![]() Parents noted poor eye contact from birth. Birth weight was 2,795 g (14th percentile), head circumference was 32 cm (9th percentile). Patient A is the second child of non-consanguineous parents, born at 39 weeks gestation after an uncomplicated pregnancy. We therefore propose to categorize the RARS2-associated phenotypes as an early onset mitochondrial epileptic encephalopathy, since this is more in agreement with clinical presentation and underlying genetic cause. Based upon these two patients and a literature study, we conclude that RARS2 mutations do not lead to a typical PCH phenotype. RC defects could not be detected in muscle biopsies taken from both patients. In this study, we report two patients with previously unreported mutations in RARS2, in whom early pontocerebellar hypoplasia was virtually absent. The canonical PCH6 phenotype consists of severe early onset epilepsy, progressive global atrophy including pons and cerebellum, lactic acidosis, and/or RC defects (Cassandrini et al. Mutations in the mitochondrial Arginine tRNA-synthetase ( RARS2) gene underlie PCH6, and the phenotype is similar to that of patients with mitochondrial respiratory chain (RC) defects (Edvardson et al. In an effort to create more clarity in the nomenclature, we focus here on PCH6 (OMIM 611523), a genetically and biochemically distinct form of PCH. 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.ĪNot all data are available of all patientsīThree out of four patients without epilepsy died before the age of 2 months These two patients expand the phenotypical spectrum associated with RARS2 mutations beyond the first report of PCH6 by Edvardson and colleagues. The splice site mutation induced skipping of exon 4. 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. Early pontocerebellar hypoplasia was virtually absent and respiratory chain (RC) defects could not be detected in muscle biopsies. 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. Mutations in the mitochondrial arginyl tRNA synthetase ( RARS2) gene are associated with Pontocerebellar Hypoplasia type 6 (PCH6). ![]()
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