Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy.

Mutations in genes encoding aminoacyl-tRNA synthetases have been reported in several neurological disorders. KARS is a dual localized lysyl-tRNA synthetase and its cytosolic isoform belongs to the multiple aminoacyl-tRNA synthetase complex (MSC). Biallelic mutations in the KARS gene were described in a wide phenotypic spectrum ranging from nonsyndromic deafness to complex impairments. Here, we report on a patient with severe neurological and neurosensory disease investigated by whole-exome sequencing and found to carry biallelic mutations c.683C>T (p.Pro228Leu) and c.871T>G (p.Phe291Val), the second one being novel, in the KARS gene. The patient presented with an atypical clinical presentation with an optic neuropathy not previously reported. At the cellular level, we show that cytoplasmic KARS was expressed at a lower level in patient cells and displayed decreased interaction with MSC. In vitro, these two KARS variants have a decreased aminoacylation activity compared with wild-type KARS, the p.Pro228Leu being the most affected. Our data suggest that dysfunction of cytoplasmic KARS resulted in a decreased level of translation of the nuclear-encoded lysine-rich proteins belonging to the respiratory chain complex, thus impairing mitochondria functions.

Clinical and Laboratorial Characteristics of Korean Children with Mitochondrial Respiratory Chain Defect / 대한소아신경학회지

PURPOSE:The study was carried out to characterized the clinical and the laboratorial features of children with mitochondrial respiratoy chain disorders in Korea. METHODS:We retrospectively analyzed the clinical and the loboratorial data of 28 children with significantly low activities in respiratory chain complexes of muscle using spectrophotometry. RESULTS:The mean age was 6.67+/-4.44 years and the ratio males to female was 1.15:1. Eighteen patients (64.3%) showed defects in Complex I, 8 (28.6%) in Complex VI, 1 (3.6%) in Complex II, and 1 in Complex I and IV. Eight cases (28.6%) were diagnosed with Leigh disease, one with MELAS, Kearns-Sayre syndrome, and Alpers disease retrospectively, but the predominant clinical presentations were a nonspecific encephalopathy (17/28, 60.7%). Epilepsy was seen in 21 (75.0%) patients, while developmental delay in 27 (96.4%) patients. Fifteen out of 28 children (53.6%), clinical symptoms mostly appeared below age of 1 year. The brain MRI showed diffuse cortical atrophy in 18 (64.3%) patients and basal ganglia signal changes in 12 (42.9%) patients. CONCLUSION:The defects in mitochondrial respiratory chain complexes should be considered in any children with an unexplained neurological condition including even epilepsy.

A Case of Mitochondrial Respiratory Chain Defect Diagnosed in the Neonatal Period / 대한주산의학회잡지

Mitochondrial diseases are classified into the three major categories, defects of fatty acid oxidation, defects of pyruvate metabolism, and defects of the respiratory chain, and all of these cause severe neurologic dysfunction in the newborn period. Defects of the mitochondrial respiratory chain present as recurrent apnea, seizures, congenital lactic acidosis, hypotonia, hepatic dysfunction and hypertrophic cardiomyopathy in the neonatal period. Laboratory findings of hyperlactataemia(>2.5mM), elevated lactate/pyruvate(L/P) ratio(>20) and ketone body ratio(>2) suggest the diagnosis of mitochondrial respiratory chain defects. We report a case of mitochondrial respiratory chain defect diagnosed in the neonatal period presenting with multiorgan failure consisting of severe metabolic acidosis, comatous mental state, respiratory distress, hepatic dysfunction, renal failure with lactic acidosis(24mM), increased L/P ratois (55.6) and ketonuria (increased ratio of 3-hydroxybutyrate/acetoacetate).