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. 2018 Oct 24;4(6):e279.
doi: 10.1212/NXG.0000000000000279. eCollection 2018 Dec.

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

Channa A Hewamadduma  1 , Nigel Hoggard  1 , Ronan O'Malley  1 , Megan K Robinson  1 , Nick J Beauchamp  1 , Ruta Segamogaite  1 , Jo Martindale  1 , Tobias Rodgers  1 , Ganesh Rao  1 , Ptolemaios Sarrigiannis  1 , Priya Shanmugarajah  1 , Panagiotis Zis  1 , Basil Sharrack  1 , Christopher J McDermott  1 , Pamela J Shaw  1 , Marios Hadjivassiliou  1
Affiliations

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

Channa A Hewamadduma et al. Neurol Genet. .

Erratum in

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.

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Figures

Figure 1
Figure 1. Schematic diagram of the SPG7 protein with important functional domains and positioning of mutations in the Sheffield cohort and all the published pathogenic mutations in the SPG7 gene
Mutations described in our cohort of patients are annotated above the SPG7 protein structure, while previously published mutations are below. Allelic frequency is noted within parenthesis. New mutations detected in our cohort are highlighted in red font. Variations denoted in blue are matching complementary DNA sequence of the reported mutations. Some large exon deletions reported are indicated in the text box. Parentheses from mutations removed to create space. AAA = ATPases associated with diverse cellular activities; Coil1 and Coil2 = coiled domain; FtsH = filamentation temperature-sensitive mutant in Escherichia coli domain; TM1 and TM2 = transmembrane domain 1 and 2. Reference sequence: NM_003119.3.
Figure 2
Figure 2. MRI of the brain in SPG7 cases shows T2 hyperintensity of the dentate nucleus
(A) T1 axial image across the dentate nucleus (DN) of a control case. (B) T1 axial section through the DN in a patient with c.1529C>T homozygous mutation. (C) T2-weighted axial image of the same control and (D) T2 axial section through DN in the same patient with c.1529C>T homozygous mutation, which demonstrates hyperintense DN (solid white arrow) compared to the normal-appearing white matter. (E) T2-weighted axial image of the same patient, which demonstrates the red nucleus (RN). The RN appears hypointense compared to normal-appearing white matter in all SPG7 and control cases (solid black arrow with white border). (F) The observation of hyperintense T2 signal of the DN was significantly more frequent in the SPG7 patients compared to the control cases (p < 0.001, χ2 test value 25.7649).
Figure 3
Figure 3. Genotype-phenotype correlation in SPG7 mutations and age at onset of symptoms
(A) Association of the position (by the functionally important regions) of the mutation and the age at onset in homozygous SPG7 cases. N terminal = up to first 140aa; FstH = 141-250aa; AAA ATpase = 306-481aa; M41 peptidase = 544-746aa; the rest = mutations in any other area(s), which is/are not described as above. We selected homozygous cases because of the uniformity they create by harboring 2 similarly, mutated alleles, to compare the effect of the mutation within functionally important domains of the SPG7 protein on the age at onset. One-way analysis of variance with multiple comparisons and post hoc Tukey test showed a significantly (p = 0.034) younger age at onset (14.63 years, SE 5.25, 95% confidence interval: 0.82–28.4) for those with homozygous mutations in the M41 peptidase domain compared to a mutational position in a functionally undefined domain (“the rest”). (B) The c.1529C>T common mutation when in the homozygous state is associated with a significantly later age at onset than when in the compound heterozygous state. (C)1529C>T patients provide a degree of mutational homogeneity, in that at least 1 allele is constant allowing comparison between homozygous and compound heterozygous states. Compound heterozygotes developed symptoms on average 5.4 years earlier than the c.1529C>T homozygotes (p = 0.022, independent samples t test for equality of mean values with equal variances assumed).
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