3-Methylglutaconic Aciduria, Type Iii

A number sign (#) is used with this entry because 3-methylglutaconic aciduria type III, also known as autosomal recessive optic atrophy-3 or optic atrophy plus syndrome, is caused by mutation in the OPA3 gene (606580).

See also autosomal dominant optic atrophy-3 (165300), an allelic disorder with a less severe phenotype.

For a phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (250950).

Description

Type III 3-methylglutaconic aciduria 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).

Clinical Features

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.

Mapping

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.

Molecular Genetics

Anikster et al. (2001) identified an intronic G-to-C 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.

In a boy with 3-methylglutaconic aciduria type III, Kleta et al. (2002) identified a homozygous deletion in the OPA3 gene (606580.0004).