PT  - JOURNAL ARTICLE
AU  - Channa A. Hewamadduma
AU  - Nigel Hoggard
AU  - Ronan O'Malley
AU  - Megan K. Robinson
AU  - Nick J. Beauchamp
AU  - Ruta Segamogaite
AU  - Jo Martindale
AU  - Tobias Rodgers
AU  - Ganesh Rao
AU  - Ptolemaios Sarrigiannis
AU  - Priya Shanmugarajah
AU  - Panagiotis Zis
AU  - Basil Sharrack
AU  - Christopher J. McDermott
AU  - Pamela J. Shaw
AU  - Marios Hadjivassiliou
TI  - Novel genotype-phenotype and MRI correlations in a large cohort of patients with <em>SPG7</em> mutations
AID  - 10.1212/NXG.0000000000000279
DP  - 2018 Dec 01
TA  - Neurology Genetics
PG  - e279
VI  - 4
IP  - 6
4099  - http://ng.neurology.org/content/4/6/e279.short
4100  - http://ng.neurology.org/content/4/6/e279.full
SO  - Neurol Genet2018 Dec 01; 4
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