Alternative titles; symbols
ORPHA: 6; DO: 0080580;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q13.2 | 3-Methylcrotonyl-CoA carboxylase 2 deficiency | 210210 | Autosomal recessive | 3 | MCCC2 | 609014 |
A number sign (#) is used with this entry because of evidence that 3-methylcrotonyl-CoA carboxylase-2 deficiency (MCC2D) is caused by homozygous or compound heterozygous mutation in the gene encoding the beta subunit of 3-methylcrotonyl-CoA carboxylase (MCCC2; 609014) on chromosome 5q13.
3-Methylcrotonylglycinuria is an autosomal recessive disorder of leucine catabolism. The clinical phenotype is highly variable, ranging from neonatal onset with severe neurologic involvement to asymptomatic adults. There is a characteristic organic aciduria with massive excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, usually in combination with a severe secondary carnitine deficiency. MCC activity in extracts of cultured fibroblasts of patients is usually less than 2% of control (summary by Baumgartner et al., 2001).
Also see 3-methylcrotonylglycinuria I (MCC1D; 210200), caused by mutation in the alpha subunit of 3-methylcrotonyl-CoA carboxylase (MCCC1; 609010).
Beemer et al. (1982) reported 2 Vietnamese sibs with isolated 3-methylcrotonyl-CoA carboxylase deficiency who presented in early childhood shortly after arriving as immigrants to the Netherlands. Both children excreted large amounts of 3-methylcrotonylglycine (MCG) and 3-hydroxyisovaleric acid (HIVA). There was no in vivo or in vitro response to biotin. One patient had transient alopecia. There were no signs of delayed neurologic development. Beemer et al. (1982) suggested that the relatively late onset in these patients was related to the change from a low-protein to a higher-protein diet after arriving in the Netherlands.
Gitzelmann et al. (1987) reported a Swiss child who presented at age 20 months with somnolence, hypoglycemia, ketoacidosis, mild hyperammonemia, and neutrophilia following a presumed gastrointestinal illness. She was found to have isolated MCC deficiency, with normal plasma biotin and biotinidase (609019). A protein-restricted diet resulted in clinical improvement, but urine 3-hydroxyisovalerate and 3-methylcrotonylglycine remained elevated. At 3 years of age, her somatic and psychomotor development was normal, and she had experienced 3 further acute episodes precipitated by infection.
Bannwart et al. (1992) described isolated biotin-resistant MCC deficiency in a son of consanguineous Kurdish parents. He presented on the first day of life with seizures and severe generalized muscular hypotonia. Psychomotor retardation was progressive, and treatment with a leucine restricted diet had no clinical effect. The patient died at age 11 months of cardiac failure after a prolonged epileptic attack.
Mourmans et al. (1995) reported a Dutch family in which 4 children under the age of 6 years had asymptomatic isolated MCC deficiency and low serum carnitine. In vitro studies showed undetectable MCC activity that was not increased by biotin addition to the medium. One child with mild developmental delay had increased levels of 3-hydroxyisovaleric acid in cerebrospinal fluid; with a protein-restricted diet, carnitine supplementation, and physiotherapy, he showed normal development.
Long-term follow-up of a patient with biotin-resistant isolated MCC2 deficiency was reported by Lehnert et al. (1996) and confirmed by mutation in the MCCC2 gene (Baumgartner et al., 2001). Soon after birth, he developed seizures and showed delayed psychomotor development. MCC activity was virtually undetectable. A low-protein leucine-free diet resulted in decreased hydroxyisovaleric acid excretion, and carnitine supplementation was started due to secondary carnitine deficiency. At 10.5 years of age, the patient attended a school for children with learning handicaps.
Gibson et al. (1998) reported isolated MCC deficiency in 4 adult women from the Amish/Mennonite population of Lancaster County, Pennsylvania. Metabolic and enzymatic investigations in these individuals were instituted after the detection of abnormal acylcarnitine profiles in blood spots obtained from their newborn children, in whom enzyme activity was normal. One woman was asymptomatic; one had fatigue and weakness, especially during pregnancy; one had myopathy, weakness, elevated liver enzymes and uric acid, and fatty liver; the last had low free and total carnitine levels.
