Ketogenic Diet for KARS-Related Mitochondrial Dysfunction and Progressive Leukodystrophy

2021 ◽  
Author(s):  
Yuka Murofushi ◽  
Itaru Hayakawa ◽  
Yuichi Abe ◽  
Tatsuyuki Ohto ◽  
Kei Murayama ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Ketogenic Diet ◽  
Early Report ◽  
Mitochondrial Protein ◽  
Protein Translation ◽  
Trna Synthetase ◽  
Vitamin Supplementation ◽  
Low Oxygen ◽  
Disease Modifying Therapy ◽  
Disease Modifying

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.

scholarly journals Two Novel Variants in YARS2 Gene Are Responsible for an Extended MLASA Phenotype with Pancreatic Insufficiency

2021 ◽  
Vol 10 (16) ◽  
pp. 3471
Author(s):  
Lidia Carreño-Gago ◽  
Diana Luz Juárez-Flores ◽  
Josep Maria Grau ◽  
Javier Ramón ◽  
Ester Lozano ◽  
...  
Keyword(s):  
Amino Acid ◽  
Pancreatic Insufficiency ◽  
Mitochondrial Protein ◽  
Premature Stop Codon ◽  
Protein Translation ◽  
Trna Synthetase ◽  
Exercise Intolerance ◽  
Compound Heterozygous ◽  
Single Nucleotide ◽  
Pathogenic Variants

Pathogenic variants in the mitochondrial tyrosyl-tRNA synthetase gene (YARS2) were associated with myopathy, lactic acidosis, and sideroblastic anemia (MLASA). However, patients can present mitochondrial myopathy, with exercise intolerance and muscle weakness, leading from mild to lethal phenotypes. Genes implicated in mtDNA replication were studied by Next Generation Sequencing (NGS) and whole exome sequence with the TruSeq Rapid Exome kit (Illumina, San Diego, CA, USA). Mitochondrial protein translation was studied following the Sasarman and Shoubridge protocol and oxygen consumption rates with Agilent Seahorse XF24 Analyzer Mitostress Test, (Agilent, Santa Clara, CA, USA). We report two siblings with two novel compound heterozygous pathogenic variants in YARS2 gene: a single nucleotide deletion in exon 1, c.314delG (p.(Gly105Alafs*4)), which creates a premature stop codon in the amino acid 109, and a single nucleotide change in exon 5 c.1391T>C (p.(Ile464Thr)), that cause a missense variant in amino acid 464. We demonstrate the pathogenicity of these new variants associated with reduced YARS2 mRNA transcript, reduced mitochondrial protein translation and dysfunctional organelle function. These pathogenic variants are responsible for late onset MLASA, herein accompanied by pancreatic insufficiency, observed in both brothers, clinically considered as Pearson’s syndrome. Molecular study of YARS2 gene should be considered in patients presenting Pearson’s syndrome characteristics and MLASA related phenotypes.

scholarly journals tRNA-Dependent Import of a Transit Sequence-Less Aminoacyl-tRNA Synthetase (LeuRS2) into the Mitochondria of Arabidopsis

2021 ◽  
Vol 22 (8) ◽  
pp. 3808
Author(s):  
Steffen Reinbothe ◽  
Claudia Rossig ◽  
John Gray ◽  
Sachin Rustgi ◽  
Diter von Wettstein ◽  
...  
Keyword(s):  
Protein Complex ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mitochondrial Protein ◽  
Protein Translation ◽  
Trna Synthetase ◽  
In Planta ◽  
Trna Synthetases ◽  
And Function

Aminoacyl-tRNA synthetases (AaRS) charge tRNAs with amino acids for protein translation. In plants, cytoplasmic, mitochondrial, and chloroplast AaRS exist that are all coded for by nuclear genes and must be imported from the cytosol. In addition, only a few of the mitochondrial tRNAs needed for translation are encoded in mitochondrial DNA. Despite considerable progress made over the last few years, still little is known how the bulk of cytosolic AaRS and respective tRNAs are transported into mitochondria. Here, we report the identification of a protein complex that ties AaRS and tRNA import into the mitochondria of Arabidopsis thaliana. Using leucyl-tRNA synthetase 2 (LeuRS2) as a model for a mitochondrial signal peptide (MSP)-less precursor, a ≈30 kDa protein was identified that interacts with LeuRS2 during import. The protein identified is identical with a previously characterized mitochondrial protein designated HP30-2 (encoded by At3g49560) that contains a sterile alpha motif (SAM) similar to that found in RNA binding proteins. HP30-2 is part of a larger protein complex that contains with TIM22, TIM8, TIM9 and TIM10 four previously identified components of the translocase for MSP-less precursors. Lack of HP30-2 perturbed mitochondrial biogenesis and function and caused seedling lethality during greening, suggesting an essential role of HP30-2 in planta.

Study of the influence of anxiety on the parameters of hand tapping in patients with postoperative epilepsy in comparison with the group of healthy volunteers

2020 ◽  
pp. 49-56
Author(s):  
E. Narodova ◽  
N. Shnayder ◽  
A. Narodov ◽  
D. Dmitrenko
Keyword(s):  
Healthy Volunteers ◽  
Theoretical Basis ◽  
Focal Epilepsy ◽  
Disease Modifying Therapy ◽  
Hand Tapping ◽  
Disease Modifying

The presented work devoted to hand tapping is intended to lay foundations in a theoretical basis for the development of a new direction of non-drug disease-modifying therapy for structural focal epilepsy, implemented through the formation of a new dominant “healthy system” based on the distraction of the patient and switching of attention.

scholarly journals Reassessment of Gene-Elusive Familial Dilated Cardiomyopathy Leading to the Discovery of a Homozygous AARS2 Variant—The Importance of Regular Reassessment of Genetic Findings

2021 ◽  
Vol 11 (3) ◽  
pp. 122-128
Author(s):  
Priya Bhardwaj ◽  
Christoffer Rasmus Vissing ◽  
Niels Kjær Stampe ◽  
Kasper Rossing ◽  
Alex Hørby Christensen ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Genetic Screening ◽  
Sanger Sequencing ◽  
Mitochondrial Protein ◽  
Trna Synthetase ◽  
Familial Dilated Cardiomyopathy ◽  
Pathogenic Variants ◽  
Case Summary ◽  
Heterozygous Carriers ◽  
Important Enzyme

Background: AARS2 encodes the mitochondrial protein alanyl-tRNA synthetase 2 (MT-AlaRS), an important enzyme in oxidative phosphorylation. Variants in AARS2 have previously been associated with infantile cardiomyopathy. Case summary: A 4-year-old girl died of infantile-onset dilated cardiomyopathy (DCM) in 1996. Fifteen years later, her 21-year-old brother was diagnosed with DCM and ultimately underwent heart transplantation. Initial sequencing of 15 genes discovered no pathogenic variants in the brother at the time of his diagnosis. However, 9 years later re-screening in an updated screening panel of 129 genes identified a homozygous AARS2 (c.1774C > T) variant. Sanger sequencing of the deceased girl confirmed her to be homozygous for the AARS2 variant, while both parents and a third sibling were all found to be unaffected heterozygous carriers of the AARS2 variant. Discussion: This report underlines the importance of repeated and extended genetic screening of elusive families with suspected hereditary cardiomyopathies, as our knowledge of disease-causing mutations continuously grows. Although identification of the genetic etiology in the reported family would not have changed the clinical management, the genetic finding allows genetic counselling and holds substantial value in identifying at-risk relatives.

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