Autosomal Dominant Spastic Paraplegias

Loureiro, José Leal; Brandão, Eva; Ruano, Luís; Brandão, Ana Filipa; Lopes, Ana M.; Thieleke‐Matos, Carolina; Miller-Fleming, Leonor; Cruz, Vítor Tedim; Barbosa, Mafalda; Silveira, Isabel; Stevanin, Giovanni; Pinto‐Basto, Jorge; Sequeiros, Jorge; Alonso, Isabel; Coutinho, Paula

doi:10.1001/jamaneurol.2013.1956

Cited by 47 publications

(18 citation statements)

References 53 publications

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“…In addition, R239C ( n = 31) [6, 9, 11, 13, 15, 17, 21, 22, 27–29, 31, 32, 36, 39, 45, 51, 53, 54, 56] and R495W ( n = 14) [15–17, 21, 32, 36, 43, 50, 52, 54] mutations were the most commonly reported mutations in all studied families. Zhao et al reported that the three families with R239C mutations were not apparently related and haplotype analysis did not exclude a distant founder effect [6].…”

Section: Discussionmentioning

confidence: 97%

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

Zhao

Liu

2017

Transl Neurodegener

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BackgroundThe hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders. Approximately 10% of the autosomal dominant (AD) HSPs (ADHSPs) have the spastic paraplegia 3A (SPG3A) genotype which is caused by ATL1 gene mutations. Currently there are more than 60 reported ATL1 gene mutations and the genotype-phenotype correlation remains unclear. The study aims to investigate the genotype-phenotype correlation in SPG3A patients.MethodsWe performed a reanalysis of the clinical features and genotype-phenotype correlations in 51 reported studies exhibiting an ATL1 gene mutation.ResultsMost HSPs-SPG3A patients exhibited an early age at onset (AAO) of <10 years old, and showed an autosomal dominant pure spastic paraplegia. We found that 14% of the HSPs-SPG3A patients presented complicated phenotypes, with distal atrophy being the most common complicated symptom. The AAO of each mutation group was not statistically significant (P > 0.05). The mutational spectrum associated with ATL1 gene mutation is wide, and most mutations are missense mutations, but do not involve the functional motif of ATL1 gene encoded atlastin-1 protein.ConclusionsOur findings indicate that there is no clear genotype-phenotype correlation in HSPs-SPG3A patients. We also find that exons 4, 7, 8 and 12 are mutation hotspots in ATL1 gene.Electronic supplementary materialThe online version of this article (doi:10.1186/s40035-017-0079-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 97%

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

Zhao

Liu

2017

Transl Neurodegener

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“…As in previously published population-based studies, SPG4 and SPG3A were the most frequent AD-HSP. 15,20,21 SPG4 accounts for up to 45% of AD-HSP and up to 20% of sporadic cases, 22 while SPG3A accounts for nearly 10% of AD-HSP. 18 SPG8 was present in 5% of our cohort, which is more common compared to previous reports.…”

Section: Discussionmentioning

confidence: 99%

“…20,26,27 This is likely due to very recent advances in genetic diagnoses of HSP compared to the common SCAs and highlights the need for good natural history data to identify parameters which influence clinical outcomes of HSP. 28 There is one study which examined the correlation between disease duration and spasticity in patients with HSP, but unfortunately, the genetic diagnoses were not reported.…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic study of hereditary spastic paraplegia in Canada

