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3-methylglutaconic aciduria type 3

Synonym(s) Autosomal recessive optic atrophy plus syndrome
Autosomal recessive optic atrophy type 3
Costeff optic atrophy syndrome
Costeff syndrome
Infantile optic atrophy with chorea and spastic paraplegia
Prevalence Unknown
Inheritance Autosomal recessive
Age of onset Childhood
  • E71.1
  • C0574084
  • C535311
MedDRA -


3-methylglutaconic aciduria type III (MGA III) is an organic aciduria characterised by the association of optic atrophy and choreoathetosis with 3-methylglutaconic aciduria. The vast majority of reported cases involved the Iraqi-Jewish population, in which the prevalence of the disorder has been estimated at around 1 in 10 000. Onset of the optic atrophy occurs during infancy with a progressive decrease in visual acuity. The choreoathetoid movement disorder manifests later, usually within the first ten years of life. Other clinical features may include spastic paraparesis, mild ataxia and cognitive deficit, dysarthria, and nystagmus. MGA III is transmitted as an autosomal recessive trait and is caused by mutations in the OPA3 gene (19q13.2-q13.3). The biological function of the OPA3 gene product remains to be defined but MGA III is hypothesised to be a primary mitochondrial disorder. Diagnosis may be suspected up on presentation with early-onset optic atrophy and choreoathetosis (particularly in individuals of Iraqi-Jewish origin) and by detection of an elevation in the levels of 3-methylglutaconic and 3-methylglutaric acid in the urine. Diagnosis can be confirmed by detection of mutations in the OPA3 gene. MGA type III can be distinguished from other forms of MGA (types I, II and IV; see these terms) on the basis of the clinical phenotype and, more specifically, from 3-MGA type I by the absence of an elevation in 3-hydroxyisovaleric acid levels and normal 3-methylglutaconyl-CoA hydratase activity in cultured fibroblasts. The differential diagnosis may also include Behr syndrome (see this term) and cerebral palsy. Prenatal testing is clinically available for affected families through molecular analysis of amniocytes or chorionic villus samples. Treatment is symptomatic only and should be managed by a multidisciplinary team. The long-term prognosis remains unknown: although the disease progresses during childhood, it appears to stabilise during early adulthood.

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  • Pr Pascale DE LONLAY

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Clinical genetics review
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