A number sign (#) is used with this entry because combined oxidative phosphorylation deficiency-14 (COXPD14) is caused by homozygous or compound heterozygous mutation in the FARS2 gene (611592) on chromosome 6p25.

Biallelic mutation in the FARS2 gene can also cause SPG77 (617046), a much less severe disorder.

Combined oxidative phosphorylation deficiency-14 (COXPD14) is a severe multisystemic autosomal recessive disorder characterized by neonatal onset of global developmental delay, refractory seizures, and lactic acidosis. Biochemical studies show deficiencies of multiple mitochondrial respiratory enzymes. Neuropathologic studies in 1 patient showed laminar cortical necrosis, characteristic of Alpers syndrome (203700) (summary by Elo et al., 2012).

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

Shamseldin et al. (2012) reported a consanguineous Saudi Arabian family in which 3 sibs had a severe mitochondrial encephalopathy. The proband was a 1.9-year-old girl with significant global developmental delay, lactic acidosis, and onset of uncontrolled seizures at age 35 days. Other features included poor feeding, poor physical growth with microcephaly (-2.4 SD), visual and hearing impairment, hypotonia, anemia, and thrombocytopenia. Laboratory studies showed high lactate, and muscle biopsy showed scattered fibers with intense NADH and SDH activity without ragged-red fibers or cytochrome c oxidase (COX)-negative fibers. Electron microscopy showed subtle mitochondrial abnormalities, but there was no deletion or depletion of mitochondrial DNA. Brain MRI showed diffuse cerebral atrophy, enlarged ventricles, and bilateral hyperintense T2-weighted lesions in the basal ganglia, consistent with Leigh syndrome (256000). There was no evidence of liver impairment. The overall picture suggested a defect in enzymes involved in oxidative phosphorylation. The proband had 2 affected sibs with developmental delay and seizures; both died before 3 months of age. Elo et al. (2012) provided some follow-up of the index patient reported by Shamseldin et al. (2012), who died at age 22 months.

Elo et al. (2012) reported a Finnish family in which 2 sisters had a fatal infantile mitochondrial encephalopathy. The proband developed treatment-resistant myoclonic seizures on the second day of life. Laboratory studies showed generalized aminoaciduria and increased lactate in the blood and cerebrospinal fluid. Initial brain MRI and EEG were normal, but EEG at 6 weeks showed multifocal spikes and brain MRI at 3 months showed severe central and cortical atrophy with signal increases in the putamina. Liver biopsy showed enlarged hepatocytes, increased glycogen, and iron and copper accumulation, but transaminases were normal. Muscle biopsy showed decreased COX immunostaining and subsarcolemmal glycogen, but no ragged-red fibers. Complex I activity in muscle was increased compared to control values, but succinate dehydrogenase was 50% and COX was 16% of control. She had microcephaly and slightly coarse retinal pigmentation, but normal optic nerve. She had no psychomotor development, and died at age 8 months. Gel electrophoresis showed a severe reduction of complex IV in the brain and skeletal muscle and partial complex I deficiency in the brain; complex I in skeletal muscles was slightly increased. In contrast, defects in respiratory chain complexes were not observed in patient fibroblasts. Neuropathologic examination showed generalized atrophy with striking subtotal laminar necrosis of the cortical ribbon. There was microcystic degeneration, lack of pyramidal cells, reactive gliosis, and areas of spongiosis. Degenerative changes were observed in the cortex, cerebellum, and brainstem. The neuropathologic changes, together with the liver involvement, were reminiscent of Alpers syndrome (203700). The patient had an older sister with a similar disorder who died of multiorgan failure at age 21 months.

Almalki et al. (2014) reported a 2.5-year-old boy, born of unrelated British Caucasian parents, with onset of severe seizures associated with hypsarrhythmia on EEG at age 6 months, followed by delayed psychomotor development. The seizures became refractory, and brain imaging showed subcortical white matter lesions and thinning of the corpus callosum. Other features included no visual awareness, increased limb tone, hyperreflexia, and mild dysmorphic features, including small anteriorly rotated ears and broad nasal root. Patient skeletal muscle and myoblasts showed an isolated complex IV deficiency, which was not observed in fibroblasts. Almalki et al. (2014) noted that the phenotype in their patient was slightly different from that reported by Shamseldin et al. (2012) and Elo et al. (2012).

