3-Methylglutaconic aciduria type 1

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Description from OMIM

Type I MGCA is a rare autosomal recessive disorder of leucine catabolism. The metabolic landmark is urinary excretion of 3-methylglutaconic acid (3-MGA) and its derivatives 3-methylglutaric acid (3-MG) and 3-hydroxyisovaleric acid (3-HIVA). Two main presentations have been described: 1 with onset in childhood associated with the nonspecific finding of psychomotor retardation, and the other with onset in adulthood of a progressive neurodegenerative disorder characterized by ataxia, spasticity, and sometimes dementia; these patients develop white matter lesions in the brain. However, some asymptomatic pediatric patients have been identified by newborn screening and show no developmental abnormalities when reexamined later in childhood (summary by Wortmann et al., 2010). Genetic Heterogeneity and Classification of Methylglutaconic Aciduria Methylglutaconic aciduria is a clinically and genetically heterogeneous disorder. Type II MGCA (MGCA2), also known as Barth syndrome (BTHS; 302060), is caused by mutation in the tafazzin gene (TAZ; 300394) on chromosome Xq28. It is characterized by mitochondrial cardiomyopathy, short stature, skeletal myopathy, and recurrent infections; cognitive development is normal. Type III MGCA (MGCA3; 258501), caused by mutation in the OPA3 gene (606580) on chromosome 19q13, involves optic atrophy, movement disorder, and spastic paraplegia. In types II and III, the elevations of 3-methylglutaconate and 3-methylglutarate in urine are modest. Type IV MGCA (MGCA4; 250951) represents an unclassified group of patients who have severe psychomotor retardation and cerebellar dysgenesis. Type V MGCA (MGCA5; 610198), caused by mutation in the DNAJC19 gene (608977) on chromosome 3q26, is characterized by early-onset dilated cardiomyopathy with conduction defects, nonprogressive cerebellar ataxia, testicular dysgenesis, and growth failure in addition to 3-methylglutaconic aciduria (Chitayat et al., 1992; Davey et al., 2006). Type VI MGCA (MGCA6; 614739), caused by mutation in the SERAC1 gene (614725) on chromosome 6q25, includes deafness, encephalopathy, and a Leigh-like syndrome. Type VII MGCA (MGCA7; 616271), caused by mutation in the CLPB gene (616254) on chromosome 11q13, includes cataracts, neurologic involvement, and neutropenia. Type VIII MCGA (MGCA8; 617248) is caused by mutation in the HTRA2 gene (606441) on chromosome 2p13. Type IX MCGA (MGCA9; 617698) is caused by mutation in the TIMM50 gene (607381) on chromosome 19q13. Eriguchi et al. (2006) noted that type I MGCA is very rare, with only 13 patients reported in the literature as of 2003. Wortmann et al. (2013) proposed a pathomechanism-based classification for 'inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature.'

Prevalence of clinical parameters (%)

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List of symptoms

Symptom/sign Organ system Percent affected Pubmed id Added on(yyyy-mm-dd) Edit/add reference
3-methylglutaconic aciduria urinary 100 % 20855850 2013-11-14
Leukodystrophy nervous 67 % 20855850 2013-11-14
Mental retardation nervous 40 % 20855850 2013-11-14
Developmental delay nervous 40 % 20855850 2013-11-14
Ataxia nervous 30 % 20855850 2013-11-14
Dementia nervous 20 % 20855850 2013-11-14
Spasticity nervous 20 % 20855850 2013-11-14
Basal ganglia pathology nervous 16 % 20855850 2013-11-14
Cerebellar syndrome nervous 10 % 20855850 2013-11-14
Optic atrophy nervous 10 % 20855850 2013-11-14
Seizures nervous 10 % 20855850 2013-11-14
Athetosis nervous 10 % 20855850 2013-11-14
Vomiting digestive 10 % 20855850 2013-11-14
Quadriplegia nervous 10 % 20855850 2013-11-14
Self mutilation nervous 10 % 20855850 2013-11-14
Insomnia nervous 10 % 20855850 2013-11-14
Hepatomegaly digestive 10 % 20855850 2013-11-14
Hyperkinesia nervous 10 % 20855850 2013-11-14
Hypoglycemia circulatory 10 % 20855850 2013-11-14

List of references:

3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy.
S B Wortmann, B H Kremer, A Graham, M A Willemsen, F J Loupatty, S L Hogg, U F Engelke, L A Kluijtmans, R J Wanders, S Illsinger, B Wilcken, J R Cruysberg, A M Das, E Morava, R A Wevers,

3-Methylglutaconic aciduria type I is a rare inborn error of leucine catabolism. It is thought to present in childhood with nonspecific symptoms; it was even speculated to be a nondisease. The natural course of disease is unknown.

Neurology - Sep 2010