Autosomal recessive hereditary spastic paraplegia—clinical and genetic characteristics of a well-defined cohort

Yoon, Grace; Baskin, Berivan; Tarnopolsky, Mark A.; Boycott, Kym M.; Geraghty, Michael T.; Sell, Erick; Goobie, Sharan; Meschino, Wendy S.; Banwell, Brenda; Ray, Peter N.

doi:10.1007/s10048-013-0366-9

Cited by 35 publications

(34 citation statements)

References 23 publications

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“…This is only the second report of SPG7 mutations in FC patients, 19 and the first report of a large cohort. These results strongly suggest that homozygous or compound heterozygous SPG7 variants explain a significant proportion of FC spastic ataxia cases (38.7% of families in our cohort).…”

Section: Discussionmentioning

confidence: 75%

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

et al. 2015

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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

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Section: Discussionmentioning

confidence: 75%

“…Only recently were three SPG7 FC cases reported from the province of Ontario. 19 The relative prevalence of SPG7 in the FC population is unknown.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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“…Mutations in SPG7 were identified as the first genetic cause of both pure and complicated forms of ARHSP [11]. Several studies have since reported SPG7 mutations as the most common cause of both pure and complicated ARHSP phenotypes [3,13]. These studies also showed that some clinical features such as speech abnormalities and cerebellar atrophy are frequently observed in patients with SPG7 mutations.…”

Section: Discussionmentioning

confidence: 99%

“…HSPs have been traditionally divided into pure and complicated forms depending on the presence of additional neurological or nonneurological features such as ataxia, intellectual disability, optic atrophy, deafness, dementia, peripheral neuropathy, and epilepsy [1]. However, although the distinction between pure and complicated forms of HSPs remains clinically useful, this distinction is not always maintained at the molecular level, as mutations in some genes can cause either a pure or a complicated phenotype [2,3]. Moreover, the clinical heterogeneity partially reflects the large genetic heterogeneity of this group of disorders with more than 70 loci mapped and 58 discovered genes, accounting for all modes of inheritance [4].…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel homozygous SPG7 mutation by whole exome sequencing in a Greek family with a complicated form of hereditary spastic paraplegia

Daoud

Papadima

Bencheikh

et al. 2015

European Journal of Medical Genetics

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“…[5][6][7][14][15][16][17][18][19][20] Although a few mutations (p.S1045L, p.R1031fs*38, p.V1215A and p.G1129R) are shared with some families, most mutations are unique.…”

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confidence: 99%

Novel mutations in the PNPLA6 gene in Boucher-Neuhäuser syndrome

et al. 2015

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On whole-exome sequencing, a novel compound heterozygous mutation (c.2923A>G/c.3523_3524insTGTCCG, p.T975A/p.1175_1176insVS) and a novel homozygous one (c.3534G>C, p.W1178C) in the PNPLA6 gene were identified in sporadic and familial Japanese patients with Boucher-Neuhäuser syndrome (BNS), respectively. However, we did not find any mutations in the PNPLA6 gene in 88 patients with autosomal recessive hereditary spastic paraplegia (ARHSP). Our study confirmed the earlier report that a PNPLA6 mutation causes BNS. This is the first report on PNPLA6 mutations in non-Caucasian patients. Meanwhile, PNPLA6 mutations might be extremely rare in Japanese ARHSP patients. Moreover, we first found hypersegmented neutrophils in two BNS patients with PNPLA6 mutations.

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Autosomal recessive hereditary spastic paraplegia—clinical and genetic characteristics of a well-defined cohort

Cited by 35 publications

References 23 publications

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

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

Identification of a novel homozygous SPG7 mutation by whole exome sequencing in a Greek family with a complicated form of hereditary spastic paraplegia

Novel mutations in the PNPLA6 gene in Boucher-Neuhäuser syndrome

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