<i>FARS2</i> mutations presenting with pure spastic paraplegia and lesions of the dentate nuclei

Sahai, Supreet K.; Steiner, Rebecca E.; Au, Margaret G.; Graham, John M.; Salamon, Norikio; Ibba, Michael; Pierson, Tyler Mark

doi:10.1002/acn3.598

Cited by 15 publications

(5 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(1 case: leukodystrophy) [20] and NARS2 (1 case: global brain atrophy) [21,22]. Our study also points to the involvement of the dentate nuclei in pathogenic FARS2 variants (3 of the 4 cases) [23][24][25]. Finally, the apparent absence of brain MRI anomalies in 5 (3 IARS2, 1 YARS2, and 1 FARS2) of the 25 patients suggests that normal brain MRI images do not exclude the diagnosis of ARS2 mutations in mitochondrial diseases.…”

Section: New Findingssupporting

confidence: 53%

Phenotypic diversity of brain MRI patterns in mitochondrial aminoacyl-tRNA synthetase mutations

Roux

Barcia

Schiff

et al. 2021

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

Background and purpose: Mitochondrial aminoacyl-tRNA synthetases-encoded by ARS2 genes-are evolutionarily conserved enzymes that catalyse the attachment of amino acids to their cognate tRNAs, ensuring the accuracy of the mitochondrial translation process. ARS2 gene mutations are associated with a wide range of clinical presentations affecting the CNS. Methods: Two senior neuroradiologists analysed brain MRI of 25 patients (age range: 3 d-25 yrs.; 11 males; 14 females) with biallelic pathogenic variants of 11 ARS2 genes in a retrospective study conducted between 2002 and 2019.Results: Though several combinations of brain MRI anomalies were highly suggestive of specific aetiologies (DARS2, EARS2, AARS2 and RARS2 mutations), our study detected no MRI pattern common to all patients. Stroke-like lesions were associated with pathogenic SARS2 and FARS2 variants. We also report early onset cerebellar atrophy and calcifications in AARS2 mutations, early white matter involvement in RARS2 mutations, and absent involvement of thalami in EARS2 mutations. Finally, our findings show that normal brain MRI results do not exclude the presence of ARS2 mutations: 5 patients with normal MRI images were carriers of pathogenic IARS2, YARS2, and FARS2 variants.Conclusion: Our study extends the spectrum of brain MRI anomalies associated with pathogenic ARS2 variants and suggests ARS2 mutations are largely underdiagnosed

show abstract

Section: New Findingssupporting

confidence: 53%

Phenotypic diversity of brain MRI patterns in mitochondrial aminoacyl-tRNA synthetase mutations

Roux

Barcia

Schiff

et al. 2021

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

show abstract

“…One patient had an originally reported VUS in the PNPLA6 gene reclassified as benign and a previously unreported VUS reported in the TBK1 gene due to a more consistent phenotype. Last, one patient had originally reported VUS in the ZFYVE26 gene reclassified as benign and a previously unreported pathogenic variant reported in the FARS2 gene (Sahai et al, 2018) due to a more consistent phenotype along with the identification of the second pathogenic variant through our CNV analysis (Table 4). As described above, the CNV analysis of 15 families from this original cohort (20%, 15/76) identified one (7%, 1/15) pathogenic/likely pathogenic variant.…”

Section: Resultsmentioning

confidence: 95%

A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders

et al. 2019

View full text Add to dashboard Cite

Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset.For new cases (n = 184), our resulting clinically relevant detection rate remained *Kathie J. Ngo and Jessica E. Rexach contributed equally to this work. ORCIDJennifer E. Posey http://orcid.org/0000-0003-4814-6765 James R. Lupski http://orcid.org/0000-0001-9907-9246 Brent L. Fogel http://orcid.org/0000-0001-9831-1576 SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section. How to cite this article: Ngo KJ, Rexach JE, Lee H, et al. A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders. Human Mutation. 2020; 41:487-501. https://doi.

show abstract

“…[ 8 ] 7 NA NA F Seizure, 2 months Normal Globally delayed development, mild facial dysmorphism, an elevated lactate level, truncal hypotonia with brisk extremity reflexes throughout, and an intermittent intention tremor Alive at 5 years of age p.R419C/a 116 kb microdeletion (het) 8 NA NA M Seizures, only within 6 weeks after birth Two small foci of T2/FLAIR hyperintensity involving the periventricular white matter and deep white matter of the right posterior frontal lobe Delayed development, cerebral palsy, metabolic acidosis, truncal hypotonia, dysarthric speech, and a mild intention tremor Alive at 13 years of age p.R419C/a 116 kb microdeletion (het) Almannai et al [ 6 ] 9 North American No F No Brain atrophy Developmental delay, spastic paraplegia Alive at 20 years of age p.H159P/p.R419C (het) 10 North American No F No NA Developmental delay, spastic paraplegia Alive at 17 years of age p.H159P/p.R419C (het) Sahai et al . [ 21 ] 11 Northern European and Ashkenazi Jewish No M No Abnormal signal hyperintensities in the bilateral dentate nuclei Spasticity in lower extremities Alive at 9 years of age p.Q216X/p.P136H (het) Meszarosova et al . [ 22 ...…”

Section: Discussionmentioning

confidence: 99%

Two Chinese siblings of combined oxidative phosphorylation deficiency 14 caused by compound heterozygous variants in FARS2

Wang

et al. 2022

Eur J Med Res

View full text Add to dashboard Cite

Background As a rare mitochondrial disease, combined oxidative phosphorylation deficiency 14 (COXPD14) is caused by biallelic variants in the phenylalanyl-tRNA synthetase 2, mitochondrial gene (FARS2) with clinical features of developmental delay, an elevated lactate level, early-onset encephalopathy, liver failure, and hypotonia. The objectives of this study were to analyze the clinical and molecular features of two Chinese siblings affected with COXPD14, and to review relevant literature. Methods Mutation screening was performed by whole exome sequencing (WES) in combination with Sanger sequencing validation to identify the disease-causing variants of the two patients. Results The two siblings presented with severe clinical features and both progressed aggressively and failed to survive after treatment abandonment. We identified two compound heterozygous FARS2 variants c.925G>A p.Gly309Ser and c.943G>C p.Gly315Arg in this proband, which were inherited from the unaffected father and mother, respectively. In addition, Sanger sequencing confirmed that the elder affected sister carried the same compound heterozygous variants. The c.925G>A p.Gly309Ser variant is known and commonly reported in COXPD14 patients, while c.943G>C p.Gly315Arg is a novel one. Neither of the variants was found in 100 Chinese healthy controls. Both variants were classified as “deleterious” and were located in the highly conserved regions of the protein. The above results suggested that the two variants were likely causative in this COXPD14-affected pedigree. Conclusions Our study expands the mutation spectrum of FARS2 and highlights the importance of genetic testing in the diagnosis of diseases with a wide variety of phenotypes, especially in the differential diagnosis of diseases.

show abstract

FARS2 mutations presenting with pure spastic paraplegia and lesions of the dentate nuclei

Cited by 15 publications

References 15 publications

Phenotypic diversity of brain MRI patterns in mitochondrial aminoacyl-tRNA synthetase mutations

Phenotypic diversity of brain MRI patterns in mitochondrial aminoacyl-tRNA synthetase mutations

A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders

Two Chinese siblings of combined oxidative phosphorylation deficiency 14 caused by compound heterozygous variants in FARS2

Contact Info

Product

Resources

About