Alternative titles; symbols
SNOMEDCT: 13144005; ORPHA: 6; DO: 0080579;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q27.1 | 3-Methylcrotonyl-CoA carboxylase 1 deficiency | 210200 | Autosomal recessive | 3 | MCCC1 | 609010 |
A number sign (#) is used with this entry because of evidence that 3-methylcrotonylglycinuria I (MCC1D) is caused by homozygous or compound heterozygous mutation in the gene encoding the alpha subunit of 3-methylcrotonyl-CoA carboxylase (MCCC1; 609010) on chromosome 3q27.
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 II (MCC2D; 210210), caused by mutation in the beta subunit of 3-methylcrotonyl-CoA carboxylase (MCCC2; 609014).
Eldjarn et al. (1970) reported a patient with excess urinary excretion of beta-methylcrotonylglycine (MCG). The main clinical features included muscular hypotonia and atrophy, suggestive of a neurologic defect. The disorder was gradually progressive despite a diet low in leucine, which reduced excretion of the abnormal metabolites. Both parents and 2 sibs excreted one of the abnormal metabolites and were considered to be heterozygous. In a follow-up report of the patient reported by Eldjarn et al. (1970), Stokke et al. (1972) noted that biotin was of no therapeutic value. Stokke et al. (1972) identified a deficiency of beta-methylcrotonyl-CoA carboxylase.
Tanaka and Isselbacher (1970) observed beta-hydroxyisovaleric aciduria induced by biotin deficiency in an experimental animal model. They concluded that the results, similar to those seen in human MCC deficiency, were caused by a metabolic block of beta-methylcrotonyl-CoA carboxylase, which is dependent on biotin.
Finnie et al. (1976) reported a 3-month-old child who presented with a history of feeding problems and failure to thrive, and later developed seizures and profound irreversible metabolic acidosis. There was gross excretion of 2-oxoglutaric and 3-hydroxyisovaleric (HIVA) acid. Postmortem liver enzyme studies showed a deficiency of 3-methylcrotonyl-CoA carboxylase.
Roth et al. (1976) reported a patient with high urinary excretion of beta-methylcrotonic acid and hydroxyphenyllactic acid, but low excretion of hydroxyisovaleric acid, and suggested that the disorder was acquired secondary to congenital heart disease.
Bartlett et al. (1984) reported a 22-month-old girl who presented in a hypotonic, unconscious state with involuntary movements of the upper limbs. She had hypoglycemia, mild metabolic acidosis, and gross neutrophilia. 3-Methylcrotonyl-CoA carboxylase activity was undetectable in fibroblasts regardless of biotin concentration in the medium. The patient recovered and remained well on a protein-restricted diet, but continued to excrete excess MCG and HIVA.
Layward et al. (1989) reported a patient who presented at age 14 months with an episode of apnea, involuntary movements, and back-arching after 4 days of diarrhea. He had severe hypoglycemia, hyperammonemia, mild metabolic acidosis, and ketonuria. A liver biopsy showed diffuse macro- and microvesicular fatty infiltration consistent with Reye syndrome. Urine organic acid analysis showed increased 3-hydroxyisovalerate and 3-methylcrotonylglycine. Cultured fibroblasts from the patient showed less than 1% normal activity and was unresponsive to biotin.
A patient reported by Rolland et al. (1991) was born of consanguineous parents and presented at age 14 months in a subcoma with hypoglycemia and ketoacidosis; at age 16 months, she had a second episode with drowsiness, diarrhea, hypoglycemia, and hypotonia. Urinary organic acid analysis showed HIVA and MCG, and cultured fibroblasts had less than 1% normal MCC activity. She recovered from the acute episodes and was treated successfully with a protein-restricted diet and carnitine supplementation, although excess urinary excretion of HIVA and MCG persisted.
Elpeleg et al. (1992) found hypotonia as the initial symptom in 4 sibs, aged 2.5 to 9 years, with isolated 3-MCC deficiency in a nonconsanguineous Tunisian-Jewish family. Plasma carnitine was markedly deficient and urinary organic acid analysis demonstrated increased excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. 3-MCC enzyme activity was reduced in skin fibroblasts. Pearson et al. (1995) reported biotin-resistant isolated MCC deficiency in a 2-year-old boy who first presented with lethargy after mild head trauma, and later with Shigella gastroenteritis. The authors emphasized the benign nature of the disorder in this patient, which was only diagnosed during episodes of metabolic decompensation. The child had normal growth and development.
Murayama et al. (1997) reported a 15-year-old Japanese girl with a former clinical diagnosis of cerebral palsy who was found to have isolated 3-MCC deficiency. She had growth retardation from birth, profound mental retardation, tonic seizures, quadriplegia with opisthotonic dystonia, and gastroesophageal reflux. Brain MRI showed marked brain atrophy. Murayama et al. (1997) noted that she was the oldest reported patient.
