F28 Novel mutations and findings in a cohort of McLeod neuroacanthocytosis, an X-linked HD phenocopy

Background McLeod syndrome (MLS) is an ultra-rare neurodegenerative X-linked disease caused by mutations in the XK gene, classified as one of the core neuroacanthocytosis syndromes. Together with the clinically very similar chorea-acanthocytosis it belongs to the heterogeneous group of ‘Huntington’s disease (HD) phenocopies’. Aims To characterize a cohort of HD phenocopies with the genetically confirmed diagnosis of McLeod syndrome. Methods This is a retrospective and prospective analysis of genotype and phenotype of sixteen McLeod cases. Results We longitudinally characterized the second largest cohort known to date. We identified novel XK mutations as well as deletions that extend into the PRRG1 gene (novel) and describe two contiguous gene deletion cases of MLS with X-linked chronic granulomatous disease (deletion also effecting the CYBB gene). This study confirms core features of MLS such as late onset hyperkinetic movements in association with neuro/myopathy, neuropsychiatric impairment, cardiac involvement, hyperCKemia. Novel aspects in this MLS series seem obstructive sleep apnea and epileptic seizure onset in childhood. Conclusions Our study expands the limited knowledge on the variable course, the various clinical manifestations and the genetic spectrum of a hereditary HD phenocopy syndrome.