3-Methylglutaconic Aciduria, Type Ix

A number sign (#) is used with this entry because of evidence that 3-methylglutaconic aciduria type IX (MGCA9) is caused by homozygous mutation in the TIMM50 gene (607381) on chromosome 19q13.

Description

MGCA9 is an autosomal recessive disorder characterized by early-onset seizures, severely delayed psychomotor development and intellectual disability. Patients have hypotonia or spasticity, and laboratory investigations show increased serum lactate and 3-methylglutaconic aciduria, suggestive of a mitochondrial defect (summary by Shahrour et al., 2017).

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

Clinical Features

Shahrour et al. (2017) reported 4 patients from 2 unrelated consanguineous families with an epileptic encephalopathy. The patients presented in the first months of life with seizures after a normal neonatal period. In 1 family, the seizures were associated with hypsarrhythmia on electroencephalogram (EEG), whereas in the other family, EEG showed mild abnormalities or depressed background activity. The seizures showed a favorable response to medication. The patients had hypotonia and delayed psychomotor development with delayed walking, severe intellectual disability, and poor or absent speech. Brain imaging showed progressive bilateral widening of the ventricles, consistent with brain atrophy. Laboratory investigations showed mildly increased serum lactate and 3-methylglutaconic aciduria. Two sibs in the first family showed failure to thrive in childhood and optic atrophy. In the first family, a 9-year-old girl was not toilet trained and was profoundly retarded, aggressive, restless, and unable to communicate. Brain imaging showed some white matter abnormalities. In the second family, a 15-year-old could walk and climb stairs but was unable to feed himself, had only 10 words, and was hyperactive and aggressive. His 10-year-old sister was not toilet trained, had no communication, showed failure to thrive with muscle weakness, spasticity, increased muscle tone, and clonus, and behaved aggressively. Brain imaging of this patient showed generalized atrophy and white matter signal abnormalities. Muscle biopsy from 1 patient in the first family showed normal activity of mitochondrial respiratory enzymes, whereas muscle biopsy from 1 patient in the second family showed decreased activity of complex V (54% of controls). Shahrour et al. (2017) noted that 3MGA is an important biomarker for mitochondrial dysfunction.

Inheritance

The transmission pattern of MGCA9 in the families reported by Shahrour et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from 2 unrelated consanguineous families with MGCA9, Shahrour et al. (2017) identified homozygous missense mutations in the TIMM50 gene (T252M, 607381.0001 and R217W, 607381.0002). The mutations, which were found by exome sequencing, segregated with the disorder in the family. The human homolog of TIMM50 failed to rescue a Tim50-null growth defect in yeast, and expression of the homologous substitution for R217W (R159W) in yeast resulted in normal growth and did not impair the import function of Tim50. These findings indicated that this substitution is tolerated in yeast, but not in humans. Although Shahrour et al. (2017) could not demonstrate the pathogenicity of the mutations in a yeast-based system, they concluded that they are disease-causing.