Combined Oxidative Phosphorylation Deficiency 32

A number sign (#) is used with this entry because of evidence that combined oxidative phosphorylation deficiency-32 (COXPD32) is caused by homozygous or compound heterozygous mutation in the MRPS34 gene (611994) on chromosome 16q13.

Description

Combined oxidative phosphorylation deficiency-32 is an autosomal recessive neurodegenerative disorder characterized by onset of delayed psychomotor development and developmental regression in infancy. Affected individuals have multiple variable symptoms, including poor or absent speech, inability to walk, and abnormal movements. Brain imaging shows T2-weighted abnormalities in the basal ganglia and brainstem consistent with Leigh syndrome (256000). Patient cells showed decreased activities of mitochondrial respiratory chain complexes, I, III, and IV, as well as impaired mitochondrial translation (summary by Lake et al., 2017).

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

Clinical Features

Lake et al. (2017) reported 6 patients from 4 unrelated families with COXPD. Two families were of Puerto Rican descent, 1 was Italian, and 1 French. Five patients presented in the first 4 to 6 months of life with developmental delay and neurodevelopmental regression. The sixth child (patient S4) presented at 10 days of age with poor feeding and neurologic symptoms, such as no eye contact, hypotonia, dystonia, and pyramidal syndrome of the lower limbs; he died at age 8.5 months. Another child (S1), born of consanguineous Italian parents, showed poor feeding, irritability, lethargy, and intermittent breathing abnormalities; he died at age 9 months. The other children were alive between 2 and 17 years of age. All had a similar disease course, with axial hypotonia, delayed psychomotor development, often with regression or loss of milestones, inability to walk, poor or absent speech, and abnormal movements, including tremor, spasticity, choreoathetoid movements, hyperkinetic movements, hyperreflexia, and dystonia. More variable features included dysconjugate eye movements, exotropia, strabismus, nystagmus, kyphoscoliosis, and mild joint contractures. Two sisters had severe microcephaly (-8 SD) and coarse facial features, and 1 patient had optic atrophy with central vision loss. Brain imaging in all patients showed abnormal T2-weighted signals in the brainstem and basal ganglia, consistent with Leigh syndrome. Muscle biopsies showed variably decreased activities of mitochondrial respiratory complexes I, III, and IV. Laboratory studies showed increased serum and CSF lactate. Postmortem examination of the brain in 1 patient showed rarefied neuropil, vascular proliferation, and gliosis affecting the brainstem, inferior cerebellar peduncles, midbrain, basal ganglia, and thalami.

Inheritance

The transmission pattern of COXPD32 in the families reported by Lake et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 6 patients from 4 unrelated families with COXPD32, Lake et al. (2017) identified homozygous or compound heterozygous mutations in the MRPS34 gene (611994.0001-611994.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patients cells showed decreased levels of MRPS34 protein, consistent with a loss of function, variably decreased activities of mitochondrial respiratory complexes I, III, and IV, and a defect in mitochondrial translation. Patient cells showed decreased levels and assembly of small mitoribosome subunit proteins with sparing of the large subunit; these findings were consistent with destabilization of the small subunit. Expression of wildtype MRPS34 rescued these cellular defects.