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A rare organic aciduria, due to deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase characterized by episodes of metabolic decompensation with hypoketotic hypoglycemia triggered by periods of fasting or infections.
ORPHA:20Classification level: Disorder
3-hydroxy-3-methylglutaric aciduria (3HMG) occurs in all ethnic groups. The conditions is extremely rare in the United States, Taiwan and mainland China where incidence is estimated at less than 1/1,000,000; however, it is more frequently observed in Saudi Arabia, Portugal and Spain. In Portugal, the birth prevalence is estimated at 1/125,000 live births.
The clinical presentation is heterogeneous, ranging from severe neonatal onset with potentially fatal outcome to presentation in adulthood. Most patients became symptomatic within the first year of life (50% in neonatal period) with episodes of metabolic decompensation triggered by periods of fasting or infections, which when left untreated may lead to neurological sequelae. Newborns or infants present with acidosis and hypoglycemia, accompanied by vomiting, dehydration, hypotonia and lethargy. Acute decompensation is triggered by infections, vaccinations, and dietary changes. The typical laboratory findings include hypoglycemia, acidosis, an increased anion gap, hyperammonemia and elevated transaminases. Long-term neurological complications are common. Half of the patients have a normal cognitive development while the remainder shows psychomotor deficits. Speech and motor developmental delay are frequent. Cerebral MRI frequently reveals diffuse abnormality in signal intensity of the cerebral white matter, thalami and basal ganglia. Other manifestations may include macrocephaly, dilated cardiomyopathy, arrhythmias, hepatomegaly and acute pancreatitis. Children are usually healthy between episodes; subsequent acute crises may be preceded by anorexia, lethargy, behavioral changes, irritability and muscle weakness. Hypoketotic hypoglycemia is characteristic.
3HMG is caused by mutations of the gene HMGCL (1p36.11).
Diagnosis is based on the tandem mass spectrometry profile of plasmatic acylcarnitines (increased C5OH and C6DC) and urinary organic acid (high levels of acids: 3-hydroxy-3-methylglutaric, 3-hydroxyisovaleric, 3-methylglutaconic and 3-methyglutaric). The diagnosis can be confirmed by mutation analysis.
Differential diagnosis includes sepsis, fatty acid oxidation disorders, organic acidurias and Reye's syndrome.
During the third trimester of gestation, amniotic fluid organic acid levels, as well as maternal urinalysis may indicate 3HMG; confirmation requires testing of cultured amniocytes or chorionic villi for molecular study.
3HMG is an autosomal recessive genetic disorder. Genetic counselling should be offered to all families.
Management and treatment
Patients must be treated by intravenous 10% glucose and supportive treatment during acute metabolic crises. Maintenance treatment requires protein/leucine-restricted diet with a leucine free amino acid mixture, restricted fat intake and regular feeding (every 3-6 hours). Carnitine supplementation is often given.
Prognosis is good for those patients who are rapidly diagnosed and survive past childhood.
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