Clinical and genetic analysis of infants with pontocerebellar hypoplasia type 6 caused by RARS2 variations

Author:

Zhao Shichao1,Lian Ruofei1,Jin Liang1,Li Mengchun1,Jia Tianming1,Xu Falin1,Du Kaixian1,Wang Lijun1,Guo Qiliang1,Dong Yan12ORCID

Affiliation:

1. Department of Pediatrics The Third Affiliated Hospital of Zhengzhou University Zhengzhou China

2. Henan Key Laboratory of Child Brain Injury Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University Zhengzhou China

Abstract

AbstractObjectiveDefects in RARS2 cause cerebellopontine hypoplasia type 6 (pontocerebellar hypoplasia type 6, PCH6, OMIM: #611523), a rare autosomal recessive inherited mitochondrial disease. Here, we report two male patients and their respective family histories.MethodsWe describe the clinical presentation and magnetic resonance imaging (MRI) findings of these patients. Whole‐exome sequencing was used to identify the genetic mutations.ResultsOne patient showed hypoglycemia, high lactic acid levels (fluctuating from 6.7 to 14.1 mmol/L), and frequent seizures after birth, with progressive atrophy of the cerebrum, cerebellum, and pons. The other patient presented with early infantile developmental and epileptic encephalopathies (EIDEEs) with an initial developmental delay followed by infantile epileptic spasm syndrome (IESS) at 5 months old, with no imaging changes. Whole‐exome sequencing identified compound heterozygous RARS2 variants c.25A>G (p.I9V) with c.1261C>T (p.Q421*) and c.1A>G (p.M1V) with c.122A>G (p.D41G) in these two patients. Of these loci, c.1261C>T and c.122A>G have not been previously reported.SignificanceOur findings have expanded the RARS2 gene variant spectrum and present EIDEEs and IESS as phenotypes which deepened the association between PCH6 and RARS2.Plain Language SummaryDefects in RARS2 cause cerebellopontine hypoplasia type 6, a rare autosomal recessive inherited mitochondrial disease. Two patients with RARS2 variants were reported in this article. One patient showed hypoglycemia, high lactic acid levels, and frequent seizures after birth, with progressive atrophy of the cerebrum, cerebellum, and Page 3 of 21 Epilepsia OpenFor Review Only pons. The other patient presented with an initial developmental delay followed by refractory epilepsy at 5 months old, with no imaging changes. Our findings deepened the association between PCH6 and RARS2.

Publisher

Wiley

Subject

Neurology (clinical),Neurology

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