Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations

Abstract

ObjectiveTo expand the clinical phenotype of POLR3A mutations by assessing the functional consequences of a missense and a splicing acceptor mutation.MethodsWe performed whole-exome sequencing for identification of likely pathogenic mutations in a 9-year-old female patient with severe generalized dystonia, metabolic acidosis, leukocytosis, hypotonia, and dysphagia. Brain MRI showed basal ganglia atrophy and presence of lactate and lipid peaks by [1H]-magnetic resonance spectroscopy. Expression levels of Pol III target genes were measured by quantitative real-time (qRT)-PCR to study the pathogenicity of the biallelic mutations in patient fibroblasts.ResultsThe patient is a compound heterozygous for a novel missense c.3721G>A (p.Val1241Met) and the splicing region c.1771-6C>G mutation in POLR3A, the gene coding for the catalytic subunit of RNA polymerase III (Pol III). Aberrant splicing was observed for the c.1771-6C>G mutation. Decreased RNA expression levels of Pol III targets (HNRNPH2, ubiquitin B, lactotransferrin, and HSP90AA1) were observed in patient fibroblasts with rescue to normal levels by overexpression of the wild-type protein but not by the p.Val1241Met variant.ConclusionsMutations in the POLR3A gene cause POLR3A-related hypomyelinating leukodystrophy with or without oligodontia or hypogonadotropic hypogonadism (HLD7, OMIM: 607694) and neonatal progeroid syndrome (OMIM: 264090), both with high phenotypic variability. We demonstrated the pathogenicity of c.1771-6C>G and c.3721G>A mutations causing an early-onset disorder. The phenotype of our patient expands the clinical presentation of POLR3A-related mutations and suggests a new classification that we propose designating as Neurodevelopmental Disorder with Regression, Abnormal Movements, and Increased Lactate.

Developmental regression and movement disorder as a phenotypic variant of POLR3A Mutation—Case report

“…Nearly similar to our case, this girl also presented with recurrent pulmonary infections and milestone regression, and was unable to talk at 2 years. Whole‐exome sequencing revealed a compound heterozygous for a missense c.3721G > A (p.Val1241Met) and the splicing region c.1771‐6C > G mutation in POLR3A, which is again very relevant to our patients' findings 2 …”

“…Whole‐exome sequencing revealed a compound heterozygous for a missense c.3721G > A (p.Val1241Met) and the splicing region c.1771‐6C > G mutation in POLR3A, which is again very relevant to our patients' findings. 2 …”

“…The two main phenotypic categories with a variety of presentations are hypomyelinating leukodystrophy‐7 (HLD7), and a rare neonatal progeroid syndrome (NPS) also known as Wiedemann‐Rautenstrauch syndrome (WDRTS). 1 , 2 …”

POLR3A variants in hereditary spastic paraparesis and ataxia: clinical, genetic, and neuroradiological findings in a cohort of Italian patients

“…Other than severe childhood-onset hypomyelinating leukodystrophy, variants in POLR3A have been associated with milder, late-onset gait disorders with central hypomyelination, and with parkinsonism dystonia with basal ganglia involvement, with or without non-neurological signs [2][3][4]. POLR3A mutations have also been reported in rare cases of autosomal recessive neonatal progeroid syndrome [5] and in a single case of severe infantile generalized dystonia and hypotonia, leukocytosis, and metabolic acidosis with a lactate peak on brain magnetic resonance spectroscopy [6]. Recently, a milder phenotype consisting of late-onset spastic ataxia has been suggested to be specific to an intronic mutation (c.1909 + 22G > A) in the POLR3A gene [7][8][9][10][11][12][13].…”

Developmental Regression and Movement Disorder as a Phenotypic Variant of POLR3A Mutation - Case Report

“…Considering that this gene is involved in the transcription of many RNA structures, its mutations can lead to a wide range of phenotypes. The two main phenotypic categories with a variety of presentations, are hypomyelinating leukodystrophy-7 (HLD7), and a rare neonatal progeroid syndrome (NPS) also known as Wiedemann-Rautenstrauch syndrome (WDRTS) (1,2).…”