Steen et al. (1999) reported a mildly retarded infant with failure to thrive who developed hypoglycemia, focal seizures, respiratory failure, and hemiparesis during a febrile episode at the age of 16 months. A brain scan was initially normal and showed hemilateral focal edema and gliosis at later stages. 3-MCC deficiency was suggested by elevated urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, and confirmed by enzyme assays. The patient was treated with protein restriction and carnitine and remained stable during the following 5 years, but hemiparesis and some developmental delay persisted. Steen et al. (1999) suggested that 3-methylcrotonyl-CoA carboxylase deficiency be added to the list of possible causes of metabolic stroke.
De Kremer et al. (2002) reported a patient from Argentina with isolated biotin-resistant MCC deficiency diagnosed at 14 months of age. Clinical features included severe psychomotor retardation, hypotonia, areflexia, and failure to thrive. The patient died at age 3 years. Brain MRI at 14 months showed multiple foci of leukodystrophy, and there were also high levels of oxypurines in the cerebrospinal fluid, which the authors suggested resulted from energetic consequences of enzyme deficiency in the brain. The findings extended the phenotype of 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 these 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 MCC1D in the patients reported by Baumgartner et al. (2001) and Gallardo et al. (2001) was consistent with autosomal recessive inheritance.
In 4 patients with MCC deficiency with less than 10% normal MCC activity, Baumgartner et al. (2001) identified homozygous mutations in the MCCA gene (see, e.g., 609010.0002-609010.0004). One of the patients had been reported by Steen et al. (1999).
In 2 patients with MCC deficiency, Gallardo et al. (2001) identified homozygous mutations in the MCCA gene (609010.0001-609010.0002).
Uematsu et al. (2007) identified compound heterozygous or homozygous mutations in the MCCA gene (see, e.g., 609101.0007) in 2 unrelated Japanese patients with MCC1 deficiency. One of the patients was a severely affected woman who had been reported by Murayama et al. (1997). Uematsu et al. (2007) stated that 28 different mutations had been reported in the MCCA gene.
Gallardo et al. (2001) reviewed preliminary reports that the use of neonatal screening of organic acidurias by tandem mass spectrometry shows that methylcrotonylglycinuria has an unexpectedly high frequency and that in certain populations it may be the most frequent organic aciduria.
Baumgartner et al. (2001) noted that the introduction of tandem mass spectrometry in newborn screening revealed an unexpectedly high incidence of MCC deficiency, occurring in approximately 1 in 50,000 individuals, rendering it the most common organic aciduria in some populations.
Stadler et al. (2006) elaborated the rationale for decision making in MCC deficiency (MCCD). In Bavaria, they screened 677,852 neonates for 25 conditions, including MCCD, basing the last screen on elevated concentrations of 3-hydroxyisovalerylcarnitine (3-HIVA-C). Genotypes of the MCCA (609010) and MCCB (609014) genes were assessed in identified newborns, their relatives, and in individuals from other regions, and correlated to biochemical and clinical phenotypes. Newborn screening revealed 8 newborns and 6 relatives with MCCD, suggesting a higher frequency than previously assumed, namely, 1:84,700. The authors found a strikingly heterogeneous spectrum of 22 novel and 8 reported mutations. Allelic variants were neither related to biochemical nor anamnestic data of the probands, all of whom showed asymptomatic or benign phenotypes. Stadler et al. (2006) found from analysis of case reports with newborn screening data that only a few individuals (less than 10%) develop symptoms. In addition, none of the symptoms reported can clearly be attributed to MCCD. Thus, MCCD is a genetic condition with low clinical expressivity and penetrance. It is represented largely as nondisease. There were no genetic or biochemical markers that would identify the few individuals potentially at risk for harmful clinical expression. The low ratio of benefit to harm was pivotal to the decision to exclude MCCD from NBS in Germany. MCCD may be regarded as exemplary of the ongoing controversy arising from the inclusion of potentially asymptomatic conditions, which generates a psychologic burden for affected families and a financial burden for health care systems.
