Mitochondrial disorder due to a defect in mitochondrial protein synthesis
-Rare developmental defect during embryogenesis
-Rare genetic disease
-Rare neurologic disease
Comment:
Compound heterozygous mutations in FARS2 (= COXPD14, FARS1, HSPC320, PheRS, SPG77) encoding the mitochondrial phenylalanyl transfer RNA (tRNA) synthetase (mtPheRS) were found in different patients with mitochondrial encephalopathy. The mutations affected e.g. the highly conserved amino acids p.I329T, p.D391V, and p.Y144C. In vitro characterization indicated reduced affinity of p.D391V mutant protein to phenylalanine, whereas p.Y144C disrupted tRNA binding. The stability of p.I329T and p.D391V mutants in a refolding assay was impaired. The results imply that these FARS2 mutations directly impair aminoacylation function and stability of mtPheRS, leading to a decrease in overall tRNA charging capacity. The clinical features of patients with FARS2 variants resemble each other closely, and the neuropathology is consistent with Alpers syndrome (PMID:22833457).
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 ... 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 ... 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.
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. ... 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).