Two Novel Heterozygote Mutations of ATM in a Chinese Family with Dystonia-Dominant Ataxia Telangiectasia and Literatures Review

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder with high clinical heterogeneity. A-T may present in complicated variable forms, mainly including classic A-T and milder forms. Contrary to the classic A-T, the milder form does not present the cardinal features of A-T, including ataxia and telangiectasia. A few ATM mutations have been reported in variant A-T cases manifested as isolated dystonia without any signs of classical A-T. To date, more than 400 disease-related ATM mutations have been identified in patients with A-T. In this study, target exome-sequencing was performed in an AT pedigree with predominant dystonia. Two novel ATM mutations, p.I2683T and p.S2860P, were identified in the family. We then reviewed previously published literatures of genetically confirmed A-T cases with predominant dystonia and summarized the clinical characteristics of dystonia-dominant A-T. To our knowledge, this is the first report of A-T patient with predominant dystonia in China. Dystonia may appear as one of the predominant manifestations or initial symptom of A-T. ATM genetic testing should be early considered for those patients with predominant dystonia, despite without accompanying ataxia or telangiectasia.

Two novel missense variants in SPTBN2 likely associated with spinocerebellar ataxia type 5

Introduction Spinocerebellar ataxias (SCAs) are a heterozygous group of neurodegenerative disorders. Spinocerebellar ataxia type 5 (SCA5) is a rare autosomal-dominant ataxia with pure cerebellum involvement. The clinical characteristics are limb and gait ataxia, trunk ataxia, sensory deficits, abnormal eye movement, dysarthria, and hyperactive tendon reflexes. Spectrin beta nonerythrocytic 2 gene (SPTBN2), coding β-III spectrin protein, was identified to be associated with SCA5. To date, more than 19 variants of SPTBN2 have been reported. Methods A family and an apparently sporadic patient with ataxia and cerebellar atrophy were recruited from Shandong Province (China). To discover the disease-causing variants, capillary electrophoresis and targeted next-generation sequencing were performed in the proband of the family and the sporadic patient. The candidate variants were verified by Sanger sequencing and analyzed by bioinformatics software. Results In our study, we verified two novel heterozygous variants in SPTBN2 in a SCA pedigree and a sporadic patient. The proband of the pedigree and her mother presented with walking instability and progressively getting worse. The sporadic patient suffered from slurred speech, walking instability, and drinking water choking cough. MRI examination of the proband and sporadic patient both displayed moderate cerebellar atrophy. The variants identified were traditionally conserved and predicted probably damaging and disease-causing by bioinformatics analysis. Conclusion We identified two novel heterozygous variants of SPTBN2 resulting in severe ataxia which further delineated the correlation between the genotype and phenotype of SCA5, and pathogenesis of variants in SPTBN2 should be further researched.

Two novel heterozygote mutations of ATM in a Chinese family with dystonia-dominant ataxia telangiectasia and literatures review

Background Ataxia-telangiectasia (A-T) is an autosomal recessive disorder with high clinical heterogeneity. A-T may present in complicated variable forms, mainly including classic A-T and milder forms. Contrary to the classic A-T, the milder form does not present the cardinal features of A-T, including ataxia and telangiectasia. A few ATM mutations have been reported in variant A-T cases manifested as isolated dystonia without any signs of classical A-T. To date, more than 400 disease-related ATM mutations have been identified in patients with A-T. Methods A pedigree with A-T and predominant dystonia were collected. Genetic testing of the proband were performed by target exome-sequencing of a panel designed to cover 101 genes associated with movement disorders. The candidate variants were further confirmed by Sanger sequencing.Results Two novel ATM variants (p.I2683T and p.S2860P) with probable pathogenicity were identified in the family. The proband presented obviously isolated segmental dystonia without any signs of ataxia and telangiectasias. We then reviewed previously published literatures of genetically confirmed A-T cases with predominant dystonia and summarized the clinical characteristics of dystonia-dominant A-T. Conclusion This is the first report of A-T patient with predominant dystonia in China. Dystonia may appear as one of the predominant manifestations or initial symptom of A-T. ATM genetic testing should be early considered for those patients with predominant dystonia, despite without accompanying ataxia or telangiectasia.

