Alternative titles; symbols
SNOMEDCT: 297232009; ORPHA: 67047; DO: 0110004;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.32 | 3-methylglutaconic aciduria, type III | 258501 | Autosomal recessive | 3 | OPA3 | 606580 |
A number sign (#) is used with this entry because 3-methylglutaconic aciduria type III (MGCA3), also known as autosomal recessive optic atrophy-3 or optic atrophy plus syndrome, is caused by homozygous mutation in the OPA3 gene (606580) on chromosome 19q13.
See also autosomal dominant optic atrophy-3 (165300), an allelic disorder with a less severe phenotype.
3-Methylglutaconic aciduria type III (MGCA3) is a neuroophthalmologic syndrome consisting of early-onset bilateral optic atrophy and later-onset spasticity, extrapyramidal dysfunction, and cognitive deficit. Urinary excretion of 3-methylglutaconic acid and of 3-methylglutaric acid is increased (Anikster et al., 2001). The phenotype is similar to Behr syndrome (210000) and may in some cases represent the same disorder (Sheffer et al., 1992; Lerman-Sagie, 1995).
For a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (250950).
Costeff et al. (1989) described 19 patients with a familial syndrome consisting of infantile optic atrophy and an early-onset extrapyramidal movement disorder dominated by chorea. About half the patients developed spastic paraparesis during the second decade of life. Ataxia and cognitive defects were common, but usually of mild degree. Seventeen of the patients were female. Seventeen patients were distributed in 7 families. The remaining 3 were sporadic cases. Their oldest patient was 26 at the last observation and several other patients were in their twenties. The youngest patients were aged 3 years. Parental consanguinity was identified in 4 of the 10 sibships; 2 instances of first-cousin parents and 2 instances of first cousins once removed were observed. Nine of the 10 families, including all of those with multiple affected sibs, belonged to the Iraqi Jewish community in Israel, a group with an estimated minimal prevalence rate of 1:10,000. The disorder bore some similarity to Behr syndrome (210000) but the neurologic aspects were distinctive.
Chitayat et al. (1992) alluded to the occurrence of 3-methylglutaconic aciduria in this disorder and designated the condition 3-methylglutaconic aciduria type III.
Sheffer et al. (1992) reported 3 patients from 2 families of Jewish Iraqi origin with early-onset optic atrophy and neurologic symptoms compatible with Behr syndrome. Neurologic signs included hyperreflexia, extensor plantar responses, spastic paraplegia, dysarthria, head nodding, and horizontal nystagmus. The patients also excreted 3-methylglutaconic acid in the urine. Inheritance was autosomal recessive.
Elpeleg et al. (1994) reported 11 new patients of Iraqi Jewish origin with the same clinical syndrome associated with 3-methylglutaconic aciduria and reviewed the clinical and biochemical findings in 36 patients. The report defined a homogeneous group of patients with type III MGCA. They differed from patients with type I MGCA by the normal 3-methylglutaconyl-CoA hydratase activity in their fibroblasts. They differed from patients with type II MGCA (302060) by the absence of cardiomyopathy, short stature, and neutropenia. In addition, the mode of transmission in type III is rather clearly autosomal recessive, whereas in type II it appears to be X-linked.
Kleta et al. (2002) reported a boy with type III 3-methylglutaconic aciduria who was born of consanguineous Kurdish Turkish parents. As a child, he had ataxic gait and 3-methylglutaconic aciduria. Decreased visual acuity with optic atrophy was diagnosed at age 9 years. At age 13, he was physically active with normal cognition, but had mild ataxic restlessness.
