Objective: To present genetics, clinical description and natural history of the disease in four members of a Polish family with novel variants in the SACS gene.

Background: Hereditary cerebellar ataxias(HCAs) are a group of neurodegenerative disorders, characterized by extensive clinical and genetic heterogenity. Thus, establishing a specific genetic cause of the majority of HCAs requires molecular genetic testing, often targeting several causative genes. ARSACS is an early-onset hereditary ataxia primarily described in individuals born in Quebec, characterized by progressive cerebellar atrophy, spasticity, and peripheral neuropathy. Subsequent reports on the prevalence of ARSACS in other regions indicate that it may be an important cause of spastic ataxia worldwide.

Methods: Four adult siblings from a Polish nonconsanguineous family were examined (see figure 1). Three affected sisters and one affected brother were 47, 45, 33, and 30 years old, respectively. The severity of ataxia was assessed using the Scale for the Assessment and Rating of Ataxia(SARA). Additionally, evaluation of lower extremity spasticity was performed using the Modified Ashworth Scale(MAS) and the Spastic Paraplegia Rating Scale(SPRS). MRI brain scans, Electroneurography(ENG), neuropsychologic and ophtalmologic examination were conducted in all affected subjects. Molecular diagnosis was obtained through Next Generation Sequencing(NGS) performed on the affected proband (Fig.1, individual II.5). Identified variants were confirmed by traditional Sanger sequencing in selected family members.

Results: NGS revealed two novel variants in the SACS gene: c.13015G>A/p.Asp4339Asn and c.10245dup/p.Ile3416Hisfs*25. Co-segregation analysis confrimed the presence of both mutations in all affected family members, whereas each healthy sibling and the mother carried one of the two pathogenic variants. Clinical characteristics are presented in table 1. Neuropsychological tests revealed deficits of auditory short-term memory and visuomotor coordination.

Conclusions: We identified two novel variants in the SACS gene in members of the first Central-Eastern European family with ARSACS. Although the clinical presentation of our patients complies with the general characteristics of ARSACS, the application of NGS provided rapid and definite diagnosis among wide and heterogeneous group of HCAs.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-variants-in-the-sacs-gene-in-a-first-central-eastern-european-family-with-autosomal-recessive-spastic-ataxia-of-charlevoix-saguenay-arsacs/