The Global Epidemiology of Hereditary Ataxia and Spastic Paraplegia: A Systematic Review of Prevalence Studies

Ruano, Luís; Melo, Cláudia; Silva, Carolina; Coutinho, Paula

doi:10.1159/000358801

Cited by 491 publications

(358 citation statements)

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“…6 Prevalence of autosomal dominant (AD) HSP ranges between 0.5 and 5.5 per 100 000 individuals and that of autosomal recessive (AR) HSP between 0.3 and 5.3 per 100 000 individuals. 7 HSP can be pure (uncomplicated) or complex according to the absence or presence of additional neurological and non-neurological manifestations. There are 467 known HSP genes.…”

Section: Introductionmentioning

confidence: 99%

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Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

et al. 2016

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Hereditary spastic paraplegias (HSP) are the second most common type of motor neuron disease recognized worldwide. We investigated a total of 25 consanguineous families from Sudan. We used next-generation sequencing to screen 74 HSPrelated genes in 23 families. Linkage analysis and candidate gene sequencing was performed in two other families. We established a genetic diagnosis in six families with autosomal recessive HSP (SPG11 in three families and TFG/SPG57, SACS and ALS2 in one family each). A heterozygous mutation in a gene involved in an autosomal dominant HSP (ATL1/SPG3A) was also identified in one additional family. Six out of seven identified variants were novel. The c.64C4T (p.(Arg22Trp)) TFG/SPG57 variant (PB1 domain) is the second identified that underlies HSP, and we demonstrated its impact on TFG oligomerization in vitro. Patients did not present with visual impairment as observed in a previously reported SPG57 family (c.316C4T (p.(Arg106Cys)) in coiled-coil domain), suggesting unique contributions of the PB1 and coiled-coil domains in TFG complex formation/function and a possible phenotype correlation to variant location. Some families manifested marked phenotypic variations implying the possibility of modifier factors complicated by high inbreeding. Finally, additional genetic heterogeneity is expected in HSP Sudanese families. The remaining families might unravel new genes or uncommon modes of inheritance.

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Section: Introductionmentioning

confidence: 99%

“…8 On the contrary, AR HSP predominates in highly consanguineous communities. 7,9,10 Thin corpus callosum-associated HSP (TCC-HSP) represents a distinct subgroup accounting for approximately one-third of all AR HSP. 11 At least nine genes have been identified to be responsible for TCC-HSP.…”

Section: Introductionmentioning

confidence: 99%

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

et al. 2016

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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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“…Spinocerebellar ataxias (SCAs) are a group of autosomal dominant neurological disorders with a prevalence of 5.5 in 100,000 1. SCAs are phenotypically characterized by gait and limb ataxia, incoordination of eye movements, and speech disturbances.…”

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confidence: 99%

Docosahexaenoic acid is a beneficial replacement treatment for spinocerebellar ataxia 38

Manes

Alberici

Gregorio

et al. 2017

Annals of Neurology

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ObjectiveSpinocerebellar ataxia 38 (SCA38) is caused by mutations in the ELOVL5 gene, which encodes an elongase involved in the synthesis of polyunsaturated fatty acids, including docosahexaenoic acid (DHA). As a consequence, DHA is significantly reduced in the serum of SCA38 subjects. In the present study, we evaluated the safety of DHA supplementation, its efficacy for clinical symptoms, and changes of brain functional imaging in SCA38 patients.MethodsWe enrolled 10 SCA38 patients, and carried out a double‐blind randomized placebo‐controlled study for 16 weeks, followed by an open‐label study with overall 40‐week DHA treatment. At baseline and at follow‐up visit, patients underwent standardized clinical assessment, brain 18‐fluorodeoxyglucose positron emission tomography, electroneurography, and ELOVL5 expression analysis.ResultsAfter 16 weeks, we showed a significant pre–post clinical improvement in the DHA group versus placebo, using the Scale for the Assessment and Rating of Ataxia (SARA; mean difference [MD] = +2.70, 95% confidence interval [CI] = +0.13 to + 5.27, p = 0.042). At 40‐week treatment, clinical improvement was found significant by both SARA (MD = +2.2, 95% CI = +0.93 to + 3.46, p = 0.008) and International Cooperative Ataxia Rating Scale (MD = +3.8, 95% CI = +1.39 to + 6.41, p = 0.02) scores; clinical data were corroborated by significant improvement of cerebellar hypometabolism (statistical parametric mapping analyses, false discovery rate corrected). We also showed a decreased expression of ELOVL5 in patients’ blood at 40 weeks as compared to baseline. No side effect was recorded.InterpretationDHA supplementation is a safe and effective treatment for SCA38, showing an improvement of clinical symptoms and cerebellar hypometabolism. Ann Neurol 2017;82:615–621

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The Global Epidemiology of Hereditary Ataxia and Spastic Paraplegia: A Systematic Review of Prevalence Studies

Cited by 491 publications

References 54 publications

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

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

Docosahexaenoic acid is a beneficial replacement treatment for spinocerebellar ataxia 38

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