Chen et al. (2023) reported a patient who presented at 3 weeks of age with tachypnea, lactic acidosis, and a severe metabolic acidosis. He also had increased tone and a divergent squint. He developed loose stools and worsening acidosis. At 4 weeks of age, he developed liver dysfunction, and at 8 weeks of age he developed seizures. He died at 9 weeks of age.

Clinical Variability

Walker et al. (2016) reported a girl with severe juvenile-onset epileptic encephalopathy. She had mildly delayed psychomotor development with speech delay, including walking at age 17 months, running at 24 months, and first word at age 3.5 years with a plateau of language skills at age 5 to 7 years. She had a first prolonged generalized tonic-clonic seizure at age 8 years, followed by progression of the epilepsy, which became refractory and associated with spike-wave discharges on EEG that also occurred during sleep. EEG also showed background slowing. She developed epilepsia partialis continua starting at age 10 years, and status epilepticus at age 13. Her neurologic status progressively declined: she was unable to follow commands or track faces, and she had unreactive pupils, near-continuous myoclonus of the right face, arm, and leg, absence of purposeful movement, and extensor plantar responses. Brain MRI showed extensive areas of T2-weighted hyperintensities. She died at age 15 years. Skeletal muscle biopsy showed type 2 fiber atrophy and myofibrillary disarray with enlarged and swollen mitochondria containing glycogen. Activities of complexes I-IV were normal in frozen skeletal muscle samples. Postmortem examination showed laminar cortical neuronal loss, necrosis, gliosis, and diminished subcortical white matter and descending corticospinal tracts. The most severely affected regions were the frontal and visual cortices. A small region of spongiform change was noted in the right thalamus. Genetic analysis identified compound heterozygous missense variants in the FARS2 gene (P85A and H135D) that occurred in the larger catalytic domain and were shown in in vitro studies to be detrimental to enzyme function. The findings expanded the phenotype associated with mutations in the FARS2 gene.

Reviews

Vantroys et al. (2017) reviewed the clinical descriptions and mutations reported in patients with COXPD14, which the authors called 'the epileptic phenotype,' and spastic paraplegia caused by mutations in the FARS2 gene.

The transmission pattern of COXPD14 in the family reported by Shamseldin et al. (2012) was consistent with autosomal recessive inheritance.

In 3 sibs, born of consanguineous Saudi Arabian parents, with COXPD14, Shamseldin et al. (2012) identified a homozygous mutation in the FARS2 gene (Y144C; 611592.0001). The mutation was identified by exome sequencing and confirmed by Sanger sequencing.

By exome sequencing of 2 sibs with fatal infantile epileptic mitochondrial encephalopathy, Elo et al. (2012) identified compound heterozygosity for 2 mutations in the FARS2 gene (611592.0002 and 611592.0003).

In a 2.5-year-old boy, born of unrelated British parents, with a variant of COXPD14, Almalki et al. (2014) identified a maternally inherited heterozygous missense mutation in the FARS2 gene (D325Y; 611592.0004) and a paternally inherited 88-kb interstitial deletion of chromosome 6p25.1, including the promoter and untranslated exon 1 of FARS2 and the 3-prime exons of the LYRM4 (613311) gene. In vitro functional expression assays showed that the D325Y mutant protein had no detectable enzyme activity and no detectable ATP binding. However, patient myoblasts did not show impaired synthesis of mitochondrial proteins, and there was no decrease in mtDNA. A missense mutation in the LYRM4 gene (R68L) has been identified in a family with COXPD19 (615595).

In a male infant with COXPD14, Chen et al. (2023) identified compound heterozygous mutations in the FARS2 gene (EX2DEL, 611592.0011 and R198L, 611592.0012). Steady state levels of mtPheRS were reduced in patient fibroblasts and complex I activity was mildly reduced. A crystal structure of FARS2 with the R198L mutation suggested that the mutation results in destabilization of the protein's core region. An aminoacylation assay demonstrated that the R198L mutation resulted in reduced tRNA charging activity.