Objective: To describe the clinical and molecular findings of a well-defined group of 11 congenital ataxia patients from 12 different families assessed in an adult Neurology outpatient clinic.

Background: Congenital ataxias are a clinically and genetically heterogeneous group of disorders. Developmental delay usually precedes overt cerebellar ataxia syndrome. Cognitive impairment. epilepsy and dysmorphic features are frequently present. However, most cases have a non-progressive course, even with improvement on the follow-up.

Method: Patients were systematically examined in usual clinical settings. Cases with cerebellar malformations other than hypoplasia were not included. In all, repeat expansion disorders (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, DRPLA and  Friedreich ataxia) were previously ruled out. In all, targeted clinical exome sequencing (CES) was performed. Copy number variants were analyzed with cytogenetic microarray.

Results: All patients presented with developmental delay. Most of the cases (10/12) remained ambulant after a mean follow up of 32 years. Pattern of inheritance was sporadic in 7, AD in 2 and X-linked/mitochondrial in 1 family. Genetic diagnosis was confirmed in 4 families (2 SPTBN2, 1, ADCK3, 1 CACNA1A). We identified three novel pathogenic variants: two in SPTBN2(NM_006946.2: p.His278Arg and p.Gln161Arg) and one in ADCK3(NM_:020247.5: p.Val364Met). The patient with the SPTBN2 variant p.Gln161Arg displayed ataxia and oculomotor apraxia while SPTBN2(p.His278Arg) and ADCK3(p.Val364Met) had a phenotype of developmental delay and isolated ataxia. We identified a previously reported variant in CACNA1A(p.Arg583Gln). The patient showed marked axial weakness on examination, but EMG, showed no abnormalities. Undiagnosed cases were further studied with a cytogenetic microarray (4/7) without findings.

Conclusion: Congenital ataxia is a well-defined clinical entity. All patient in this series presented with developmental delay and a non-progressive or slowly progressive ataxia. Herein, we report three novel pathogenic variants: SPTBN2(NM_006946.2: p.His278Arg and p.Gln161Arg). Further in-deep molecular characterization of congenital ataxia patients is needed to understand distinct pathophysiological pathways.

References: 1. Valence S, Cochet E, Rougeot C, et al. Exome sequencing in congenital ataxia identifies two new candidate genes and highlights a pathophysiological link between some congenital ataxias and early infantile epileptic encephalopathies. Genet. Med. 2018; 21(3): 553-563.
2. Bertini E, Zanni G, Boltshauser E. Nonprogressive congenital ataxias. Handb Clin Neurol 2018;155:91-103.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-genetic-spectrum-of-a-series-of-congenital-ataxias-patients/