TECPR2 mutations and HSP combined phenotype

SERGIO NEMIROVSKY; ALBERTO ESPAY; ADRIAN TURJANSKI; MARTIN CESARINI; EMILIA GATTO; JUAN BUSTAMANTE

Boston

Congreso; 2017 AAN Anual Meeting; 2017

American Academy of Neurology

Objective: to describe a patient of non-Bukharian origin harboring a novel TECPR2 gene with a complicated HSP phenotypeBackground: Hereditary spastic paraparesis (HSP) is a heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and paralysis. HSP may occur as pure form or as a complicated HSP where classical symptoms are accompanied by other neurological manifestations. Recently, Oz-Levi et al. identified, in Jewish Bukharians, a novel and rare recessive HSP (HSP 49), caused by a mutation in the TECPR2 gene that encodes TECPR2 protein implicated in autophagia.Design/Methods: Whole-exome sequencing was performed in a 45 years-old man suffering of progressive cerebellar ataxia and paraparesis since the age of 31, when he noticed postural instability. Examination at our clinic at age of 42 years of age revealed cerebellar ataxia, spasticity, pyramidal signs (bilateral Babinski and Hoffman signs), sensory neuropathy, dysarthria and attention and executive cognitive impairment. Brain MRI showed cerebellar atrophy. Friedereich ataxia, SCA1,2,3, and 6 molecular tests were negatives. Extensive blood and metabolic testing were normal. Family history was irrelevant.Results: Variant prioritization revealed two consecutive heterozygous SNPs on the same haplotype in the TECPR2 gene, predicting the nonsynonymous change of p.Lys795Asn and p.Pro796Ser. Mean PhastCons for the region (14:102901531-102901551) was 0.898 (StDev: 0.216). Based on bioinformatics algorithms, the Lysine 795 to Asparagine change was considered as damaging for the protein (Mutation Taster: 0.997, SIFT: 0.004, Polyphen: 0.982). Computational modeling of the TECPR2 structure shows that Proline 796 is located at the end of a beta sheet, so replacement by Serine may disrupt the correct folding of the protein. Also, Human Splicing Finder predicted alteration of an Exonic Splice Enhancer and the induction of a new splicing donor site.Conclusions: We believe these changes to be causative of an alteration in autophagia processes that lead to an adult onset HSP 49-type of neurological disorder.