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

• Published in: Neurology. Genetics 2020-12, Vol.6 (6), p.e521-e521
• Main Authors: Zanette, Vanessa, Reyes, Aurelio, Johnson, Mark, do Valle, Daniel, Robinson, Alan J., Monteiro, Vaneisse, Telles, Bruno Augusto, L.R. Souza, Ricardo, S.F. Santos, Mara L, Benincá, Cristiane, Zeviani, Massimo
• Format: Article
• Language: English
• ISSN: 2376-7839; 2376-7839
• DOI: 10.1212/NXG.0000000000000521

To expand the clinical phenotype of mutations by assessing the functional consequences of a missense and a splicing acceptor mutation. We 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 [ H]-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. The patient is a compound heterozygous for a novel missense c.3721G>A (p.Val1241Met) and the splicing region c.1771-6C>G mutation in , 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. Mutations in the gene cause -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 -related mutations and suggests a new classification that we propose designating as Neurodevelopmental Disorder with Regression, Abnormal Movements, and Increased Lactate.