A Patient with a Novel <b><i>RARS2</i></b> Variant Exhibiting Liver Involvement as a New Clinical Feature and Review of the Literature

Abstract

Pontocerebellar hypoplasia (PCH) is a heterogeneous neurodevelopmental disorder that is characterized by decreased brainstem and cerebellum volume. Pontocerebellar hypoplasia type 6 (PCH6) is a mitochondrial disease associated with autosomal recessive inheritance that results from mutations in the <i>RARS2</i> gene. In this case report, we describe a new clinical presentation with a novel <i>RARS2</i> pathogenic variant. We report here on 2 siblings who presented with neonatal lactic acidosis, microcephaly, growth retardation, persistent seizures, and cholestasis with a previously undefined <i>RARS2</i> pathogenic variant. In our literature review, we evaluated the clinical features and pathogenic variants of 34 patients reported in 16 publications since the initial identification of <i>RARS2</i> pathogenic variants in PCH6 in 2007. Both siblings were detected with c.1564G&#x3e;A (p.Val522Ile), a novel homozygous pathogenic variant of the <i>RARS2</i> gene. Imaging revealed advanced cerebral atrophy and cerebellar hypoplasia, while the basal ganglia and pons were preserved. At follow-up, the elevations in liver function test results and cholestasis had regressed while the LDH and GGT elevations persisted. Both siblings showed microcephaly on follow-up and started to suffer seizures. Severe developmental delay and nutritional problems were observed, and both died in infancy. <i>RARS2</i> pathogenic variant is a mitochondrial disease that causes severe mental, motor, and developmental retardation, as well as short life expectancy. Our patients are the first cases with liver involvement in PCH6 and a novel homozygous <i>RARS2</i> pathogenic variant to be reported in the literature. This additional phenotype can be considered as making a valid contribution to the literature.