Yahalom et al. (2014) described 28 patients with MGCA3, ranging in age from 6 months to 68 years, from 21 Middle Eastern families, predominantly of Iraqi origin. Consanguinity was documented in 9 families. 3-Methylglutaconic aciduria was found in all 17 patients tested. Symptoms usually manifested in infancy or early childhood with delayed milestones. Ataxia and chorea, which were prominent features in childhood, were usually mild or moderate and did not appear to progress with age. Progressive pyramidal dysfunction presented later, leading to a high frequency of gait impairment, although most patients maintained ambulation. Dysarthria was seen in 22 patients. All 8 patients who had a neuroophthalmologic evaluation had optic atrophy, and visual acuity was severely affected in 6 of them. Of 8 patients who had MRIs, cerebellar atrophy was seen in 7, pontine atrophy in 3, and optic chiasm atrophy in 4. There was no evidence of cognitive deterioration with age.
Carmi et al. (2015) reported a 5-year-old girl, born to consanguineous Syrian Jewish parents, with an atypical presentation of type III MGCA. She had normal development until 7 months of age, when she developed dystonia and chorea and had regression of milestones. She also had unilateral optic atrophy, and 3-methylglutaconic aciduria was detected. At age 10 months, brain MRI and EEG were normal. Repeat urine testing did not show 3-methylglutaconic aciduria, but molecular testing confirmed MGCA3. At age 17 months, she developed focal seizures, and an EEG showed bilateral epileptic activity. At age 5 years, she had bilateral optic atrophy, choreoathetosis, and generalized hypotonia; she could not stand or walk, and had no effective speech due to severe dysarthria.
By using a DNA pooling strategy to perform a genomewide screen followed by a high density search for shared segments among affected individuals in candidate regions identified in the initial screen, Nystuen et al. (1997) demonstrated linkage to 19q13.2-q13.3. A lod score of 6.14 at zero recombination was obtained for the CTG repeat in the 3-prime untranslated region of the myotonic dystrophy protein kinase gene. Among the candidate genes within the 1 Mb segment which showed linkage disequilibrium was muscle type creatine kinase (CKM; 123310). However, single-strand conformation analysis and complete sequencing of the CKM gene region showed no abnormalities in the Iraqi Jewish patients.
The transmission pattern of MGCA3 in the patients reported by Anikster et al. (2001) was consistent with autosomal recessive inheritance.
Anikster et al. (2001) identified a homozygous splice site mutation in the OPA3 gene (606580.0001) in several Iraqi Jewish patients with 3-methylglutaconic aciduria type III. The authors suggested that milder mutations of OPA3 should be sought in patients with optic atrophy with later onset, even in the absence of additional neurologic abnormalities. Yahalom et al. (2014) identified the same splice mutation in the OPA3 gene in 14 patients with MGCA3, all but one of whom were from Iraqi Jewish families. Carmi et al. (2015) identified this splice site mutation in another Iraqi Jewish patient with MGCA3.
In a boy, born of first-cousin Kurdish-Turkish parents, with 3-methylglutaconic aciduria type III, Kleta et al. (2002) identified a homozygous deletion in the OPA3 gene (606580.0004).
In an 18-year-old patient, born to nonconsanguineous Indian parents, with MGCA3, Ho et al. (2008) identified a presumed homozygous nonsense mutation in exon 2 of the OPA3 gene (Q139X; 606580.0006). The unaffected father was a carrier for this mutation but DNA from the mother was not available for testing. The authors could not exclude the possibility that the patient had inherited deletion of exon 2 from the mother.
In 2 cousins (family DYAF09), born to consanguineous Pakistani parents, with MGCA3, Arif et al. (2013) identified a homozygous missense mutation in the OPA3 gene (L11Q; 606580.0005). The mutation, which was identified by genomewide homozygosity mapping and exome sequencing, segregated with the disorder in the family. The variant was not present in the NHLBI Exome Sequencing Project database.
