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Novel genotype-phenotype and MRI correlations in a large cohort of patients with SPG7 mutations.

ABSTRACT: 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.

SUBMITTER: Hewamadduma CA

PROVIDER: S-EPMC6244025 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Novel genotype-phenotype and MRI correlations in a large cohort of patients with <i>SPG7</i> mutations.

Hewamadduma Channa A CA Hoggard Nigel N O'Malley Ronan R Robinson Megan K MK Beauchamp Nick J NJ Segamogaite Ruta R Martindale Jo J Rodgers Tobias T Rao Ganesh G Sarrigiannis Ptolemaios P Shanmugarajah Priya P Zis Panagiotis P Sharrack Basil B McDermott Christopher J CJ Shaw Pamela J PJ Hadjivassiliou Marios M

Neurology. Genetics 20181024 6

<h4>Objective</h4>To clinically, genetically, and radiologically characterize a large cohort of <i>SPG7</i> patients.<h4>Methods</h4>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 <i>SPG7</i>. We analyzed MRI. We reviewed all published <i>SPG7</i> mutations for correlations.<h4>Results</h4>We identified 42 cases with biallelic <i>SPG7</i> mutations, inclu ...[more]

PMID: 30533525

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Dataset Information

Novel genotype-phenotype and MRI correlations in a large cohort of patients with SPG7 mutations.

Publications

Novel genotype-phenotype and MRI correlations in a large cohort of patients with <i>SPG7</i> mutations.

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