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HEREDITARY MONOGENIC DISEASES

           

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)

Deficiency of acyl CoA dehydrogenase medium chain (MCAD deficiency or MCADD) is a congenital disorder of mitochondrial oxidation of fatty acids characterized by a metabolic crisis rapidly evolving and often presented as hypoketotic hypoglycemia, lethargy, vomiting, convulsions and coma. It can be fatal in the absence of an urgent medical intervention.

The estimated prevalence of MCADD at birth is in a range of 1 / 4,900 to 1 / 27,000 in Caucasian populations, and is higher in northern European descent. The estimated prevalence at birth worldwide is 1 / 14,600.

MCADD is transmitted by autosomal recessive inheritance and it is caused by mutations in the gene ACADM (1p31), encoding mitochondrial protein MCAD. At first, the most common mutation c.985A>G (p.Lys329Glu) was responsible for 80% of clinical cases, but currently have been identified many other mutations in ACADM gene.

MCADD usually occurs between 3 and 24 months in previously healthy children. However, neonatal presentations are well described, like presentations in adults, if sufficient metabolic attacks (as a significant intake of alcohol) are given. In any case, many affected individuals remain asymptomatic throughout life. Normally hypoketotic hypoglycemia, lethargy and vomiting are triggered by infection, fasting or surgical procedures. However, some patients may have a progressive metabolic crisis despite ketosis and normal blood glucose levels. During a crisis, a patient may show lethargy, vomiting, respiratory arrest, seizures, hepatomegaly and rapid evolution towards cardiac arrest unless urgent treatment is started. Brain injuries that can occur in these episodes can cause an increased risk of long-term neurological damage. Sometimes sudden unexplained death may be the first manifestation of the disease. Historically, about 25% of patients die undiagnosed during the first presentation of a crisis.

The diagnosis is made by identifying an abnormal pattern characteristic of acylcarnitines (increase C6, C8 and increased ratio of C8/C10 with outliers of dicarboxylic acids C6 to C10, hexanoilglicina and suberilglicina urine) in tests drops of plasma or dry blood. The final confirmation is obtained by analysis of mutations. Currently, the MCADD is included in newborn screening programs in many European countries, such as the UK, Germany, Netherlands, Portugal and Spain.

Differential diagnosis includes other disorders of mitochondrial oxidation of fatty acids such as multiple deficiency of acyl-CoA dehydrogenase (MADD).

The main goal of treatment is to strictly avoid fasting, and avoid medium chain triglycerides, but no other special dietary restriction is necessary. There are guidelines for safe time interval between meals for infants and young children. In symptomatic patients, simple carbohydrates are delivered orally (glucose tablets) or intravenously until the blood glucose concentration is kept above 5 mmol/L (must avoid artificial sweeteners). During intercurrent infections the patient can have an emergency regime and in case of decompensation immediate medical attention is necessary.

The prognosis is very good in diagnosed patients that avoid fasting and are properly treated for a disease or intercurrent metabolic crisis.

GENE OR REGION STUDIED


  • ACADM