Combined Oxidative Phosphorylation Deficiency 4

A number sign (#) is used with this entry because of evidence that combined oxidative phosphorylation deficiency-4 (COXPD4) is caused by homozygous or compound heterozygous mutation in the gene encoding mitochondrial elongation factor Tu (TUFM; 602389) on chromosome 16p11.

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

Clinical Features

Valente et al. (2007) described 2 infants with neonatal lactic acidosis, rapidly progressive encephalopathy, severely decreased mitochondrial protein synthesis, and combined deficiency of mtDNA-related mitochondrial respiratory chain (MRC) complexes. One had a mutation in the EFG1 gene (GFM1; 606639) and thus had COXPD1. The other had an extremely severe syndrome dominated by lactic acidosis and rapidly fatal encephalopathy, with diffuse cystic leukodystrophy and micropolygyria, a developmental abnormality of the brain that occurs well before birth. Two days after birth, the infant developed acute respiratory distress and severe metabolic acidosis, with 2 episodes of generalized hypertonia. Serum lactic acid was markedly elevated. Brain CT scan showed several hypodense lesions. The lactic acidosis was partially corrected by intravenously administered bicarbonate. She was relatively well until the age 6 months, when she had another episode of severe metabolic crisis. Thereafter acute episodes punctuated a relentless downhill course characterized by severe psychomotor regression with microcephaly, generalized axial hypotonia with limb spasticity, and nystagmus. Modest elevation of hepatic enzymes in blood and episodic hyperammonemia indicated mild liver involvement that never progressed to hepatic failure. Other tissues, notably the heart, were clinically spared. The patient died at the age of 14 months.

Kohda et al. (2016) reported 2 unrelated infants with COXPD4. Patient 559 had lactic acidosis, hyperammonemia, abnormalities of the basal ganglia on brain imaging, and complex IV deficiency. Patient 622 had intrauterine growth retardation, premature birth, respiratory failure, hypotonia, lactic acidosis, and combined complex deficiencies. Each proband had a similarly affected sib. Additional clinical details were limited.

Inheritance

The transmission pattern of COXPD4 in the families reported by Kohda et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In an infant with combined oxidative phosphorylation deficiency, Valente et al. (2007) detected a homozygous missense mutation in the TUFM gene (R339Q; 602389.0001).

In 4 infants from 2 unrelated families with COXPD4, Kohda et al. (2016) identified biallelic mutations in the TUFM gene (602389.0002-602389.0003). The mutations, which were found by high-throughput exome sequencing of 142 unrelated patients with childhood-onset mitochondrial respiratory chain disorders, were confirmed by Sanger sequencing. The mutations segregated with the disorder in the families. Complementation with wildtype TUFM restored the complex I and IV assembly and complex IV activity levels in fibroblasts from 1 of the patients (patient 622).