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3-methylglutaconic aciduria type 4
3-methylglutaconic aciduria (3-MGA) type IV, or unclassified 3-MGA, is a clinically heterogeneous disorder characterised by increased 3-methylglutaconic acid excretion in individuals that cannot be classified as having one of the other forms of 3-MGA (3-MGA I, II or III; see these terms). The prevalence of this disorder is unknown. Patients usually present during the first year of life with neurological findings including psychomotor retardation, hypotonia, developmental delay, seizures and progressive spasticity, together with severe failure to thrive. Cardiomyopathy, hepatic dysfunction, eye anomalies, microcephaly, deafness, dysmorphism, neonatal hypoglycaemia, thrombocytopaenia and lactic acidosis have also been reported. Cerebellar dysgenesis may be revealed by magnetic resonance imaging. In contrast, a small number of asymptomatic patients have been diagnosed as having 3-MGA type IV. The disorder has been reported to be inherited as an autosomal recessive trait. The aetiology remains unknown: unlike patients with 3-MGA type I, individuals with 3MGA type IV display normal 3-methylglutaconyl-CoA hydratase activity in cultured fibroblasts. Mitochondrial respiratory chain abnormalities have been detected in some 3MGA type IV patients but the clinical heterogeneity associated with this disorder suggests that the 3-methylglutaconic aciduria seen in 3-MGA type IV patients may result from a variety of causes and genetic factors. 3-methylglutaconic aciduria can be diagnosed by analysis of urinary organic acid excretion but specific diagnosis of 3-MGA type IV requires exclusion of all other forms of 3-MGA. 3-MGA type IV can be distinguished from the type I disorder by normal excretion of 3-hydroxyisovaleric acid. 3-MGA type II may be excluded by the mode of inheritance (transmission is X-linked recessive in 3-MGA type II) and on the basis of the clinical phenotype (the type II disorder is characterised by neutropaenia, skeletal myopathy, dilated cardiomyopathy and growth delay). Depending on the manifestations present, clinical differentiation of types III and IV may be more problematic, but the occurrence of 3-MGA type III is largely restricted to the Iraqi-Jewish population. As the genetic factors responsible for the other forms of 3-MGA have now been determined, molecular analysis provides a valuable tool for accurate diagnosis. In addition to other forms of 3-MGA, the differential diagnosis should also include cerebral palsy, dilated cardiomyopathy with ataxia (see this term) and other organic acidurias. At present there is no effective treatment for 3-MGA type IV and a leucine-restricted diet appears to be of no benefit. The prognosis depends on the clinical phenotype but the neurological complications can be severe with a potentially fatal disease course.
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