RT Journal Article SR Electronic T1 Novel genotype-phenotype and MRI correlations in a large cohort of patients with SPG7 mutations JF Neurology Genetics JO Neurol Genet FD Lippincott Williams & Wilkins SP e279 DO 10.1212/NXG.0000000000000279 VO 4 IS 6 A1 Channa A. Hewamadduma A1 Nigel Hoggard A1 Ronan O'Malley A1 Megan K. Robinson A1 Nick J. Beauchamp A1 Ruta Segamogaite A1 Jo Martindale A1 Tobias Rodgers A1 Ganesh Rao A1 Ptolemaios Sarrigiannis A1 Priya Shanmugarajah A1 Panagiotis Zis A1 Basil Sharrack A1 Christopher J. McDermott A1 Pamela J. Shaw A1 Marios Hadjivassiliou YR 2018 UL http://ng.neurology.org/content/4/6/e279.abstract AB Objective To clinically, genetically, and radiologically characterize a large cohort of SPG7 patients.Methods We used data from next-generation sequencing panels for ataxias and hereditary spastic paraplegia to identify a characteristic phenotype that helped direct genetic testing for variations in SPG7. We analyzed MRI. We reviewed all published SPG7 mutations for correlations.Results We identified 42 cases with biallelic SPG7 mutations, including 7 novel mutations, including a large multi-exon deletion, representing one of the largest cohorts so far described. We identified a characteristic phenotype comprising cerebellar ataxia with prominent cerebellar dysarthria, mild lower limb spasticity, and a waddling gait, predominantly from a cohort of idiopathic ataxia. We report a rare brain MRI finding of dentate nucleus hyperintensity on T2 sequences with SPG7 mutations. We confirm that the c.1529C>T allele is frequently present in patients with long-standing British ancestry. Based on the findings of the present study and existing literature, we confirm that patients with homozygous mutations involving the M41 peptidase domain of SPG7 have a younger age at onset compared to individuals with mutations elsewhere in the gene (14 years difference, p < 0.034), whereas c.1529C>T compound heterozygous mutations are associated with a younger age at onset compared to homozygous cases (5.4 years difference, p < 0.022).Conclusions Mutant SPG7 is common in sporadic ataxia. In patients with British ancestry, c.1529C>T allele represents the most frequent mutation. SPG7 mutations can be clinically predicted by the characteristic hybrid spastic-ataxic phenotype described above, along with T2 hyperintensity of the dentate nucleus on MRI.DN=dentate nuclei; HCA=hereditary cerebellar ataxias; HSP=hereditary spastic paraplegia; NGS=Next-generation sequencing; PEO=Progressive external ophthalmoplegia; RN=red nuclei; SARA=Scale for the assessment and rating of ataxia