org>.

WEBSITES

Matern, D., P. Rinaldo, N. Robin, "Medium-chain acyl-coenzyme: a dehydrogenase deficiency." GeneClinics. <http://www.geneclinics.org/profiles/mcad/details.html>

OMIM—Online Mendelian Inheritance in Man.<http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?201450>.

Pediatric Database (PEDBASE) Homepage.<http://www.icondata.com/health/pedbase/files/MCADDEF1.HTM>.

Paul A. Johnson