Heterozygous STUB1 missense variants cause ataxia, cognitive decline, and STUB1 mislocalization

ObjectiveTo identify the genetic cause of autosomal dominant ataxia complicated by behavioral abnormalities, cognitive decline, and autism in 2 families and to characterize brain neuropathologic signatures of dominant STUB1-related ataxia and investigate the effects of pathogenic variants on STUB1 localization.MethodsClinical and research-based exome sequencing was used to identify the causative variants for autosomal dominant ataxia in 2 families. Gross and microscopic neuropathologic evaluations were performed on the brains of 4 affected individuals in these families.ResultsMutations in STUB1 have been primarily associated with childhood-onset autosomal recessive ataxia, but here we report heterozygous missense variants in STUB1 (p.Ile53Thr and p.The37Leu) confirming the recent reports of autosomal dominant inheritance. Cerebellar atrophy on imaging and cognitive deficits often preceded ataxia. Unique neuropathologic examination of the 4 brains showed the marked loss of Purkinje cells (PCs) without microscopic evidence of significant pathology outside the cerebellum. The normal pattern of polarized somatodendritic STUB1 protein expression in PCs was lost, resulting in aberrant STUB1 localization in the distal PC dendritic arbors.ConclusionsThis study confirms a dominant inheritance pattern in STUB1-ataxia in addition to a recessive one and documents its association with cognitive and behavioral disability, including autism. In the most extensive analysis of cerebellar pathology in this disease, we demonstrate disruption of STUB1 protein in PCs as part of the underlying pathogenesis.

Pure-Tone Hearing Thresholds and Brainstem Auditory Evoked Potentials in Sporadic Ataxia

Introduction Spinocerebellar ataxia (SCA) is part of a genetic and clinical heterogeneous group of neurodegenerative diseases characterized by progressive cerebellar ataxia. Objective To describe the results of audiological and electrophysiological hearing evaluations in patients with sporadic ataxia (SA). Methods A retrospective cross-sectional study was carried out with 11 patients submitted to the following procedures: anamnesis, otorhinolaryngological evaluation, tonal and vocal audiometry, acoustic immittance and brainstem auditory evoked potential (BAEP) tests. Results The patients presented with a prevalence of gait imbalance, of dysarthria, and of dysphagia; in the audiometric and BAEPs, four patients presented with alterations; in the acoustic immittance test, five patients presented with alterations, predominantly bilateral. Conclusion The most evident alterations in the audiological evaluation were the prevalence of the descending audiometric configuration between the frequencies of 2 and 4 kHz and the absence of the acoustic reflex between the frequencies of 3 and 4 kHz bilaterally. In the electrophysiological evaluation, the patients presented changes with a prevalence of increased I, III and V wave latencies and the interval in the interpeak I-III, I-V and III-V. In the present study, it was observed that auditory complaints did not have a significant prevalence in this type of ataxia, which does not occur in some types of autosomal recessive and dominant ataxia.

Paula Coutinho’s outstanding contribution to the definition of Machado-Joseph disease

ABSTRACT Machado-Joseph disease, also known as spinocerebellar ataxia type 3, is the most common form of autosomal dominant ataxia in the world. Paula Coutinho, a highly-regarded Portuguese neurologist worldwide, had a seminal participation in the definition of this disease, more than 40 years ago.

Spinocerebellar ataxia type 10 in the South of Brazil: the Amerindian-Belgian connection

Spinocerebellar ataxia type 10 (SCA10) is a rare form of autosomal dominant ataxia found predominantly in patients from Latin America with Amerindian ancestry. The authors report the history of SCA10 families from the south of Brazil (the states of Paraná and Santa Catarina), emphasizing the Belgian-Amerindian connection.