Alternative titles; symbols
SNOMEDCT: 237951008; ORPHA: 67046; DO: 0110002;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q22.31 | 3-methylglutaconic aciduria, type I | 250950 | Autosomal recessive | 3 | AUH | 600529 |
A number sign (#) is used with this entry because of evidence that 3-methylglutaconic aciduria type I (MGCA1) is caused by homozygous or compound heterozygous mutation in the AUH gene (600529), which encodes 3-methylglutaconyl-CoA hydratase, on chromosome 9q22.
3-Methylglutaconic aciduria type I (MGCA1) 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: one 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 (MGCA7B, 616271 and MGCA7A, 619835), caused by mutation in the CLPB gene (616254) on chromosome 11q13, includes cataracts, neurologic involvement, and neutropenia. Type VIII MGCA (MGCA8; 617248) is caused by mutation in the HTRA2 gene (606441) on chromosome 2p13. Type IX MGCA (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.'
Greter et al. (1978) described brother and sister with choreoathetosis, spastic paraparesis, dementia, optic atrophy, and, in the urine, increased amounts of 3-methylglutaric and 3-methylglutaconic acids. The excretion was increased by leucine loading. 3-Methylglutaconic acid is known to be an intermediate in the catabolism of leucine. 3-Methylglutaconyl-CoA hydratase was postulated to be the deficient enzyme.
Robinson et al. (1976) gave a brief report of a case of 3-methylglutaconic aciduria. The clinical picture was somewhat different and the amounts of the 2 organic acids in the urine were about 5 times greater. The hydratase mentioned above was about 30% of normal in skeletal muscle. The authors were not convinced that the primary enzyme defect was in 3-methylglutaconyl-CoA hydratase.
In fibroblasts from 2 brothers with 3-methylglutaconic aciduria reported by Duran et al. (1982), Narisawa et al. (1986) demonstrated deficiency (2 to 3% of normal) of 3-methylglutaconyl-CoA hydratase. The phenotype in these brothers was different from that in the cases reported by Greter et al. (1978) and others, with a progressive degenerative neurologic disorder and lesser amounts of 3-methylglutaconic acid in the urine. In patients of the latter type, Narisawa et al. (1986) found normal activity of 3-MG-CoA-hydratase. In the sibs with deficiency, the clinical picture was similar. Both had retardation of speech development and in 1 this was the only abnormality. Motor development was also delayed in the older brother, who walked first at 2 years of age and had a short attention span. He had had an unexplained episode of unconsciousness lasting nearly a day. He responded to an 18-hour fast with symptomatic hypoglycemia and metabolic acidosis. Fasting did not produce hypoglycemia in the younger brother. Fibroblasts of the parents, who were not known to be related, were not available for study. Fibroblasts from patients with the neurologic degenerative form of 3-methylglutaconic aciduria had normal levels of the enzyme 3-MG-CoA-hydratase. Defects in all 8 enzymes involved in leucine degradation have been reported; see Figure 1 of Narisawa et al. (1986).
Gibson et al. (1991) emphasized phenotypic heterogeneity of this metabolic disorder.
Zeharia et al. (1992) described a seemingly 'new' variant in 2 sibs with normal enzyme activity who had choreoathetoid movements, optic atrophy, and mild developmental delay. The boy demonstrated developmental improvement in his second year of life and his sister developed well, with normal school performance.
Kuhara et al. (1992) reported 3-methylglutaconic aciduria discovered during pregnancy in 2 women who were generally healthy.
Gibson et al. (1998) described 3 patients with this disorder, bringing the total number of patients identified with 3-MG-CoA hydratase deficiency to 8 (7 families). The phenotypic presentation has varied from mild, including delayed development of language and hyperchloremic acidosis associated with gastroesophageal reflux, to a much more severe phenotype, including seizures, cerebellar findings, and atrophy of the basal ganglia.
Shoji et al. (1999) reported a 9-month-old Japanese boy with type I MGCA, who was born of consanguineous parents. He showed progressive neurologic impairment with quadriplegia, athetoid movements, and severe psychomotor retardation from age 4 months.