Anikster, Y., Kleta, R., Shaag, A., Gahl, W. A., Elpeleg, O. Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. Am. J. Hum. Genet. 69: 1218-1224, 2001. [PubMed: 11668429] [Full Text: https://doi.org/10.1086/324651]
Arif, B., Kumar, K. R., Seibler, P., Vulinovic, F., Fatima, A., Winkler, S., Nurnberg, G., Thiele, H., Nurnberg, P., Jamil, A. Z., Bruggemann, A., Abbas, G., Klein, C., Lohmann, K. A novel OPA3 mutation revealed by exome sequencing: an example of reverse phenotyping. JAMA Neurol. 70: 783-787, 2013. [PubMed: 23700088] [Full Text: https://doi.org/10.1001/jamaneurol.2013.1174]
Carmi, N., Lev, D., Leshinsky-Silver, E., Anikster, Y., Blumkin, L., Kivity, S., Lerman-Sagie, T., Zerem, A. Atypical presentation of Costeff syndrome--severe psychomotor involvement and electrical status epilepticus during slow wave sleep. Europ. J. Paediat. Neurol. 19: 733-736, 2015. [PubMed: 26190011] [Full Text: https://doi.org/10.1016/j.ejpn.2015.06.006]
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]
Costeff, H., Gadoth, N., Apter, N., Prialnic, M., Savir, H. A familial syndrome of infantile optic atrophy, movement disorder, and spastic paraplegia. Neurology 39: 595-597, 1989. [PubMed: 2494568] [Full Text: https://doi.org/10.1212/wnl.39.4.595]
Elpeleg, O. N., Costeff, H., Joseph, A., Shental, Y., Weitz, R., Gibson, K. M. 3-Methylglutaconic aciduria in the Iraqi-Jewish 'optic atrophy plus' (Costeff) syndrome. Dev. Med. Child Neurol. 36: 167-172, 1994. [PubMed: 7510656] [Full Text: https://doi.org/10.1111/j.1469-8749.1994.tb11825.x]
Ho, G., Walter, J. H., Christodoulou, J. Costeff optic atrophy syndrome: new clinical case and novel molecular findings. J. Inherit. Metab. Dis. 31 (Suppl. 2): S419-S423, 2008. [PubMed: 18985435] [Full Text: https://doi.org/10.1007/s10545-008-0981-z]
Kleta, R., Skovby, F., Christensen, E., Rosenberg, T., Gahl, W. A., Anikster, Y. 3-Methylglutaconic aciduria type III in a non-Iraqi-Jewish kindred: clinical and molecular findings. Molec. Genet. Metab. 76: 201-206, 2002. [PubMed: 12126933] [Full Text: https://doi.org/10.1016/s1096-7192(02)00047-1]
Lerman-Sagie, T. Behr syndrome. (Letter) Pediat. Neurol. 12: 90 only, 1995. [PubMed: 7538304] [Full Text: https://doi.org/10.1016/0887-8994(95)95022-u]
Nystuen, A., Costeff, H., Elpeleg, O. N., Apter, N., Bonne-Tamir, B., Mohrenweiser, H., Haider, N., Stone, E. M., Sheffield, V. C. Iraqi-Jewish kindreds with optic atrophy plus (3-methylglutaconic aciduria type 3) demonstrate linkage disequilibrium with the CTG repeat in the 3-prime untranslated region of the myotonic dystrophy protein kinase gene. Hum. Molec. Genet. 6: 563-569, 1997. [PubMed: 9097959] [Full Text: https://doi.org/10.1093/hmg/6.4.563]
Sheffer, R. N., Zlotogora, J., Elpeleg, O. N., Raz, J., Ben-Ezra, D. Behr's syndrome and 3-methylglutaconic aciduria. Am. J. Ophthal. 114: 494-497, 1992. [PubMed: 1384336] [Full Text: https://doi.org/10.1016/s0002-9394(14)71864-1]
Yahalom, G., Anikster, Y., Huna-Baron, R., Hoffmann, C., Blumkin, L., Lev, D., Tsabari, R., Nitsan, Z., Lerman, S. F., Ben-Zeev, B., Pode-Shakked, B., Sofer, S., Schweiger, A., Lerman-Sagie, T., Hassin-Baer, S. Costeff syndrome: clinical features and natural history. J. Neurol. 261: 2275-2282, 2014. [PubMed: 25201222] [Full Text: https://doi.org/10.1007/s00415-014-7481-x]