Ketogenic Diet for KARS-Related Mitochondrial Dysfunction and Progressive Leukodystrophy

Abstract

KARS encodes lysyl-tRNA synthetase, which is essential for protein translation. KARS mutations sometimes cause impairment of cytoplasmic and mitochondrial protein synthesis, and sometimes lead to progressive leukodystrophies with mitochondrial signature and psychomotor regression, and follow a rapid regressive course to premature death. There has been no disease-modifying therapy beyond supportive treatment. We present a 5-year-old male patient with an asymmetrical leukodystrophy who showed overt evidence of mitochondrial dysfunction, including elevation of lactate on brain MR spectroscopy and low oxygen consumption rate in fibroblasts. We diagnosed this patient's condition as KARS-related leukodystrophy with cerebral calcification, congenital deafness, and evidence of mitochondrial dysfunction. We employed a ketogenic diet as well as multiple vitamin supplementation with the intention to alleviate mitochondrial dysfunction. The patient showed alleviation of his psychomotor regression and even partial restoration of his abilities within 4 months. This is an early report of a potential disease-modifying therapy for KARS-related progressive leukodystrophy without appreciable adverse effects.

KARS‐related diseases with macrothrombocytes and pulmonary arterial hypertension

“…Patient 2 was a 5‐year‐old boy who showed congenital deafness, developmental delay, regression, left spastic paralysis, and leukodystrophy, as previously described (Figure S2). 3 We noticed only later his macrothrombocytes with normal platelet counts (237,000/μl, Figure 1k). About 10% of platelets were large and the MPV was 9.3 fl.…”

“…KARS abnormality often causes mitochondrial dysfunction, showing a lactate peak in magnetic resonance spectroscopy (MRS) and mitochondrial respiratory chain abnormalities in fibroblasts 1 . Patient 2 had abnormalities in MRS and fibroblast consumption rate, which means that there was mitochondrial dysfunction and abnormal oxidative metabolism 3 . In the hematological system, KARS ‐related diseases have been associated with anemia, neutropenia, thrombocytopenia, and pancytopenia without any morphological description (domestic cases in Table S2).…”

“…1 Bi-allelic pathogenic variants in KARS1 express various phenotypes, including sensorineural hearing and visual loss, neuropathy, and leukodystrophy. 1 Bi-allelic KARS1 variants are associated with multisystem diseases, including hematological and cardiovascular involvement; [1][2][3][4] however, morphological features in the hematological system or pulmonary artery hypertension (PAH) have apparently not been reported. We report two cases of KARS-related diseases presenting with vacuolated macrothrombocytes and one with PAH in addition.…”

“…1 Patient 2 had abnormalities in MRS and fibroblast consumption rate, which means that there was mitochondrial dysfunction and abnormal oxidative metabolism. 3 In the hematological system, KARS-related diseases have been associated with anemia, neutropenia, thrombocytopenia, and pancytopenia without any morphological description (domestic cases in Table S2). 1,2 In our patients, erythroid and myeloid systems were not affected.…”

Recessive aminoacyl-tRNA synthetase disorders: lessons learned from in vivo disease models

“…For example, multiple patients with recessive ARS1 diseases have experienced improvements following personalized amino acid and protein supplementation to compensate for reduced aminoacylation efficiency ( Hadchouel et al, 2015 ; Kopajtich et al, 2016 ; Das et al, 2020 ; Lenz et al, 2020b ; Kok et al, 2021 ). Improvements were also observed in a patient with biallelic KARS2 mutations following multivitamin supplementation and adherence to a ketogenic diet ( Murofushi et al, 2022 ), and in a patient with DARS2 mutations following treatment with a derivative of succinic acid to support mitochondrial function ( Bedova et al, 2020 ). Larger-scale clinical studies and further exploration of whether therapeutic benefits can similarly be achieved for other recessive ARS diseases are important next steps.…”