Bartlett, K., Bennett, M. J., Hill, R. P., Lashford, L. S., Pollitt, R. J., Worth, H. G. J. Isolated biotin-resistant 3-methylcrotonyl CoA carboxylase deficiency presenting with life-threatening hypoglycaemia. J. Inherit. Metab. Dis. 7: 182 only, 1984. [PubMed: 6441868] [Full Text: https://doi.org/10.1007/BF01805608]
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]
de Kremer, R. D., Latini, A., Suormala, T., Baumgartner, E. R., Larovere, L., Civallero, G., Guelbert, N., Paschini-Capra, A., Depetris-Boldini, C., Mayor, C. Q. Leukodystrophy and CSF purine abnormalities associated with isolated 3-methylcrotonyl-CoA carboxylase deficiency. Metab. Brain Dis. 17: 13-18, 2002. [PubMed: 11893004] [Full Text: https://doi.org/10.1023/a:1014096112916]
Eldjarn, L., Jellum, E., Stokke, O., Pande, H., Waaler, P. E. Beta-hydroxyisovaleric aciduria and beta-methylcrotonylglycinuria: a new inborn error of metabolism. Lancet 296: 521-522, 1970. Note: Originally Volume 2. [PubMed: 4194964] [Full Text: https://doi.org/10.1016/s0140-6736(70)90140-6]
Elpeleg, O. N., Havkin, S., Barash, V., Jakobs, C., Glick, B., Shalev, R. S. Familial hypotonia of childhood caused by isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency. J. Pediat. 121: 407-410, 1992. [PubMed: 1517917] [Full Text: https://doi.org/10.1016/s0022-3476(05)81796-2]
Finnie, M. D. A., Cottrall, K., Seakins, J. W. T., Snedden, W. Massive excretion of 2-oxoglutaric acid and 3-hydroxyisovaleric acid in a patient with a deficiency of 3-methylcrotonyl-CoA carboxylase. Clin. Chim. Acta 73: 513-519, 1976. [PubMed: 1000869] [Full Text: https://doi.org/10.1016/0009-8981(76)90155-8]
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]
Holzinger, A., Roschinger, W., Lagler, F., Mayerhofer, P. U., Lichtner, P., Kattenfeld, T., Thuy, L. P., Nyhan, W. L., Koch, H. G., Muntau, A. C., Roscher, A. A. Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency. Hum. Molec. Genet. 10: 1299-1306, 2001. [PubMed: 11406611] [Full Text: https://doi.org/10.1093/hmg/10.12.1299]
Layward, E. M., Tanner, M. S., Pollitt, R. J., Bartlett, K. Isolated biotin-resistant 3-methylcrotonyl CoA-carboxylase deficiency presenting as a Reye syndrome-like illness. J. Inherit. Metab. Dis. 12: 339-340, 1989. [PubMed: 2515383] [Full Text: https://doi.org/10.1007/BF01799234]
McLean, J., Stewart, G. Mitochondrial inclusions in fibroblast culture from a patient with beta-methylcrotonylglycinuria. J. Med. Genet. 11: 257-269, 1974. [PubMed: 4372354] [Full Text: https://doi.org/10.1136/jmg.11.3.257]
Murayama, K., Kimura, M., Yamaguchi, S., Shinka, T., Kodama, K. Isolated 3-methylcrotonyl-CoA carboxylase deficiency in a 15-year-old girl. Brain Dev. 19: 303-305, 1997. [PubMed: 9187484] [Full Text: https://doi.org/10.1016/s0387-7604(97)86920-3]
Pearson, M. A., Aleck, K. A., Heidenreich, R. A. Benign clinical presentation of 3-methylcrotonylglycinuria. J. Inherit. Metab. Dis. 18: 640-641, 1995. [PubMed: 8598648] [Full Text: https://doi.org/10.1007/BF02436012]
Rolland, M. O., Divry, P., Zabot, M. T., Guibaud, P., Gomez, S., Lachaux, A., Loras, I. Isolated 3-methylcrotonyl-CoA carboxylase deficiency in a 16-month-old child. J. Inherit. Metab. Dis. 14: 838-839, 1991. [PubMed: 1779635] [Full Text: https://doi.org/10.1007/BF01799962]
Roth, K., Cohn, R., Yandrasitz, J., Preti, G., Dodd, P., Segal, S. Beta-methylcrotonic aciduria associated with lactic acidosis. J. Pediat. 88: 229-235, 1976. [PubMed: 1249684] [Full Text: https://doi.org/10.1016/s0022-3476(76)80987-0]
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]
Stadler, S. C., Polanetz, R., Maier, E. M., Heidenreich, S. C., Nieder, B., Mayerhofer, P. U., Lagler, F., Koch, H.-G., Santer, R., Fletcher, J. M., Ranieri, E., Das, A. M., and 14 others. Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency: population heterogeneity of MCCA and MCCB mutations and impact on risk assessment. Hum. Mutat. 27: 748-759, 2006. [PubMed: 16835865] [Full Text: https://doi.org/10.1002/humu.20349]
Steen, C., Baumgartner, E. R., Duran, M., Lehnert, W., Suormala, T., Fingerhut, R., Stehn, M., Kohlschutter, A. Metabolic stroke in isolated 3-methylcrotonyl-CoA carboxylase deficiency. Europ. J. Pediat. 158: 730-733, 1999. [PubMed: 10485305] [Full Text: https://doi.org/10.1007/s004310051189]
Stokke, O., Eldjarn, L., Jellum, E., Pande, H., Waaler, P. E. Beta-methylcrotonyl-CoA carboxylase deficiency: a new metabolic error in leucine degeneration. Pediatrics 49: 726-735, 1972. [PubMed: 5035417]
Tanaka, K. R., Isselbacher, K. J. Experimental beta-hydroxyisovaleric aciduria induced by biotin deficiency. (Letter) Lancet 296: 930-931, 1970. Note: Originally Volume 2. [PubMed: 4097310] [Full Text: https://doi.org/10.1016/s0140-6736(70)92104-5]
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]