Chrestian¹,

Dupré²,

Gan‐Or

et al. 2017

Neurol Genet

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Objective:To describe the clinical, genetic, and epidemiologic features of hereditary spastic paraplegia (HSP) in Canada and to determine which clinical, radiologic, and genetic factors determine functional outcomes for patients with HSP.Methods:We conducted a multicenter observational study of patients who met clinical criteria for the diagnosis of HSP in the provinces of Alberta, Ontario, and Quebec from 2012 to 2015. Characteristics of the participants were analyzed using descriptive statistics. The main outcome measure for a subset of the cohort (n = 48) was the Spastic Paraplegia Rating Scale. We also used the SPATAX-EUROSPA disability stage (disability score) to assess disability (n = 65).Results:A total of 526 patients were identified with HSP across the country, and 150 patients had a confirmed genetic diagnosis. Mutations were identified in 15 different genes; the most common were SPAST (SPG4, 48%), ATL1 (SPG3A, 16%), SPG11 (8%), SPG7 (7%), and KIAA0196 (SPG8, 5%). The diagnosis of SPG4 was associated with older age at symptom onset (p = 0.0017). SPG4 and SPG3A were less associated with learning disabilities compared to other subtypes of HSP, and SPG11 was strongly associated with progressive cognitive deficits (odds ratio 87.75, 95% confidence interval 14.04–548.24, p < 0.0001). SPG3A was associated with better functional outcomes compared to other HSP subtypes (p = 0.04) on multivariate analysis. The strongest predictor of significant disability was abnormal brain MRI (p = 0.014).Conclusions:The most important predictors of disability in our HSP cohort were SPG11 mutations and abnormal brain MRI. Accurate molecular characterization of well-phenotyped cohorts and international collaboration are essential to establish the natural history of these rare neurodegenerative disorders.

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“…SPG11 and SPG15 are the two major loci for this entity, comprising more than 40% of cases, while SPG21/ACP33 (maspardin), SPG44 (GJC2), SPG49/56 (CYP2U1), SPG46 (GBA2), SPG47 (AP4B1), SPG54 (DDHD2), and SPG63 (AMPD2) are less frequent [5,21]. Truncating mutations in the ZFYVE26 gene leading to loss of function of spastizin cause SPG15 and Kjellin's syndrome characterized by central retinal degeneration in addition to TCC, and similar clinical and imaging presentations to SPG11 with TCC and WM hyperintensities in MRI [13,14,27,28].…”

Section: Discussionmentioning

confidence: 99%

“…There are currently 76 different HSP, and 59 of them have been identified according to their genotypic classification by mapped genetic loci or mutated genes so far, with that number steadily increasing [4]. The most common AD-HSP are SPG4, SPG3A, and SPG31, caused by mutations in the genes spastin , atlastin , and REEP1, respectively, and account for more than 50% of AD-HSP [3,4,5]. Among the most common AR-HSP are SPG11 and SPG5, depending on the population [3,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20].…”

Section: Introductionmentioning

confidence: 99%

Novel Compound Heterozygous <b><i>Spatacsin</i></b> Mutations in a Greek Kindred with Hereditary Spastic Paraplegia SPG11 and Dementia

Fraidakis¹,

Brunetti

Blackstone

et al. 2016

Neurodegener Dis

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SPG11 belongs to the autosomal recessive hereditary spastic paraplegias (HSP) and presents during childhood or puberty with a complex clinical phenotype encompassing learning difficulties, ataxia, peripheral neuropathy, amyotrophy, and mental retardation. We hereby present the case of a 30-year-old female patient with complex autosomal recessive HSP with thinning of the corpus callosum (TCC) and dementia that was compound heterozygous with two novel mutations in the SPG11 gene. Sequence analysis of the SPG11 gene revealed two novel mutations in a compound heterozygous state in the index patient (c.2431C>T/p.Gln811Ter and c.6755_6756insT/p.Glu2252Aspfs*88). MRI showed abnormal TCC, white matter (WM) hyperintensities periventricularly, and the ‘ears of the lynx' sign. Diffusion tensor imaging showed a mild-to-moderate decrease in fractional anisotropy and an increase in mean diffusivity in WM compared to age-matched controls, while magnetic resonance spectroscopy showed abnormal findings in affected WM with a decrease in N-acetyl-aspartate in WM regions of interest. This is the first SPG11 kindred from the Greek population to be reported in the medical literature.

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Autosomal Dominant Spastic Paraplegias

Cited by 47 publications

References 53 publications

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

Clinical and genetic study of hereditary spastic paraplegia in Canada

Novel Compound Heterozygous <b><i>Spatacsin</i></b> Mutations in a Greek Kindred with Hereditary Spastic Paraplegia SPG11 and Dementia

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