New insights into the phenotype of FARS2 deficiency

Vantroys, Elise; Larson, Austin; Friederich, Marisa W.; Knight, Kaz M.; Swanson, Michael A.; Powell, Christopher A.; Smet, Joél; Vergult, Sarah; Paepe, Boél De; Seneca, Sara; Roeyers, Herbert; Menten, Björn; Minczuk, Michal; Vanlander, Arnaud; Hove, Johan Van; Coster, Rudy Van

doi:10.1016/j.ymgme.2017.10.004

Cited by 39 publications

(38 citation statements)

References 34 publications

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“…One child (P361L & V174del) had additional findings of bradykinesia and dystonia, whereas the other (P361L & A154V) also developed epilepsy. Both had neuroimaging abnormalities in the frontopontine pyramidal tracts, thalamus, and cerebellar atrophy . In contrast to the subjects with pure spastic paraplegia, these individuals could be classified as complex spastic paraplegia due to their combination of spasticity and other significant neurological issues.…”

Section: Discussionmentioning

confidence: 97%

“…Many of these severe cases were also associated with lactic acidosis or liver disease . Several moderate phenotypes have also been reported with diffuse cortical dysfunction, but had more functional capabilities . Examples included two siblings with compound heterozygous mutations (R419C & microdeletion) presenting with intellectual disability, truncal hypotonia, appendicular hypertonicity, and neonatal epilepsy) .…”

Section: Discussionmentioning

confidence: 99%

“…Examples included two siblings with compound heterozygous mutations (R419C & microdeletion) presenting with intellectual disability, truncal hypotonia, appendicular hypertonicity, and neonatal epilepsy) . Additional moderate subjects included two unrelated children with diffuse cortical dysfunction and lactic acidosis . One child (P361L & V174del) had additional findings of bradykinesia and dystonia, whereas the other (P361L & A154V) also developed epilepsy.…”

Section: Discussionmentioning

confidence: 99%

“…Similar to many mt‐aaRSs, FARS2 has been linked with a severe mitochondrial syndrome associated with an infantile‐onset epileptic encephalopathy and/or fatal Alpers‐like syndrome . More moderate phenotypes consisting of cognitive disability, motor delays, and epilepsy have also been reported . In its mildest form, FARS2 presented with a pure spastic paraplegia syndrome in a consanguineous Chinese family with homozygous mutations (spastic paraplegia type 77; SPG77 MIM#617046) …”

Section: Introductionmentioning

confidence: 99%

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

Sahai

Steiner

et al. 2018

Ann Clin Transl Neurol

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Mutations in FARS2, the gene encoding the mitochondrial phenylalanine‐tRNA synthetase (mtPheRS), have been linked to a range of phenotypes including epileptic encephalopathy, developmental delay, and motor dysfunction. We report a 9‐year‐old boy with novel compound heterozygous variants of FARS2, presenting with a pure spastic paraplegia syndrome associated with bilateral signal abnormalities in the dentate nuclei. Exome sequencing identified a paternal nonsense variant (Q216X) lacking the catalytic core and anticodon‐binding regions, and a maternal missense variant (P136H) possessing partial enzymatic activity. This case confirms and expands the phenotype related to FARS2 mutations with regards to clinical presentation and neuroimaging findings.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Sahai

Steiner

et al. 2018

Ann Clin Transl Neurol

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“…To date at least 21 pathogenic variants have been reported for HsmitPheRS that were found to be associated with disease conditions with moderate to severe symptoms. The clinical phenotypic expression of the pathogenic variants of the FARS2 gene show pleiotropic effects, from spastic paraplegia to infantile Alpers encephalopathy (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). The effects of some of these mutations on enzyme function have been investigated.…”

Section: Introductionmentioning

confidence: 99%

Biophysical characterization Of Alpers encephalopathy associated mutants of human mitochondrial phenylalanyl‐tRNA synthetase

2019

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Mutations in nucleus‐encoded mitochondrial aminoacyl‐tRNA synthetases (mitaaRSs) lead to defects in mitochondrial translation affecting the expression and function of 13 subunits of the respiratory chain complex leading to diverse pathological conditions. Mutations in the FARS2 gene encoding human mitochondrial phenylalanyl‐tRNA synthetase (HsmitPheRS) have been found to be associated with two different clinical representations, infantile Alpers encephalopathy and spastic paraplegia. Here we have studied three pathogenic mutants (Tyr144Cys, Ile329Thr, and Asp391Val) associated with Alpers encephalopathy to understand how these variants affect the biophysical properties of the enzyme. These mutants have already been reported to have reduced aminoacylation activity. Our study established that the mutants are significantly more thermolabile compared to the wild‐type enzyme with reduced solubility in vitro. The presence of aggregation‐prone insoluble HsmitPheRS variants could have a detrimental impact on organellar translation, and potentially impact normal mitochondrial function. © 2019 IUBMB Life, 71(8): 1141–1149, 2019 © 2019 IUBMB Life, 71(8):1141–1149, 2019

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In vitro human cell culture models in a bench‐to‐bedside approach to epilepsy

Danačíková,

Straka,

Daněk

et al. 2024

Epilepsia Open

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Epilepsy is the most common chronic neurological disease, affecting nearly 1%–2% of the world's population. Current pharmacological treatment and regimen adjustments are aimed at controlling seizures; however, they are ineffective in one‐third of the patients. Although neuronal hyperexcitability was previously thought to be mainly due to ion channel alterations, current research has revealed other contributing molecular pathways, including processes involved in cellular signaling, energy metabolism, protein synthesis, axon guidance, inflammation, and others. Some forms of drug‐resistant epilepsy are caused by genetic defects that constitute potential targets for precision therapy. Although such approaches are increasingly important, they are still in the early stages of development. This review aims to provide a summary of practical aspects of the employment of in vitro human cell culture models in epilepsy diagnosis, treatment, and research. First, we briefly summarize the genetic testing that may result in the detection of candidate pathogenic variants in genes involved in epilepsy pathogenesis. Consequently, we review existing in vitro cell models, including induced pluripotent stem cells and differentiated neuronal cells, providing their specific properties, validity, and employment in research pipelines. We cover two methodological approaches. The first approach involves the utilization of somatic cells directly obtained from individual patients, while the second approach entails the utilization of characterized cell lines. The models are evaluated in terms of their research and clinical benefits, relevance to the in vivo conditions, legal and ethical aspects, time and cost demands, and available published data. Despite the methodological, temporal, and financial demands of the reviewed models they possess high potential to be used as robust systems in routine testing of pathogenicity of detected variants in the near future and provide a solid experimental background for personalized therapy of genetic epilepsies.Plain Language SummaryEpilepsy affects millions worldwide, but current treatments fail for many patients. Beyond traditional ion channel alterations, various genetic factors contribute to the disorder's complexity. This review explores how in vitro human cell models, either from patients or from cell lines, can aid in understanding epilepsy's genetic roots and developing personalized therapies. While these models require further investigation, they offer hope for improved diagnosis and treatment of genetic forms of epilepsy.

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New insights into the phenotype of FARS2 deficiency

Cited by 39 publications

References 34 publications

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

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

Biophysical characterization Of Alpers encephalopathy associated mutants of human mitochondrial phenylalanyl‐tRNA synthetase

In vitro human cell culture models in a bench‐to‐bedside approach to epilepsy

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