Wiley et al. (1999) reported a boy, born of first-cousin parents of Lebanese extraction, who was found on newborn screening to have 3-methylglutaconic aciduria type I. In this patient and his younger asymptomatic sib, Ly et al. (2003) identified a homozygous mutation in the AUH gene (600529.0003). At 2.5 years of age, the boy was healthy, with entirely normal growth and development. Wortmann et al. (2010) provided follow-up of the Lebanese sibs reported by Ly et al. (2003). At ages 9 and 6.5 years, both had normal development and unremarkable physical examinations. Brain imaging was not performed.
Illsinger et al. (2004) reported a German boy with type I MGCA who had normal psychomotor development, but repeated febrile seizures. He carried a homozygous mutation (600529.0005) in the AUH gene. Wortmann et al. (2010) reported follow-up of the German patient reported by Illsinger et al. (2004). At age 10 years, he showed normal development and attended regular school but had attention-deficit/hyperactivity disorder. Brain MRI showed mild signal abnormalities in the deep frontal white matter with sparing of the U-fibers. The authors suggested that these changes may represent the earliest stages of a slowly progressive neurodegenerative disorder.
Eriguchi et al. (2006) reported a 55-year-old woman who presented with progressive forgetfulness, unsteady gait, hyperreflexia, cerebellar ataxia, dysarthria, and urinary incontinence. Brain MRI showed leukoencephalopathy with hyperintensities in the cerebral white matter extending into the subcortical U-fibers and in the middle cerebellar peduncles. Urine amino acid analysis showed a pattern consistent with type I MGCA. She was born of first-cousin parents and had normal development. Genetic analysis identified a homozygous mutation (600529.0002) in the AUH gene.
Wortmann et al. (2010) reported 2 unrelated patients with genetically confirmed type I MGCA who first developed symptoms as adults. A Dutch woman presented with progressive visual loss with optic atrophy at age 35, and developed dysarthria, limb ataxia, and gait ataxia over the following 16 years. A British man presented with mild cerebellar ataxia at age 30, which progressed to spastic paraparesis, nystagmus, and dementia over the next 29 years. Brain MRI at ages 61 and 50 years, respectively, showed extensive confluent white matter abnormalities in both patients. Lesions were restricted to the supratentorial region with involvement of the deep and subcortical white matter, but sparing of the cerebellum and corpus callosum. Wortmann et al. (2010) noted that patients with adult-onset show a distinct clinical pattern of progressive ataxia and spasticity associated with brain white matter lesions.
Mercimek-Mahmutoglu et al. (2011) described 9- and 14-year-old sibs, born of consanguineous Pakistani parents, who had variable expressivity of MGCA1. The older sib had a learning disability, attention deficit-hyperactivity disorder, and leukoencephalopathy. She had an abnormal EEG showing a dysrhythmic background. Brain MRI showed abnormal patchy signal in the frontal and parietal subcortical white matter, and MRS showed an abnormal peak reflective of 3-hydroxyisovaleric acid. The younger sib had severe speech delay, oromotor weakness, and tongue overflow movements. He had normal cognitive abilities and a normal EEG. Brain MRI was not performed. Neither sib had a history of metabolic decompensation.
The transmission pattern of MGCA1 in the patients reported by Ijlst et al. (2002) was consistent with autosomal recessive inheritance.
By mutation analysis of the AUH gene in 2 unrelated patients with 3-methylglutaconyl aciduria type I, Ijlst et al. (2002) identified homozygosity for a nonsense mutation (600529.0001) and a splice site mutation (600529.0002), respectively.
In the patient with MGCA1 reported by Shoji et al. (1999), Matsumori et al. (2005) identified homozygosity for a splice site mutation in the AUH gene (600529.0004).
In a Dutch woman and a British man with MGCA1, Wortmann et al. (2010) identified compound heterozygous (600529.0006 and 600529.0007) and homozygous (600529.0008) mutations in the AUH gene, respectively.
