Combined Oxidative Phosphorylation Deficiency 15

A number sign (#) is used with this entry because combined oxidative phosphorylation deficiency-15 (COXPD15) is caused by homozygous or compound heterozygous mutation in the MTFMT gene (611766) on chromosome 15q22.

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

Clinical Features

Tucker et al. (2011) reported 2 unrelated probands with combined oxidative phosphorylation deficiency. The first patient presented at age 9 years with acquired strabismus and mildly decreased visual acuity. She had a history of mild developmental delay affecting speech and coordination, and also had reading difficulties. Brain MRI showed T2-weighted hyperintense lesions in several brain regions, including the lentiform nuclei, caudate, midbrain tectum, red nuclei, corpus callosum, and subcortical white matter. CSF lactate was increased, although blood lactate levels were normal. Echocardiography showed short PR waves and delta waves consistent with Wolff-Parkinson-White syndrome. At age 21 years, she worked a menial job. Family history revealed a maternal first cousin with a similar but more severe disorder. That patient had global developmental delay, optic atrophy, impaired vision, pyramidal tract signs, incoordination, and Wolff-Parkinson-White syndrome. In a second family, a girl was first evaluated for obesity at age 5 years and was found to have a pituitary adenoma. Brain MRI also showed bilateral signal abnormalities in the putamen, globus pallidus, and brainstem. There was progression of these lesions to include white matter changes. Serum and CSF lactate were elevated. She developed seizures, acute neurologic decompensation, and died several months later. Tissue samples and cell lines from all the patients showed deficiencies of complexes I and IV, with deficient complex III in some samples. There was no evidence of mtDNA depletion. Patient fibroblasts showed reduced levels of most mtDNA-encoded proteins, suggesting a defect in mitochondrial translation.

Neeve et al. (2013) reported 2 German sisters, born of unrelated parents, with COXPD15. Both patients had developmental delay, affecting speech more than motor skills, and hypotonia. The older sister, aged 16 years, had short stature, slight dysarthria, mild ataxia, and clumsy fine finger movements. Brain MRI showed mild signal abnormalities in the dorsal periventricular white matter and increased T2-weighted signal intensities in the caudate and putamen, consistent with Leigh syndrome (256000). The younger sister, aged 6 years, had short stature and mild intention tremor, but no ataxia. Brain MRI was normal. Both girls had mild cognitive dysfunction and poor speech. Skeletal muscle analysis of the older sister showed mild lipid accumulation in type 1 fibers, but no ragged-red fibers. Activities of mitochondrial complexes I and IV were decreased compared to normal; complexes II and III were normal.

Haack et al. (2014) reported 9 patients from 8 unrelated families with COXPD15. The phenotype was variable in severity, but all had an encephalomyopathic phenotype with onset in infancy or early childhood of delayed psychomotor development and subsequent retardation, gait ataxia, and hypotonia. Seven patients had microcephaly. Other features observed in some patients included nystagmus and spasticity. Laboratory studies showed increased serum and CSF lactate, often with increased alanine. Muscle biopsies showed mitochondrial complex I deficiency (range, 7 to 89% of normal), with some also showing complex IV deficiency (range, 45% to normal). Seven patients had abnormal increased T2-weighted signal abnormalities in the basal ganglia and/or midbrain, consistent with classic Leigh syndrome, and some had additional subcortical white matter lesions. None of the patients had severe involvement of other organs, although several had ventricular septal defect or thickening of the ventricular septum. Two patients died in early childhood, some showed episodic decompensation, and others were able to attend special school or do supervised shelter work. One patient was wheelchair-bound with spastic quadriplegia in his twenties.

Inheritance

The transmission pattern of COXPD15 in the families reported by Tucker et al. (2011) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 unrelated patients with COXPD15, Tucker et al. (2011) identified compound heterozygosity for 2 mutations in the MTFMT gene (611766.0001-611766.0003). The mutations were identified by next-generation sequencing of coding exons from nuclear-encoded mitochondrial-associated genes. MTFMT activity was 9% in 1 patient and 56% in the other patient. Patient fibroblasts also lacked detectable formylmethionine tRNA-met. In patients cells, the biochemical defects were rescued by exogenous expression of wildtype MTFMT. Both patients had some residual MTFMT activity, as evidenced by the presence of decreased levels of formylated MTCO1 (516030) in patient cells.

In 2 German sisters with COXPD15, Neeve et al. (2013) identified compound heterozygous mutations in the MTFMT gene (611766.0004 and 611766.0005). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Myoblasts from 1 of the patients showed a severe decrease in MTFMT protein, as well as decreases in mitochondrial complexes I and IV. Complex V appeared to be unstable.

Haack et al. (2014) identified compound heterozygous MTFMT mutations in 9 patients from 8 families with COXPD15. Eight of the 9 patients carried a c.626C-T transition (611766.0001) on 1 allele, making it the most common variant. Some of the other mutations had previously been reported (see, e.g., 611766.0004) and some were novel (see, e.g., 611766.0007 and 611766.0008). Patient cells showed a severe decrease in MTFMT protein, and all of the mutations were predicted to result in a loss of function. The mutations were identified using several techniques, including exome sequencing, high resolution melting curve analysis, and Sanger sequencing. Exome sequencing initially failed to detect the mutations in several patients.