Combined Oxidative Phosphorylation Deficiency 3

A number sign (#) is used with this entry because combined oxidative phosphorylation deficiency-3 (COXPD3) is caused by homozygous or compound heterozygous mutation in the TSFM gene (604723) on chromosome 12q14.

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

Clinical Features

Smeitink et al. (2006) reported 2 unrelated patients with COXPD3. The first proband was the child of consanguineous Turkish parents. Muscular hypotonia, sucking weakness, and severe lactic acidosis were the initial clinical signs and symptoms, followed by rhabdomyolysis with elevated creatine kinase values. Generalized convulsions began on the third day of life. Despite intensive treatment, the patient died of progressive encephalomyopathy and respiratory failure at age 7 weeks. The second proband was the offspring of consanguineous Kurdish Jewish parents. The mother reported a paucity of fetal movements throughout pregnancy. At age 36 hours, apathy, irregular breathing, and severe muscular hypotonia were noted. Laboratory investigations revealed severe metabolic acidosis with increased serum lactate level, blood ketone levels, and serum ammonia levels. Echocardiographic examination disclosed severe concentric hypertrophic cardiomyopathy with normal contractility. Death occurred at age 7 weeks.

Smits et al. (2011) reported a patient with COXPD3 characterized by onset of lactic acidosis and muscular hypotonia within 3 days after birth and death within the first few months of life. The patient had encephalomyopathy and hypertrophic cardiomyopathy, as well as hepatomegaly. Fibroblasts and muscle tissue showed combined complex I, III, and IV deficiencies.

Shamseldin et al. (2012) reported a 2-month-old girl from Chile with intrauterine growth retardation and neonatal hypotonia. She had poor reflexes, poor feeding, and lactic acidosis. Muscle biopsy showed ragged-red fibers, COX deficiency, and decreased activity of mitochondrial complexes I and IV. She died at age 2 months. A previous sib had died of lactic acidosis.

Ahola et al. (2014) reported 2 Finnish sisters, born of unrelated parents, with COXPD3. One presented with dilated cardiomyopathy at 10 months of age, and the other with hypertrophic cardiomyopathy at 16 months of age. The cardiac dysfunction resolved over time, and both had stable cardiac function on medication. One patient showed a decline in cognitive function during the school-age years, and brain MRI showed signal intensities in the basal ganglia consistent with Leigh syndrome (LS; 256000). The other patient had mild learning difficulties and normal brain imaging. Both developed optic atrophy with visual impairment as teenagers. At ages 21 and 15 years, respectively, the girls had mild muscle weakness and evidence of a mild axonal sensorimotor neuropathy. The more severely affected girl had frequent dystonic movements. Her muscle biopsy showed combined mitochondrial respiratory defects, with decreased activities of complex I+III (32% of normal) and complex IV (45% of normal). Muscle biopsy of the less severely affected girl showed complex IV deficiency (18% of normal). An unrelated Finnish boy presented at age 15 years with optic neuropathy; brain MRI was normal. He had mild tremor in the trunk and limbs and difficulties with balance, and electrophysiologic studies showed a peripheral axonal neuropathy associated with loss of myelinated axons on sural nerve biopsy. He had no cardiac symptoms and normal cognitive function. Muscle biopsy showed some COX-deficient fibers, but respiratory chain enzyme activities were normal. Ahola et al. (2014) emphasized the phenotypic variability of this disorder and noted that cardiac dysfunction in infancy may improve with time.

Molecular Genetics

In 2 unrelated patients with COXPD3, Smeitink et al. (2006) identified a homozygous mutation in the TSFM gene (R333W; 604723.0001). The fact that the same mutation was associated with distinct clinical phenotypes suggested that genetic modifiers of the mitochondrial translation apparatus may have been operative.

Smits et al. (2011) identified a homozygous R333W mutation in in TSFM in a patient with COXPD3 who was part of a cohort of 27 patients with combined OXPHOS deficiencies.

Shamseldin et al. (2012) identified a homozygous R333W mutation in TSFM in a Chilean infant with lethal COXPD3. The mutation was identified by exome sequencing.

In 3 Finnish patients from 2 unrelated families with variable clinical manifestations of COXPD3, Ahola et al. (2014) identified compound heterozygous mutations in the TSFM gene (604723.0002-604723.0004).