In 2 Pakistani sibs, born to consanguineous parents, with MGCA1, Mercimek-Mahmutoglu et al. (2011) identified a homozygous deletion of exons 1-3 in the AUH gene (600529.0009). The mutation was found by PCR and Sanger sequencing of the AUH gene, which failed to amplify exons 1-3 in the sibs.
Chitayat, D., Chemke, J., Gibson, K. M., Mamer, O. A., Kronick, J. B., McGill, J. J., Rosenblatt, B., Sweetman, L., Scriver, C. R. 3-Methylglutaconic aciduria: a marker for as yet unspecified disorders and the relevance of prenatal diagnosis in a 'new' type ('type 4'). J. Inherit. Metab. Dis. 15: 204-212, 1992. [PubMed: 1382150] [Full Text: https://doi.org/10.1007/BF01799632]
Davey, K. M., Parboosingh, J. S., McLeod, D. R., Chan, A., Casey, R., Ferreira, P., Snyder, F. F., Bridge, P. J., Bernier, F. P. Mutation of DNAJC19, a human homologue of yeast inner mitochondrial co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition. J. Med. Genet. 43: 385-393, 2006. [PubMed: 16055927] [Full Text: https://doi.org/10.1136/jmg.2005.036657]
Duran, M., Beemer, F. A., Tibosch, A. S., Bruinvis, L., Ketting, D., Wadman, S. K. Inherited 3-methylglutaconic aciduria in two brothers--another defect of leucine metabolism. J. Pediat. 101: 551-554, 1982. [PubMed: 6181239] [Full Text: https://doi.org/10.1016/s0022-3476(82)80698-7]
Eriguchi, M., Mizuta, H., Kurohara, K., Kosugi, M., Yakushiji, Y., Okada, R., Yukitake, M., Hasegawa, Y., Yamaguchi, S., Kuroda, Y. 3-methylglutaconic aciduria type I causes leukoencephalopathy of adult onset. Neurology 67: 1895-1896, 2006. [PubMed: 17130438] [Full Text: https://doi.org/10.1212/01.wnl.0000244467.01362.54]
Gibson, K. M., Sherwood, W. G., Hoffmann, G. F., Stumpf, D. A., Dianzani, I., Schutgens, R. B. H., Barth, P. G., Weismann, U., Bachmann, C., Schrynemackers-Pitance, P., Verloes, A., Narisawa, K., Mino, M., Ohya, N., Kelley, R. I. Phenotypic heterogeneity in the syndromes of 3-methylglutaconic aciduria. J. Pediat. 118: 885-890, 1991. [PubMed: 1710267] [Full Text: https://doi.org/10.1016/s0022-3476(05)82199-7]
Gibson, K. M., Wappner, R. S., Jooste, S., Erasmus, E., Mienie, L. J., Gerlo, E., Desprechins, B., De Meirleir, L. Variable clinical presentation in three patients with 3-methylglutaconyl-coenzyme A hydratase deficiency. J. Inherit. Metab. Dis. 21: 631-638, 1998. [PubMed: 9762598] [Full Text: https://doi.org/10.1023/a:1005476315892]
Greter, J., Hagberg, B., Steen, G., Sodenhjelm, U. 3-Methylglutaconic aciduria: report on a sibship with infantile progressive encephalopathy. Europ. J. Pediat. 129: 231-238, 1978. [PubMed: 720359] [Full Text: https://doi.org/10.1007/BF00441354]
Ijlst, L., Loupatty, F. J., Ruiter, J. P. N., Duran, M., Lehnert, W., Wanders, R. J. A. 3-Methylglutaconic aciduria type I is caused by mutations in AUH. Am. J. Hum. Genet. 71: 1463-1466, 2002. Note: Erratum: Am. J. Hum. Genet. 73: 709 only, 2003. [PubMed: 12434311] [Full Text: https://doi.org/10.1086/344712]
Illsinger, S., Lucke, T., Zschocke, J., Gibson, K. M., Das, A. M. 3-methylglutaconic aciduria type I in a boy with fever-associated seizures. Pediat. Neurol. 30: 213-215, 2004. [PubMed: 15033206] [Full Text: https://doi.org/10.1016/j.pediatrneurol.2003.09.016]
