Genetic spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias

Background Although many causative genes have been uncovered in recent years, genetic diagnosis is still missing for approximately 50% of autosomal recessive cerebellar ataxia (ARCA) patients. Few studies have been performed to determine the genetic spectrum and clinical profile of ARCA patients in the Chinese population. Methods Fifty-four Chinese index patients with unexplained autosomal recessive or sporadic ataxia were investigated by whole-exome sequencing (WES) and copy number variation (CNV) calling with ExomeDepth. Likely causal CNV predictions were validated by CNVseq. Results Thirty-eight mutations including 29 novel ones were identified in 25 out of the 54 patients, providing a 46.3% positive molecular diagnostic rate. Ten different genes were involved, of which four most common genes were SACS, SYNE1, ADCK3 and SETX, which accounted for 76.0% (19/25) of the positive cases. The de novo microdeletion in SACS was reported for the first time in China and the uniparental disomy of ADCK3 was reported for the first time worldwide. Clinical features of the patients carrying SACS, SYNE1 and ADCK3 mutations were summarized. Conclusions Our results expand the genetic spectrum and clinical profiles of ARCA patients, demonstrate the high efficiency and reliability of WES combined with CNV analysis in the diagnosis of suspected ARCA, and emphasize the importance of complete bioinformatics analysis of WES data for accurate diagnosis.

Spinocerebellar Ataxia Type 28 in a Chinese Pedigree: A Case Report and Literature Review

Spinocerebellar ataxia (SCA) is a common neurogenetic disease, which mainly manifests as ataxia of posture, gait and limbs, cerebellar dysarthria, cerebellar and supranuclear eye movement disorders. It is found that SCA is a kind of progressive neurodegenerative disease including many subtypes, which is mainly mapped to two genetic patterns as: autosomal dominant cerebellar ataxia (ADCA) and autosomal recessive cerebellar ataxia (ARCA). Molecular genetic diagnosis functions as a necessity in its clinical diagnosis and treatment. In our previous clinical work, we found a family with ataxia who presented a c.1852A > G missense mutation in the exon region of AFG3L2 gene by whole exome sequencing (WES) and Sanger validation. Spinocerebellar ataxia type 28 (SCA28) was suspected, which was not reported in the previous literature. We here report the case and review the literature.

Genetic Spectrum and Clinical Features in a Cohort of Chinese Patients with Autosomal Recessive Cerebellar Ataxias

Background: Although many causative genes have been uncovered in recent years, genetic diagnosis is still missing for approximately 50% of autosomal recessive cerebellar ataxia (ARCA) patients. Few studies have been performed to determine the genetic spectrum and clinical profiles of ARCA patients in the Chinese population.Methods: Fifty-four Chinese index patients with unexplained autosomal recessive or sporadic ataxia were investigated by whole-exome sequencing (WES) and copy number variation (CNV) calling with Exome Depth. Likely causal CNV predictions were validated by CNVseq. Results: Thirty-eight mutations including 29 novel ones were identified in 25 out of 54 patients, providing a 46.3% positive molecular diagnostic rate. Ten different genes were involved, and the four most common genes were SACS, SYNE1, ADCK3 and SETX, which accounted for 76.0% (19/25) of the positive cases. The de novo microdeletion in SACS was firstly reported in China and the uniparental disomy of ADCK3 was reported for the first time worldwide. Furthermore, the clinical features of the patients carrying SACS, SYNE1and ADCK3 mutations were summarized. Conclusions: Our results expand the genetic spectrum and clinical profiles of ARCA patients, demonstrate the high efficiency and reliability of WES combined CNV analysis in diagnosing suspected ARCA, and emphasize the importance of complete bioinformatics analysis of WES data in making an accurate diagnosis.

Three adult-onset autosomal recessive ataxias

Purpose of reviewThis review will increase vigilance for 3 autosomal recessive ataxias that look different clinically when presenting in adulthood rather than childhood.Recent findingsA study found a high allelic frequency for repeat expansions in the RFC1 gene, a cause of Cerebellar Ataxia, Neuropathy, Vestibular Areflexia syndrome, which presents exclusively in adults. This implies that autosomal recessive etiologies of adult-onset cerebellar ataxias may be more common than previously thought.SummaryAdult-onset cerebellar ataxias are commonly caused by mutations inherited in either an autosomal dominant or X-linked pattern, as most autosomal recessive mutations cause disease at earlier ages. However, some autosomal recessive etiologies such as Late-onset Tay Sachs disease, Very Late-Onset Friedreich's Ataxia, and ARSACS emerge in adulthood, with age at presentation influencing the progression and clinical signs of the disease. This review will cover the genetics, clinical presentation, and necessary diagnostic steps required to identify 3 causes of Autosomal Recessive Cerebellar Ataxia that manifest differently in adults vs children.

Novel MAG Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype

Homozygous variants in MAG, encoding myelin-associated glycoprotein (MAG), have been associated with complicated forms of hereditary spastic paraplegia (HSP). MAG is a glycoprotein member of the immunoglobulin superfamily, expressed by myelination cells. In this study, we identified a novel homozygous missense variant in MAG (c.124T>C; p.Cys42Arg) in a Portuguese family with early-onset autosomal recessive cerebellar ataxia with neuropathy and oculomotor apraxia. We used homozygosity mapping and exome sequencing to identify the MAG variant, and cellular studies to confirm its detrimental effect. Our results showed that this variant reduces protein stability and impairs the post-translational processing (N-linked glycosylation) and subcellular localization of MAG, thereby associating a loss of protein function with the phenotype. Therefore, MAG variants should be considered in the diagnosis of hereditary cerebellar ataxia with oculomotor apraxia, in addition to spastic paraplegia.