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

ABSTRACT: Objective:To expand the clinical phenotype of POLR3A mutations by assessing the functional consequences of a missense and a splicing acceptor mutation. Methods: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 [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. Results: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 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. Conclusions:Mutations 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.

SUBMITTER: Zanette V

PROVIDER: S-EPMC7577545 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by <i>POLR3A</i> mutations.

Zanette Vanessa V Reyes Aurelio A Johnson Mark M do Valle Daniel D Robinson Alan J AJ Monteiro Vaneisse V Telles Bruno Augusto BA L R Souza Ricardo R S F Santos Mara L ML Benincá Cristiane C Zeviani Massimo M

Neurology. Genetics 20201007 6

<h4>Objective</h4>To expand the clinical phenotype of <i>POLR3A</i> mutations by assessing the functional consequences of a missense and a splicing acceptor mutation.<h4>Methods</h4>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 [<sup>1</sup>H]-magnetic ...[more]

PMID: 33134517

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Project description:BACKGROUND:In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. METHODS:We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. RESULTS:We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. CONCLUSIONS:This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.

Dataset Information

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

Publications

Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by <i>POLR3A</i> mutations.

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