Clinical and genetic findings in a cohort of Chinese patients with autosomal recessive spinocerebellar ataxia

Autosomal recessive spinocerebellar ataxia (SCAR) is a rare and complex group of diseases. Clinical examination reveals a prominent “ataxia” feature that may involve both the central and peripheral nervous systems, as well as other systems and organs. SCAR should be considered in patients younger than 30 years of age who present with chronic progressive gait disturbance and imbalance.1

The genetic etiology for SCAR has been hypothesized for decades. Revolutionary gene-sequencing techniques, especially next generation sequencing (NGS), have revealed numerous SCAR-causing genes.2 Previous reports showed mutations in a wide range of genes. We therefore investigated the genetic cause and clinical features of patients with SCAR at our center.

This study was approved by the Department of Neurology, Huashan Hospital, and Shanghai Jing-An District Centre Hospital. A diagnosis of cerebella ataxia was made by up to two neurologists. From January 2015 to July 2019, patients with cerebella ataxia as the dominant complaint and an age at onset (AAO) of under 30 years were continuously recruit data movement disorder clinic. Exclusion criteria included: (a) Patients with a family history of a dominant inheritance pattern; (b) Cerebella ataxia caused by other non-genetic factors, such as inflammation, neoplasm, infection, and toxicity confirmed by medical history, laboratory test or auxiliary examinations. Targeted sequencing, with a panel containing more than 4000 causative genes related to human disease from the Online Mendelian Inheritance in Man database (Agilent, Santa Clara, California), was performed in probands after consent. A variant screening protocol was undertaken as described in Supplementary methods. The ataxia-related genes in this panel are listed in the Supplementary table. The variants found were confirmed by Sanger sequencing and co-segregation analysis. Variants that had not previously been reported as mutations were classified according to American College of Medical Genetics and Genomics criteria.3

A total of 35 probands were recruited. The average AAO was 19.3 ± 7.5 years. Of these probands, 26 underwent genetic testing. Nineteen variants, related to 11 genes, were diagnosed with SCAR. Based on the Genetic Nomenclature of Recessive Cerebellar Ataxias proposed by the International Parkinson and Movement Disorder Society,4 we subdivided patients into three groups: group A (with an ATX prefix), including ATX-SETX (n = 4, 15.4%), ATX-NPC1 (n = 3, 11.5%), ATX-CYP27A1 (n = 2, 7.7%), ATX-SYNE1 (n = 1, 3.8%), group B (with ATX/HSP or HSP/ATX prefix), including HSP/ATX-GBA2 (n = 2, 7.7%), ATX/HSP-SACS (n = 1, 3.8%), and group C (others), including MYC-CLN6 (n = 2, 7.7%), MYC-SCARB2 (n = 1, 3.8%), MYC/ATX-NEU1(n = 1, 3.8%), DYT/ATX-ATP7B (n = 1, 3.8%), NHLRC1 (n = 1, 3.8%). In group A, all patients mainly exhibited cerebellar ataxia; four probands with senataxin (SETX) mutations showed neuropathy, and three with Niemann-Pick disease, type C1 (NPC1) mutations complained of cognitive decline. In group B, all three probands showed spastic paraparesis. In group C, all six probands presented with cerebellar ataxia and other neurological features, such as seizures, myoclonus, and dementia. Magnetic resonance imaging revealed cerebellar atrophy in most cases. Clinical features are summarized in Table 1.

Our study investigated causative genes in patients with young-onset SCAR and expanded the mutations spectrum of SCAR based on NGS results. Genes causing SCAR were detected in 73.1% (19/26) of probands. Fourteen novel variants were revealed (for detailed information see Supplementary table), and clinical features were in accordance with those of previous reports. All probands were classified into three groups according to the new nomenclature. Friedreich's ataxia (FRDA) was reported as the most frequently occurring SCAR, followed by ataxia-telangiectasia or ataxia with oculomotor apraxia,1 while ATX-SETX gene mutations were most frequently found in our cohort. However, the identification of dynamic mutations was not undertaken for most patients because FRDA is a very rare cause of inherited ataxia in China.5 Other limitations of our study included the small sample size used, and lack of further studies on the function of the novel mutations.

In conclusion, SCAR includes complex, disabling, inherited, neurodegenerative diseases with a diagnosis that mainly relies on gene testing. Improvements in NGS technologies and bioinformatics tools, and a reduction in their cost, enhance the availability of gene-sequencing techniques for the diagnosis of SCAR.

CONFLICT OF INTEREST

These authors reported no conflict of interest.