Baykal et al. (2005) reported a child, born of consanguineous Turkish parents, who presented on the second day of life with dehydration, cyanosis, no sucking, generalized muscular hypotonia, encephalopathy, respiratory depression requiring mechanic ventilation, macrocephaly, severe acidosis, and hypoglycemia. Biochemical findings of elevated urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine suggested MCC deficiency, which was confirmed by enzyme analysis. Cerebral ultrasonography and cranial CT findings revealed progressive changes, including disseminated encephalomalacia, cystic changes, ventricular dilatation and cerebral atrophy. Treatment with high-dose biotin and protein-restricted diet was ineffective, and the patient died at the age of 33 days with progressive neurologic deterioration. Mutation analysis revealed a homozygous mutation in the MCCC2 gene (609014.0010). Baykal et al. (2005) concluded that early-onset severe necrotizing encephalopathy should be included in the differential diagnosis of isolated MCC deficiency.
Shepard et al. (2015) performed whole-exome sequencing on DNA from 33 cases of MCC deficiency and 108 healthy controls and examined these data for associations between MCC mutational status, genetic ancestry, or consanguinity and the absence or presence/specificity of clinical symptoms in MCC deficiency cases. Shepard et al. (2015) determined that individuals with nonspecific clinical phenotypes are highly inbred compared with cases of MCC deficiency that are asymptomatic and with healthy controls. For 5 of the 10 individuals, Shepard et al. (2015) discovered a homozygous damaging mutation in a disease gene that is likely to underlie their nonspecific clinical phenotypes previously attributed to MCC deficiency. The authors concluded that nonspecific phenotypes attributed to MCC deficiency are associated with consanguinity and are likely not due to mutations in the MCC enzyme, but result from rare homozygous mutations in other disease genes.
The transmission pattern of MCC2D in the patients reported by Baumgartner et al. (2001) was consistent with autosomal recessive inheritance.
In the Kurdish patient with MCC2 deficiency reported by Bannwart et al. (1992), Baumgartner et al. (2001) identified a homozygous mutation in the MCCC2 gene (609014.0002).
In the Swiss patient reported by Gitzelmann et al. (1987), Baumgartner et al. (2001) identified a heterozygous mutation in the MCCC2 gene (609014.0001). Although the patient was presumed to be compound heterozygous, a second allele was not identified. The same mutation was identified in the homozygous state in an asymptomatic Mennonite woman from Lancaster county, Pennsylvania. The authors noted that the ancestors of this group of Mennonites originated from Switzerland. Gallardo et al. (2001) identified the same homozygous mutation in 2 asymptomatic Amish/Mennonite patients reported by Gibson et al. (1998).
In a patient with very mild MCC deficiency reported by Mourmans et al. (1995), Baumgartner et al. (2001) identified a heterozygous mutation in the MCCC2 gene (609014.0007). A second allele was not identified.
In a Japanese girl with MCC2 deficiency, Uematsu et al. (2007) identified compound heterozygosity for 2 mutations in the MCCC2 gene (609014.0008; 609014.0009). She developed generalized seizures and impaired consciousness during gastroenteritis at age 1 year and was diagnosed as having a Reye-like syndrome with resultant motor and mental retardation. Two additional asymptomatic Japanese patients with MCC2 deficiency were also found to have different compound heterozygous mutations in the MCCC2 gene. Uematsu et al. (2007) stated that 41 mutations had been identified in the MCCC2 gene.
