Novel genotype-phenotype and MRI correlations in a large cohort of patients with <i>SPG7</i> mutations
Date
2018Author
Hewamadduma, Channa A.Hoggard, Nigel
O'Malley, Ronan
Robinson, Megan K.
Beauchamp, Nick J.
Segamogaite, Ruta
Martindale, Jo
Rodgers, Tobias
Rao, Ganesh
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Shanmugarajah, Priya
![ORCID logo](https://orcid.org/sites/default/files/images/orcid_16x16.png)
Sharrack, Basil
McDermott, Christopher J.
Shaw, Pamela J.
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ISSN
2376-7839Source
Neurology GeneticsVolume
4Issue
6Google Scholar check
Metadata
Show full item recordAbstract
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.