SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases

Abstract

Hereditary cerebellar ataxias and hereditary spastic paraplegias are clinically and genetically heterogeneous and often overlapping neurological disorders. Mutations in SPG7 cause the autosomal recessive spastic paraplegia type 7 (SPG7), but recent studies indicate that they are also one of the most common causes of recessive cerebellar ataxia. In Quebec, a significant number of patients affected with cerebellar ataxia and spasticity remain without a molecular diagnosis. We performed wholeexome sequencing in three French Canadian (FC) patients affected with spastic ataxia and uncovered compound heterozygous variants in SPG7 in all three. Sanger sequencing of SPG7 exons and exon/intron boundaries was used to screen additional patients. In total, we identified recessive variants in SPG7 in 22 FC patients belonging to 12 families (38.7% of the families screened), including two novel variants. The p.(Ala510Val) variant was the most common in our cohort. Cerebellar features, including ataxia, were more pronounced than spasticity in this cohort. These results strongly suggest that variants affecting the function of SPG7 are the fourth most common form of recessive ataxia in FC patients. Thus, we propose that SPG7 mutations explain a significant proportion of FC spastic ataxia cases and that this gene should be considered in unresolved patients. INTRODUCTIONHereditary cerebellar ataxias and hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous and often overlapping neurological disorders. HSPs are characterized by a predominant progressive spasticity and weakness in the lower limbs due to degeneration of the corticospinal tracts, 1 whereas the main feature of cerebellar ataxias is progressive cerebellar degeneration leading to impaired balance, gait and speech. 2 Both HSP and hereditary ataxias can be associated with other neurological and non-neurological features, resulting in complex phenotypes with frequent intra-and inter-familial variability. Significantly, cerebellar ataxias are very often associated with pyramidal involvement leading to 450% of recessive ataxias manifesting as spastic ataxias. 3 Because of the individual rarity and genetic heterogeneity of these conditions, their molecular diagnosis remains challenging and time-consuming.Mutations in the gene SPG7 were the first identified genetic cause of autosomal recessive HSP in 1998 (MIM602783). 4 Since then, a significant number of causative mutations were found in several HSP cohorts from different populations. 5-14 SPG7 can be characterized by a pure or complex HSP phenotype. Increasingly, reports documented that cerebellar ataxia and cerebellar atrophy on magnetic resonance imaging (MRI) are the most frequent additional features in complex SPG7 cases. 6,7,9,12,15 In a study of a large Dutch cohort, cerebellar ataxia was found in 57% of cases and it was even the

Prevalence and phenotype of the c.1529C>T SPG7 variant in adult‐onset cerebellar ataxia in Italy

“…Overall, the frequency of SPG7-related cerebellar ataxias in our cohort was lower when compared with previously reported surveys from other populations, ranging from 18.6% in British patients to 19.3% in French-Canadian cases [13,19]. This frequency may indicate a lower prevalence of the variant in patients of Italian ancestry with SPG7.…”

“…This difference was maintained when comparing age at onset of our homozygous individuals with that of classical patients with SPG7 from the literature who were negative for the p.Ala510Val allele [age at onset (mean AE SD), 50.6 AE 7.40 vs. 34.8 AE 12.8 years; P = 0.0004] [12][13][14][17][18][19][20][21][22].…”

Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism

“…Meta‐analysis combining these data with other cohorts of SPG7 patients can be expected to yield further genotype‐phenotype correlations. Ataxia was present in 65% of the patients as expected, given that pathogenic variants in SPG7 are one of the most common causes of recessive adult‐onset undiagnosed cerebellar ataxia . SPG7 s creening has been proposed in the differential diagnosis of spastic ataxia.…”

“…No clear phenotype/genotype correlation has been reported, and these pathogenic variants may result in both pure (lower limb pyramidal weakness with spasticity) or complicated hereditary spastic paraplegia (HSP) phenotypes, with the presence of additional features such as ataxia, intellectual disability, optic atrophy, deafness, dementia, peripheral neuropathy, and epilepsy. 6 Recent studies indicate that SPG7 pathogenic variants are one of the most common causes of recessive adultonset undiagnosed cerebellar ataxia, 7,8 and SPG7 patients may show a wide variety of signs and symptoms, including spastic paraparesis, progressive external ophthalmoplegia (PEO), and optical neuropathy. 1,4,9,10 The clinical spectrum of SPG7 disease continues to expand, and recently levodopa-responsive parkinsonism has been described in 2 patients.…”

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

“…SPG7 , identified as a cause of HSP in 1998, 7 was not systematically considered a cause of predominant (and even pure) cerebellar ataxia until 15 years later. 8 Yet, within the past 2 years, it has been appreciated as one of the most common causes of autosomal-recessive cerebellar ataxia, 9,10 and the cerebellar features may be even more pronounced than spasticity in some cohorts. 10 Mutations in PNPLA6 were identified as a cause of autosomal-recessive HSP complicated by motor axonal neuropathy in 2008, leading to the designation SPG39.…”