Bannwart, C., Wermuth, B., Baumgartner, R., Suormala, T., Wiesmann, U. N. Isolated biotin-resistant deficiency of 3-methylcrotonyl-CoA carboxylase presenting as a clinically severe form in a newborn with fatal outcome. J. Inherit. Metab. Dis. 15: 863-868, 1992. [PubMed: 1293382] [Full Text: https://doi.org/10.1007/BF01800223]
Baumgartner, M. R., Almashanu, S., Suormala, T., Obie, C., Cole, R. N., Packman, S., Baumgartner, E. R., Valle, D. The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency. J. Clin. Invest. 107: 495-504, 2001. [PubMed: 11181649] [Full Text: https://doi.org/10.1172/JCI11948]
Baykal, T., Gokcay, G. H., Ince, Z., Dantas, M. F., Fowler, B., Baumgartner, M. R., Demir, F., Can, G., Demirkol, M. Consanguineous 3-methylcrotonyl-CoA carboxylase deficiency: early-onset necrotizing encephalopathy with lethal outcome. J. Inherit. Metab. Dis. 28: 229-233, 2005. [PubMed: 15877210] [Full Text: https://doi.org/10.1007/s10545-005-4559-8]
Beemer, F. A., Bartlett, K., Duran, M., Ghneim, H. K., Wadman, S. K., Bruinvis, L., Ketting, D. Isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase deficiency in two sibs. Europ. J. Pediat. 138: 351-354, 1982. [PubMed: 7128647] [Full Text: https://doi.org/10.1007/BF00442517]
Gallardo, M. E., Desviat, L. R., Rodriguez, J. M., Esparza-Gordillo, J., Perez-Cerda, C., Perez, B., Rodriguez-Pombo, P., Criado, O., Sanz, R., Morton, D. H., Gibson, K. M., Le, T. P., Ribes, A., Rodriguez de Cordoba, S., Ugarte, M., Penalva, M. A. The molecular basis of 3-methylcrotonylglycinuria, a disorder of leucine catabolism. Am. J. Hum. Genet. 68: 334-346, 2001. [PubMed: 11170888] [Full Text: https://doi.org/10.1086/318202]
Gibson, K. M., Bennett, M. J., Naylor, E. W., Morton, D. H. 3-methylcrotonyl-coenzyme A carboxylase deficiency in Amish/Mennonite adults identified by detection of increased acylcarnitines in blood spots of their children. J. Pediat. 132: 519-523, 1998. [PubMed: 9544913] [Full Text: https://doi.org/10.1016/s0022-3476(98)70032-0]
Gitzelmann, R., Steinmann, B., Niederwieser, A., Fanconi, S., Suormala, T., Baumgartner, R. Isolated (biotin-resistant) 3-methylcrotonyl-CoA carboxylase deficiency presenting at age 20 months with sopor, hypoglycaemia, and ketoacidosis. J. Inherit. Metab. Dis. 10 (suppl. 2): 290-292, 1987.
Lehnert, W., Niederhoff, H., Suormala, T., Baumgartner, E. R. Isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase deficiency: long-term outcome in a case with neonatal onset. Europ. J. Pediat. 155: 568-572, 1996. [PubMed: 8831079] [Full Text: https://doi.org/10.1007/BF01957906]
Mourmans, J., Bakkeren, J., de Jong, J., Wevers, R., van Diggelen, O. P., Suormala, T., Baumgartner, R., Wendel, U. Isolated (biotin-resistant) 3-methylcrotonyl-CoA carboxylase deficiency: four sibs devoid of pathology. J. Inherit. Metab. Dis. 18: 643-645, 1995. [PubMed: 8598650] [Full Text: https://doi.org/10.1007/BF02436014]
Shepard, P. J., Barshop, B. A., Baumgartner, M. R., Hansen, J.-B., Jepsen, K., Smith, E. N., Frazer, K. A. Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD. Genet. Med. 17: 660-667, 2015. [PubMed: 25356967] [Full Text: https://doi.org/10.1038/gim.2014.157]
Uematsu, M., Sakamoto, O., Sugawara, N., Kumagai, N., Morimoto, T., Yamaguchi, S., Hasegawa, Y., Kobayashi, H., Ihara, K., Yoshino, M., Watanabe, Y., Inokuchi, T., Yokoyama, T., Kiwaki, K., Nakamura, K., Endo, F., Tsuchiya, S., Ohura, T. Novel mutations in five Japanese patients with 3-methylcrotonyl-CoA carboxylase deficiency. J. Hum. Genet. 52: 1040-1043, 2007. [PubMed: 17968484] [Full Text: https://doi.org/10.1007/s10038-007-0211-9]