Loss-of-function mutations in Lysyl-tRNA synthetase cause various leukoencephalopathy phenotypes

Abstract

ObjectiveTo expand the clinical spectrum of lysyl-tRNA synthetase (KARS) gene–related diseases, which so far includes Charcot-Marie-Tooth disease, congenital visual impairment and microcephaly, and nonsyndromic hearing impairment.MethodsWhole-exome sequencing was performed on index patients from 4 unrelated families with leukoencephalopathy. Candidate pathogenic variants and their cosegregation were confirmed by Sanger sequencing. Effects of mutations on KARS protein function were examined by aminoacylation assays and yeast complementation assays.ResultsCommon clinical features of the patients in this study included impaired cognitive ability, seizure, hypotonia, ataxia, and abnormal brain imaging, suggesting that the CNS involvement is the main clinical presentation. Six previously unreported and 1 known KARS mutations were identified and cosegregated in these families. Two patients are compound heterozygous for missense mutations, 1 patient is homozygous for a missense mutation, and 1 patient harbored an insertion mutation and a missense mutation. Functional and structural analyses revealed that these mutations impair aminoacylation activity of lysyl-tRNA synthetase, indicating that defective KARS function is responsible for the phenotypes in these individuals.ConclusionsOur results demonstrate that patients with loss-of-function KARS mutations can manifest CNS disorders, thus broadening the phenotypic spectrum associated with KARS-related disease.

Ketogenic Diet for KARS-Related Mitochondrial Dysfunction and Progressive Leukodystrophy

“…Thus, we diagnosed this patient's condition as KARS-related progressive leukodystrophy with cerebral calcification, involvement of corticospinal tracts, congenital deafness, and evidence of mitochondrial dysfunction. [1][2][3][4] As both MRS and mitochondrial oxygen consumption rate in fibroblasts showed evidence of mitochondrial dysfunction in our patient, we started him on vitamin supplementation (B1, C, E, biotin, carnitine, and CoQ 10 ) at the age of 5 years and 8 months. In addition, to correct his abnormal mitochondrial function, we started him on a KD with a ketone-to-nonketone ratio of 3:1 at 5 years and 10 months.…”

“…11,13 These findings are the case in our patient and previously reported patients with KARS mutations. [1][2][3][4] From these facts, some researchers assumed that dysfunction of mitochondrial ARS is more likely to be contributing to the pathogenesis of these disorders. Whereas, one study revealed that a reduced activity of cytoplasmic isoform of lysyl-tRNA synthetase and a slightly increased activity of mitochondrial isoform were expressed in fibroblasts of patients with KARS mutations and a reduced activity of the complexes I and IV.…”

“…Biallelic mutations in the KARS gene impair cytoplasmic and mitochondrial protein synthesis, and they were reported in patients with a peripheral neuropathy, nonsyndromic hearing impairment, leukodystrophies, and severe neurodevelopmental defects. [1][2][3][4] Patients with leukodystrophies often follow a regressive course to premature death. 1 To date, no disease-modifying therapy is available, and treatment is only supportive.…”

Progressive Early Onset Leukodystrophy Related to Biallelic Variants in the KARS Gene: The First Case Described in Latin America

“…A variable clinical presentation of the disease has been associated with the KARS gene mutations; all those disorders, have been linked to an autosomal recessive inheritance pattern mechanism [12,13]. Among the most affected organs, are those with high energy demand such as the brain, heart, skeletal muscle and kidneys, probably secondary to the mitochondrial disfunction with a secondary impaired oxidative phosphorylation [13].…”

“…In the absence of an etiology of the patient's condition, a WES was performed where two variants in the KARS gene were identified; the variant c.1514G > A (p.Arg505His) classified as pathogenic (rs778748895) previously reported in the Literature (4,11,12). The variant c.371G > A (p.Ala526Val), which has been classified as probably pathogenic, has not been previously reported in the literature.…”