Combined Oxidative Phosphorylation Deficiency 39

A number sign (#) is used with this entry because of evidence that combined oxidative phosphorylation deficiency-39 (COXPD39) is caused by homozygous or compound heterozygous mutation in the GFM2 gene (606544) on chromosome 5q13.

Description

Combined oxidative phosphorylation deficiency-39 (COXPD39) is an autosomal recessive multisystem disorder resulting from a defect in mitochondrial energy metabolism. Affected individuals show global developmental delay, sometimes with regression after normal early development, axial hypotonia with limb spasticity or abnormal involuntary movements, and impaired intellectual development with poor speech. More variable features may include hypotonia, seizures, and features of Leigh syndrome (256000) on brain imaging. There are variable deficiencies of the mitochondrial respiratory chain enzyme complexes in patient tissues (summary by Glasgow et al., 2017).

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

Clinical Features

Dixon-Salazar et al. (2012) reported 2 sibs, born of consanguineous parents, with a severe neurodevelopmental disorder. The patients had microcephaly, simplified gyral pattern and pachygyria on brain imaging, and insulin-dependent diabetes. One of the affected sibs had died, but the age at death and cause of death were not provided. The patients were part of a large cohort of 188 probands from consanguineous unions with genetic forms of neurodevelopmental disorders who underwent exome sequencing.

Fukumura et al. (2015) reported 2 Japanese sisters with a severe neurodevelopmental disorder. Both patients were born with arthrogryposis multiplex congenita and showed severe hypotonia. The older sib had enlarged lateral ventricles and hypoplasia of the corpus callosum, but no cortical malformations. She developed refractory seizures with hypsarrhythmia at age 3 months, and died at age 13 months after showing no developmental progress. Brain imaging of the younger sib showed progressive cerebellar atrophy and abnormal signals restricted to the midbrain suggestive of Leigh syndrome. By age 7 years, she was ventilator-dependent and bedridden with spasticity, bradycardia, and lack of developmental progress. Laboratory studies, including serum and cerebrospinal fluid (CSF) lactate, were normal, but magnetic resonance spectroscopy (MRS) showed a lactate peak. Fibroblasts from the second patient showed approximately 50% decreased activities of mitochondrial complexes III and IV compared to controls, but normal complexes I and II.

Glasgow et al. (2017) reported 2 unrelated patients with COXPD39. Both were noted to have developmental delay and regression of developmental milestones around 2 years of age after normal early development. They acquired some speech, but later lost language skills and developed dysarthria (patient 1) or loss of language (patient 2). Both had loss of motor skills and lost the ability to walk in childhood. Patient 1 had intrauterine growth retardation and asymptomatic hypoglycemia in the newborn period. He was able to walk at 14 months and run at age 5, but developed dystonia and spasticity in the lower limbs. Patient 2 developed a severe seizure disorder and had myopathic facies with drooling, axial hypotonia with hypertonic limbs, and dystonic involuntary movements. Brain imaging in both patients showed T2-weighted abnormalities in the basal ganglia, consistent with Leigh syndrome, as well as abnormalities in other brain regions, including volume loss in the corpus callosum and cerebellum. Laboratory studies showed increased serum and CSF lactate. Analysis of patient fibroblasts and skeletal muscle showed variable decreases in several mitochondrial respiratory complexes, most notably complexes I and IV. These findings were consistent with tissue-specific manifestations.

Inheritance

The transmission pattern of COXPD39 in the families reported by Glasgow et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of consanguineous parents, with a neurodevelopmental disorder consistent with COXPD39, Dixon-Salazar et al. (2012) identified a homozygous missense mutation in the GFM2 gene (D576E; 606544.0001). The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in 200 controls. The mutation occurred at a highly conserved residue and was predicted to damage the protein, but functional studies were not performed.

In 2 Japanese sisters with COXPD39, Fukumura et al. (2015) identified compound heterozygous mutations in the GFM2 gene (606544.0002 and 606544.0003). Studies of patient cells confirmed that both mutations resulted in nonsense-mediated mRNA decay, consistent with a loss of function. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.

In 2 unrelated patients with COXPD39, Glasgow et al. (2017) identified biallelic mutations in the GFM2 gene (606544.0004-606544.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro functional expression studies in patient fibroblasts did not show a defect in translation of mitochondrial proteins, but Glasgow et al. (2017) postulated that GFM2 acts later in the process. Patient skeletal muscle and fibroblasts showed variable decreased levels and activities of several subunits of mitochondrial complexes I, III, and IV.