Combined Oxidative Phosphorylation Deficiency 27

A number sign (#) is used with this entry because of evidence that combined oxidative phosphorylation deficiency-27 (COXPD27) is caused by homozygous or compound heterozygous mutation in the CARS2 gene (612800) on chromosome 13q34.

For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Clinical Features

Coughlin et al. (2015) reported a boy, born of unrelated Scandinavian parents, with a combined mitochondrial respiratory chain deficiency associated with epileptic encephalopathy and a complex movement disorder. The patient presented at 5 weeks of age with opisthotonus and feeding difficulties resulting in failure to thrive. He later showed delayed psychomotor development, hypotonia, and abnormal movements, such as chorea, dystonia with oculogyric episodes, and myoclonus. At age 3 years, 10 months, he developed refractory complex partial epilepsy and status epilepticus. By age 8 years or so, he did not have antigravity movements or purposeful eye movements. Brain imaging showed progressive cortical atrophy, atrophy of the white matter with abnormal T2-weighted signals, thin corpus callosum, and cerebellar atrophy. Serum lactate was increased, and liver biopsy showed microvesicular steatosis and decreased activity of mitochondrial respiratory chain enzyme complexes I, III, and IV. Muscle biopsy showed normal histology, mildly decreased activities of complexes I and IV, and a compensatory increase in mitochondrial DNA. Incomplete assembly of complex V was also detected in patient cells.

Clinical Variability

Hallmann et al. (2014) reported 2 sibs, born of consanguineous Turkish parents, with a neurodegenerative disorder reminiscent of the mitochondrial disorder myoclonus epilepsy with ragged-red fibers (MERRF; 545000). The patients died at ages 28 and 18 years. The proband developed generalized myoclonic epilepsy at age 9 years and was able to attend school until the fourth grade. His sister developed myoclonus at age 5, and generalized seizures at age 10-12 years. She showed cognitive decline and left school before the second grade. Both patients showed progressive visual and hearing impairment and progressive tetraparesis. Brain imaging findings were variable, but consistent with neurodegeneration, including brain atrophy and white matter lesions. The girl had increased serum lactate, but the brother had normal lactate levels. Muscle biopsies from the patients were not available. Coughlin et al. (2015) commented that the sibs reported by Hallmann et al. (2014) had a similar complex and progressive epileptic disorder to the boy reported by them, although the ages at onset varied.

Inheritance

The transmission pattern of COXPD27 in the family reported by Coughlin et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of consanguineous Turkish parents, with a neurodegenerative disorder clinically similar to COXPD27, Hallmann et al. (2014) identified a homozygous splice site mutation in the CARS2 gene (612800.0001). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Analysis of parental cells showed that the mutation caused a splicing defect and the skipping of exon 6, which resulted in an in-frame deletion. Further functional studies were not performed, but the mutation was predicted to result in mitochondrial dysfunction and impaired translation.

In a boy, born of unrelated Scandinavian parents, with COXPD27, Coughlin et al. (2015) identified compound heterozygous mutations in the CARS2 gene (612800.0002 and 612800.0003). The mutations were identified by exome sequencing and segregated with the disorder in the family. Patient cells showed a decrease in CARS2 protein levels, and Northern blot analysis of patient fibroblasts showed a decrease in the ratio of aminoacylated and deacylated mt-tRNA(Cys) compared to controls. The assembly defect of mitochondrial complex V in patient cells was rescued by transfection with wildtype CARS2. Sanger sequencing of all 15 coding exons and exon-intron boundaries of CARS2 in 15 additional patients with a mitochondrial disorder did not identify potential pathogenic mutations; in addition, 8 international mitochondrial and exome sequencing centers were contacted to evaluate existing exome sequencing data, but no other patients with potential CARS2 mutations were identified.