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What is Medium Chain Acyl-CoA Dehydrogenase Deficiency?

What is Medium Chain Acyl-CoA Dehydrogenase Deficiency?

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is a treatable inherited disease in which the body cannot turn certain fatty acids into energy due to a deficient enzyme. As a result, partially metabolized fatty acids can accumulate in body tissues, causing damage to the brain, liver, and other organs. If treated early and consistently, people with Mcad Deficiency can live normal lives.

Children with untreated MCAD deficiency are prone to quick-developing, life-threatening health problems including seizures, breathing problems, brain damage, coma, and death. The liver may also be enlarged. It is thought that a small percentage of sudden infant death syndrome is due to undiagnosed MCAD deficiency.

The first symptoms of the disease usually appear in infancy or early childhood. These include vomiting, lack of energy, and low blood sugar. Rarely, these symptoms do not appear until adulthood. Often the episodes of metabolic crisis can be triggered by long periods without eating or by illness.

Women whose fetuses have MCAD deficiency are more prone to certain pregnancy complications and should speak with their physician.

Case presentation

We report on two siblings with mild MCAD deficiency associated with a novel splice site mutation in the ACADM gene. The younger sibling was detected by newborn screening, while the older sister was missed, but diagnosed later on by genetic family testing. Both children were found to be compound heterozygous for the common c.985A > G (p.K329E) mutation and a novel splice site mutation, c.600-18G > A, in the ACADM gene.

To determine the biological consequence of the c.600-18G > A mutation putative missplicing was investigated at RNA level in granulocytes and monocytes of one of the patients. The splice site mutation was shown to lead to partial missplicing of the ACADM pre-mRNA. Of three detected transcripts two result in truncated, non-functional MCAD proteins as reflected by the reduced octanoyl-CoA oxidation rate in both patients. In one patient a decrease of the octanoyl-CoA oxidation rate was found during a febrile infection indicating that missplicing may be temperature-sensitive.

Normal Function

The ACADM gene provides instructions for making an enzyme called medium-chain acyl-CoA dehydrogenase (MCAD). This enzyme functions within mitochondria, the energy-producing centers in cells. MCAD is essential for fatty acid oxidation, which is the multistep process that breaks down (metabolizes) fats and converts them to energy.

MCAD is required to metabolize a group of fats called medium-chain fatty acids. These fatty acids are found in foods and body fat and are produced when larger fatty acids are metabolized. Fatty acids are a major source of energy for the heart and muscles. During periods without food (fasting), fatty acids are also an important energy source for the liver and other tissues.

Health Conditions Related to Genetic Changes

More than 80 mutations in the ACADM gene have been found to cause medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Many of these mutations change single protein building blocks (amino acids) in the MCAD enzyme. The most common change replaces the amino acid lysine with the amino acid glutamic acid at position 304 in the enzyme (written as Lys304Glu or K304E). This mutation and other amino acid substitutions alter the enzyme’s structure, severely reducing or eliminating its activity. Other types of mutations lead to an abnormally small and unstable enzyme that cannot function.

With a shortage (deficiency) of functional MCAD enzyme, medium-chain fatty acids are not metabolized properly. As a result, these fats are not converted to energy, which can lead to some features of this disorder such as lack of energy (lethargy) and low blood sugar (hypoglycemia). Medium-chain fatty acids or partially metabolized fatty acids may build up in tissues and damage the liver and brain. This abnormal buildup causes the other signs and symptoms of MCAD deficiency.

Other Names for This Gene

  • ACAD1
  • ACADM_HUMAN
  • acyl-CoA dehydrogenase, C-4 to C-12 straight chain
  • MCAD
  • MCADH

Consent

All individuals in our study were recruited by physician-initiated referral. The study was conducted in accordance with the Declaration of Helsinki protocols and approved by the institutional ethics review board of Freiburg University Hospital, Germany.

Written informed consent for molecular studies was obtained from the affected individuals and/or their legal guardians in accordance with current German law (GenDG). A copy of the written consent is available for review by the Editor of this journal. Control samples and primary cells were collected from ancestry-, sex- and age-matched healthy individuals under the same criteria and regulations.

Case presentations

Patient 1, a 7-year-old girl, is the first child of non-consanguineous German parents. She was born spontaneously at 41 weeks of gestation after an uneventful pregnancy. Birth weight, birth length and head circumference were 3280 g (56th percentile), 53 cm (87th percentile) and 35 cm (50th percentile), respectively.

Three hours after birth she was admitted to the intensive care unit with suspected newborn infection. She was pale, tachypnoeic and required CPAP ventilation with up to 60 % oxygen. Laboratory parameters were indicative of systemic infection (Interleukin 6 727 pg/ml, reference range 

Under antibiotic treatment her general condition ameliorated quickly, and the child was dismissed from hospital on day 10. NBS results including acylcarnitine analysis were unremarkable. After dismission from hospital no further problems occurred and the child developed normally.

Five years later her younger sister, patient 2, was born and NBS was suggestive of MCADD. Urinary organic acid analysis biochemically confirmed the diagnosis. Mutation analysis revealed compound heterozygosity for the common missense mutation c.985A > G and an intronic sequence variant, c.600-18G > A, which has not been described previously.

Genetic family screening was performed showing that the older sister (patient 1) was also compound heterozygous for the same two mutations. Heterozygosity for the c.985A > G (p.K329E) mutation was detected in the healthy mother, while the healthy father and the healthy 3-year-old brother were found to be heterozygous for the intronic sequence variant.

How common is Medium Chain Acyl-CoA Dehydrogenase Deficiency?

MCAD deficiency is most common in Caucasians from Northern Europe. In the United States, the disease affects approximately 1 in 17,000 people. Affected Americans are often of Northern European ancestry. The disease is rare among Hispanics, African Americans, Asians, and Native Americans in the United States.

Studies have found high rates of MCAD deficiency in Northern Germany (1 in 4,900) and Southern Germany (1 in 8,500). One study found that Germans and Turks are equally affected.

How is Medium Chain Acyl-CoA Dehydrogenase Deficiency treated?

The key to treatment for people with MCAD deficiency is to avoid fasting, or long periods without eating. Infants will need to be fed frequently with a special diet low in fat. Consuming cornstarch can provide a sustained release of energy and allow for longer gaps between meals. Certain types of fat should be avoided while high amounts of carbohydrates can be beneficial. If the person is unable to consume food, intravenous glucose may be necessary. People with MCAD deficiency should speak with their medical team to devise a specialized diet.

Investigations

  • These may be normal in between attacks.
  • Acutely – hypoglycaemia.
  • U&E may show high or low bicarbonate and reduced anion gap.
  • LFTs may show elevated enzymes, low plasma carnitine.
  • Urine – medium-chain dicarboxylic aciduria and absent ketones.

Skin biopsy can be performed to confirm diagnosis of primary carnitine deficiency – demonstrating reduced carnitine transport in fibroblasts. Fibroblasts may be used for fatty acid oxidation studies or enzyme assay.

Prognosis

About 25% of patients with undiagnosed MCAD deficiency die at or shortly after the first presentation. A further large group of undiagnosed patients presents too late to prevent long-term neurological disability.

If the diagnosis is made early, children with this deficiency can expect to lead a full and normal life, with simple dietary treatment aimed mainly at the avoidance of fasting.

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What is Medium Chain Acyl-CoA Dehydrogenase Deficiency?

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