A study in a Turkish family with ataxia and points to MTCL1 as a candidate gene for autosomal dominant cerebellar ataxia

Objectives: Inherited ataxias are a group of highly heterogeneous neurological disorders representing a significant diagnostic challenge in clinical practice. We performed next-generation sequencing(NGS) in a case with progressive cerebellar ataxia of suspected autosomal dominant(AD) inheritance. We found a novel heterozygous microtubule cross-linking factor 1(MTCL1) loss of function variant in a 17-year-old patient. We propose MTCL1 as a candidate gene for AD cerebellar ataxia in humans. Method: We studied a Turkish family with progressive degenerative ataxia affecting mainly the cerebellum. AD inheritance was suspected based on the family history(the same mutation was detected in the mother) and early age of onset(<30 years). Absence of the clinic in the mother(Also kranial MRG and neurophysiological studies were normal) may be due to the lack of penetrance. We evaluated neurological and neuropsychological examination by pediatric neurologists, detailed biochemical and genetic testing. Structural, inflammatory, toxic disorders were excluded as acquired causes. We performed NGS analysis with ataxia panel on genomic DNA from whole blood. The disease-causing variant was studied in all available family members by direct Sanger sequencing. Results and Conclusion: We found a novel heterozygous MTCL1 loss of function variant c.49C>T(p.GLN17Ter) in a 17-year-old patient with progressive cerebellar ataxia, mild intellectual disability, episodic pain in the lower limbs. MTCL1 encodes a microtubule-associated protein highly expressed in cerebellar Purkinje cells; its knockout in a mouse model causes ataxia. We propose MTCL1 as a candidate gene for AD cerebellar ataxia in humans.
Keywords: ataxia, autosomal dominant , cerebellum, MTCL1