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3-hydroxy-3-methylglutaric aciduria

Orpha number ORPHA20
Synonym(s) 3-hydroxy-3-methylglutaryl-CoA lyase deficiency
Hydroxymethylglutaric aciduria
Prevalence Unknown
Inheritance Autosomal recessive
Age of onset Infancy
Neonatal
ICD-10
  • E71.1
ICD-O -
OMIM
UMLS
  • C1533587
MeSH -
MedDRA -
SNOMED CT
  • 410059004

Summary

3-hydroxy-3-methylglutaric aciduria (3HMG) is an organic aciduria, due to deficiency of 3-hydroxy-3-methylglutaryl-CoA-lyase (a key enzyme in ketogenesis and leucine metabolism) usually presenting in infancy with episodes of metabolic decompensation triggered by periods of fasting or infections, which when left untreated are life-threatening and may lead to neurological sequelae.

Prevalence of 3HMG is estimated to be <1 per 100,000 live births. 3HMG occurs in all ethnic groups, but is more frequent in people from Saudi Arabia, Portugal and Spain. In Portugal the prevalence is 1 in 102,554.

Newborns (30% of cases), or infants present with acidosis and hypoglycemia; accompanied by vomiting, dehydration, hypotonia and lethargy. Acute crisis, usually triggered by catabolism (fasting, excessive physical exertion, infections and immunization) may lead to apnea, in some cases progressing to coma. Other manifestations may include macrocephaly, delayed development, dilated cardiomyopathy (see this term), 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. Rare cases of late, post-pubescent onset have been reported. Patients may also present with features similar to those of Reye's syndrome (see this term) with hyperammonemia, hepatomegaly and encephalopathy.

3HMG is caused by mutations of the gene HMGCL (1p36.11) that encodes 3-hydroxy-3-methylglutaryl-CoA-lyase, leading to an inability to process leucine from proteins and a reduced ability to synthesize ketones.

Hypoketotic hypoglycemia is characteristic. Diagnosis is made by measuring plasmatic acylcarnitines (increased C5OH and C6DC acylcarnitine) and urinary organic acid profile (high level of 3-hydroxy-3-methylglutaric acid, 3-hydroxy-isovaleric acid, 3-methylglutaconic acid and 3-methyglutaric acid). Cerebral MRI frequently shows diffuse abnormality in signal intensity of the cerebral white matter and abnormal signal intensity of the thalami and basal ganglia. Definitive diagnosis requires enzyme activity assays and/or genetic testing.

Differential diagnosis include sepsis, disorders of fatty acid oxidation and organic acidurias and Reye's syndrome (see these terms).

During the third trimester of gestation, amniotic fluid organic acid levels, as well as maternal urinalysis may indicate 3HMG; confirmation requires direct enzyme activity testing of cultured amniocytes of chorionic villi or molecular study.

3HMG is an autosomal recessive genetic disorder. Genetic counseling should be offered to at-risk couples informing them of the 25% chance of having an affected child.

Patients must be given intravenous glucose, bicarbonate and supportive treatment during acute metabolic crises. Maintenance requires leucine-free amino acids mixture for infants and regular feeding (every 3-6 hours). Children must avoid metabolic stress (i.e., intense physical activity, infections) as much as possible and a special diet must be conceived to avoid high protein and high fat foods, often using special medical food products. A highly regulated food plan will remain necessary throughout life.

3HMG is fatal in 20% of cases, however, prognosis is good for those patients who are rapidly diagnosed and survive past childhood. With careful dietary management, metabolic crises may be absent during adulthood. Neurological damage sustained during hypoglycemic coma may be irreversible, potentially leading to hearing or vision loss, learning difficulties and cognitive impairments.

Expert reviewer(s)

  • Dr Anabela BANDEIRA
  • Dr Laura VILARINHO

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Detailed information

Emergency guidelines
  • EN (2012,pdf)
Article for general public
  • ES (2011,pdf)
  • FR (2011,pdf)
  • NL (2011,pdf)
  • EN (2011,pdf)
  • PT (2011,pdf)
  • IT (2011,pdf)
  • DE (2011,pdf)
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