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HEREDITARY MONOGENIC DISEASES

           

Glutaryl-CoA type 2

Multiple acyl CoA-dehydrogenase deficiency (MADD), or glutaric acidemia type II, is an alteration of the oxidation of fatty acids and amino acids.

It is a clinically heterogeneous disorder with severe neonatal-onset presentation which includes metabolic acidosis, cardiomyopathy and hepatopathy, or cases of mild childhood or adulthood disease such as episodic metabolic decompensations, muscle weakness and respiratory failure.

The prevalence is estimated at 1/200,000 births, with large variations between countries and ethnicities.
Patients with MADD are grouped into three broad clinical phenotypes:

1) Neonatal onset with congenital anomalies. Premature infants with severe non-ketosis hypoglycemia, hypotonia, hepatomegaly and severe metabolic acidosis with the onset of the symptoms within the first 24 hours of life, which can lead to death during the first week of life.

2) Neonatal onset without abnormalities (phenotypes 1 and 2 are referred to as MADD-severe [S]). Symptoms of hypotonia, tachypnea, hepatomegaly, metabolic acidosis and hypocetosis hypoglycemia during the first 24-48 hours.

Severe cardiomyopathy is usually the cause of death during the first weeks of life.

3) Mild and/or late onset (MADD-mild [M]). Wide range of symptoms from vomiting, metabolic acidosis and hypocetosis hypoglycemia during the first months, to acute pseudo-Reye syndrome with ketoacidosis and lipid storage myopathy during adolescence or adulthood.

The neonatal screening program is available in some countries.
The analysis of organic acids in urine shows an increase in various combinations of dicarboxylic acids, glutaric acid, ethylmalonic acid, 2-hydroxyglutarate and glycine conjugates. An increase in C4-C18 acylcarnitins is observed in blood, although patients may have a severe decrease in carnitine, which may limit the extent of these abnormalities. In fibroblasts, the oxidative flow of fatty acids and the analysis of acylcarnitine after incubation with palmitic acid are usually abnormal.

Diagnostic confirmation is obtained by analyzing the mutations. MADD is caused by mutations in the ETFA (15q23-q25), ETFB (19q13.3-q13.4) and ETFDH (4q32-q35) genes, which code for the alpha and beta subunits of electronic transfer flavoprotein (ETF) and the ETF-coenzyme Q-oxidoreductase. The dysfunction of any of these two flavoproteins causes the alteration of the oxidation of fatty acids.

Genetic counseling is recommended. It is possible to make a prenatal diagnosis when two pathogenic mutations have been identified in the family. MADD is inherited as an autosomal recessive character.

MADD-S is invariably lethal. Milder phenotypes have a better prognosis.

GENE OR REGION STUDIED


  • ETFDH