Kuhara, T., Matsumoto, I., Saiki, K., Takabayashi, H., Kuwabara, S. 3-Methylglutaconic aciduria in two adults. (Letter) Clin. Chim. Acta 207: 151-153, 1992. [PubMed: 1375542] [Full Text: https://doi.org/10.1016/0009-8981(92)90159-n]
Ly, T. B., Peters, V., Gibson, K. M., Liesert, M., Buckel, W., Wilcken, B., Carpenter, K., Ensenauer, R., Hoffmann, G. F., Mack, M., Zschocke, J. Mutations in the AUH gene cause 3-methylglutaconic aciduria type I. Hum. Mutat. 21: 401-407, 2003. [PubMed: 12655555] [Full Text: https://doi.org/10.1002/humu.10202]
Matsumori, M., Shoji, Y., Takahashi, T., Shoji, Y., Takada, G. A molecular lesion in a Japanese patient with severe phenotype of 3-methylglutaconic aciduria type I. Pediat. Int. 47: 684-686, 2005. [PubMed: 16354225] [Full Text: https://doi.org/10.1111/j.1442-200x.2005.02130.x]
Mercimek-Mahmutoglu, S., Tucker, T., Casey, B. Phenotypic heterogeneity in two siblings with 3-methylglutaconic aciduria type I caused by a novel intragenic deletion. Molec. Genet. Metab. 104: 410-413, 2011. [PubMed: 21840233] [Full Text: https://doi.org/10.1016/j.ymgme.2011.07.021]
Narisawa, K., Gibson, K. M., Sweetman, L., Nyhan, W. L., Duran, M., Wadman, S. K. Deficiency of 3-methylglutaconyl-coenzyme A hydratase in two siblings with 3-methylglutaconic aciduria. J. Clin. Invest. 77: 1148-1152, 1986. [PubMed: 3082934] [Full Text: https://doi.org/10.1172/JCI112415]
Robinson, B. H., Sherwood, W. G., Lampty, M., Lowden, J. A. Beta-methyl glutaconic aciduria: a new disorder of leucine metabolism. (Abstract) Pediat. Res. 10: 371 only, 1976.
Shoji, Y., Takahashi, T., Sawaishi, Y., Ishida, A., Matsumori, M., Shoji, Y., Enoki, M., Watanabe, H., Takada, G. 3-methylglutaconic aciduria type I: clinical heterogeneity as a neurometabolic disease. J. Inherit. Metab. Dis. 22: 1-8, 1999. [PubMed: 10070612] [Full Text: https://doi.org/10.1023/a:1005421111554]
Wiley, V., Carpenter, K., Wilcken, B. Newborn screening with tandem mass spectrometry: 12 months' experience in NSW Australia. Acta Paediat. Suppl. 88: 48-51, 1999. [PubMed: 10626578] [Full Text: https://doi.org/10.1111/j.1651-2227.1999.tb01157.x]
Wortmann, S. B., Duran, M., Anikster, Y., Barth, P. G., Sperl. W., Zschocke, J., Morava, E., Wevers, R. A. Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature. J. Inherit. Metab. Dis. 36: 923-928, 2013. [PubMed: 23296368] [Full Text: https://doi.org/10.1007/s10545-012-9580-0]
Wortmann, S. B., Kremer, B. H., Graham, A., Willemsen, M. A., Loupatty, F. J., Hogg, S. L., Engelke, U. F., Kluijtmans, L. A., Wanders, R. J., Illsinger, S., Wilcken, B., Cruysberg, J. R., Das, A. M., Morava, E., Wevers, R. A. 3-methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy. Neurology 75: 1079-1083, 2010. [PubMed: 20855850] [Full Text: https://doi.org/10.1212/WNL.0b013e3181f39a8a]
Zeharia, A., Elpeleg, O. N., Mukamel, M., Weitz, R., Ariel, R., Mimouni, M. 3-Methylglutaconic aciduria: a new variant. Pediatrics 89: 1080-1082, 1992. [PubMed: 1594352]