<i><scp>RARS</scp>2</i> mutations in a sibship with infantile spasms

Ngoh, Adeline; Brás, José; Guerreiro, Rita; Meyer, Esther; McTague, Amy; Dawson, Eleanor; Mankad, Kshitij; Gunny, Roxana; Clayton, Peter T.; Mills, Philippa B.; Thornton, Rachel; Lai, Ming; Forsyth, Rob; Kurian, Manju A.

doi:10.1111/epi.13358

Cited by 25 publications

(30 citation statements)

References 13 publications

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“…Including the two patients we report here, 29 patients with RARS2 mutations are described in literature so far (Namavar et al 2011a;Cassandrini et al 2013;Rankin et al 2010;Glamuzina et al 2012;Kastrissianakis et al 2013;Joseph et al 2014;Li et al 2015;Lax et al 2015;Nishri et al 2016;Ngoh et al 2016;Alkhateeb et al 2016). Splice site, nonsense, or missense mutations are identified throughout the RARS2 gene, but no patients with biallelic null mutations were identified, supporting the assumption that complete abolishment of tRNA-arg would be lethal.…”

Section: Discussionsupporting

confidence: 65%

RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy?

et al. 2016

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Mutations in the mitochondrial arginyl tRNA synthetase (RARS2) gene are associated with Pontocerebellar Hypoplasia type 6 (PCH6). Here we report two patients, compound heterozygous for RARS2 mutations, presenting with early onset epileptic encephalopathy and (progressive) atrophy of both supra-and infratentorial structures. Early pontocerebellar hypoplasia was virtually absent and respiratory chain (RC) defects could not be detected in muscle biopsies. Both patients carried a novel missense mutation c.1544A>G (p.(Asp515Gly)) in combination with either a splice site (c.297+2T>G) or a frameshift (c.452_454insC) mutation. The splice site mutation induced skipping of exon 4.These two patients expand the phenotypical spectrum associated with RARS2 mutations beyond the first report of PCH6 by Edvardson and colleagues. We propose to classify RARS2-associated phenotypes as an early onset mitochondrial encephalopathy, since this is more in agreement with both clinical presentation and underlying genetic cause.

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Section: Discussionsupporting

confidence: 65%

RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy?

et al. 2016

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“…Affected children have decreased levels of oxidative phosphorylation components, with variably decreased mitochondrial respiratory chain activities in multiple complexes, and biochemical evidence of mitochondrial impairment. [35][36][37] To date, approximately 30 patients have been reported with pathogenic variants in RARS2. 35 In an open-label study, 5 children with RARS2 deficiency were given EPI-743 over a 12-month treatment phase, followed by an ongoing extension phase.…”

Section: Rars2 Deficiencymentioning

confidence: 99%

Clinical Trials in Mitochondrial Disease

Enns

Cohen

2017

Journal of Inborn Errors of Metabolism and Screening

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Mitochondrial dysfunction results in the production of an abnormally high amount of reactive oxygen and nitrogen species, which results in redox imbalance and glutathione deficiency. Therapeutics such as EPI-743 (a-tocotrienol quinone) and RP103 (cysteamine bitartrate) have the theoretical potential to improve redox imbalance by increasing intracellular glutathione and are currently under investigation in multiple clinical trials. This review provides an update on the use of these compounds in clinical trials related to primary and secondary mitochondrial disorders. These clinical trials have not only provided hope to affected patients and their families and caregivers, but also will serve as important stepping stones for further studies as our understanding of mitochondrial disease pathogenesis continues to improve.

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“…611523) with autosomal recessive inheritance (2). To the best of our knowledge, 23 cases with RARS2 mutations have been reported in the literature thus far (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). PCH6 is a rare mitochondrial disease.…”

Section: Introductionmentioning

confidence: 99%

“…The age of disease onset varies from birth (6,11,14,15) to 9 months old (8). The common initial symptoms of mitochondrial disease include hypotonia (1,2,4,(6)(7)(8), epileptic seizures (5,6,8,9,11), encephalopathy (1,2,4,6,10) and feeding difficulties (2,3). Furthermore, other uncommon initial presentations have been suggested, including hypoglycemia (6,11), tachypnea (2,10) and cyanosis (7).…”

Section: Introductionmentioning

confidence: 99%

“…The common initial symptoms of mitochondrial disease include hypotonia (1,2,4,(6)(7)(8), epileptic seizures (5,6,8,9,11), encephalopathy (1,2,4,6,10) and feeding difficulties (2,3). Furthermore, other uncommon initial presentations have been suggested, including hypoglycemia (6,11), tachypnea (2,10) and cyanosis (7). Almost all patients developed early-onset epileptic seizures (1)(2)(3)5,6,9,11) and the age of onset may vary from 1 day (5) to 9 months old (8).…”

Section: Introductionmentioning

confidence: 99%

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Distinct magnetic resonance imaging features in a patient with novel RARS2 mutations: A case report and review of the literature

Zhang

et al. 2017

Exp Ther Med

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Pontocerebellar hypoplasia type 6 (PCH6) is a rare autosomal recessive disease that occurs due to mutations in the mitochondrial arginyl-tRNA synthetase 2 (RARS2) gene. To the best of our knowledge, 23 cases with relatively complete clinical data have been reported thus far. In the present study, a case with PCH6 caused by novel RARS2 mutations is described, in which distinct magnetic resonance imaging (MRI) features were identified. In addition, 23 PCH6 cases found in the literature were reviewed. Early onset hypotonia (43.48%), epileptic seizures (34.78%), encephalopathy (26.08%) and feeding difficulties (17.39%) were common initial symptoms of PCH6. During disease progression, the patients presented refractory epileptic seizures (94.12%), feeding problems (60.87%), severe developmental delay (100%), microcephaly (88.89%) and hyperlactacidemia (76.47%). The clinical features of the present patient were suggestive of PCH6, with early onset epilepsy, feeding difficulties, severe developmental delay, microcephaly, hearing loss and hyperlactacidemia. According to available MRI data from 20 reported cases with PCH6, the characteristic finding in MRI was pontocerebellar dysplasia or progressive cerebral/pontocerebellar atrophy in 16 cases, while 4 cases did not present pontocerebellar hypoplasia, and no basal ganglia involvement was observed in any of the cases. Distinctive MRI features were also identified in the present case, including pontocerebellar preservation after 1 year of age, as well as a high diffusion-weighted imaging signal suggesting intracellular edema in the cerebellar hemispheres, basal ganglia, thalamus and corpus callosum. Progressive loss of cerebral white matter and cortical volume were common features shared by all patients. In conclusion, in the present study, two novel heterozygous mutations were identified in RARS2, namely c.1718C>T(p.Thr573Ile) and c.991A>G (p.Ile331Val). Thus, the present case enriched the phenotypic and genotypic spectrum of the RARS2 mutations.

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RARS2 mutations in a sibship with infantile spasms

Cited by 25 publications

References 13 publications

RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy?

RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy?

Clinical Trials in Mitochondrial Disease

Distinct magnetic resonance imaging features in a patient with novel RARS2 mutations: A case report and review of the literature

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