Clinical features of hereditary spastic paraplegia due to spastin mutation

McDermott, Christopher J.; Burness, Christine; Kirby, Janine; Cox, Laura; Rao, Dasappaiah Ganesh; Hewamadduma, Channa; Sharrack, Basil; Hadjivassiliou, Marios; Chinnery, Patrick F.; Dalton, Ann; Shaw, Pamela J.

doi:10.1212/01.wnl.0000223315.62404.00

Cited by 120 publications

(96 citation statements)

References 26 publications

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“…In total, the SPG4 families accounted for 44.4% (24/54) of AD-HSP and 4.5% (3/66) of the apparently sporadic SPG in this cohort. The SPAST mutation frequency in AD-HSP was similar to that reported in previous studies [5,6]. According to Beetz et al [28] and Depienne et al [29], approximately 20% of HSP patients carry micro-rearrangements, including deletions and duplications in the SPAST gene.…”

Section: Discussionsupporting

confidence: 86%

“…Of the current total of 71 HSP loci, 10 genes and 7 additional loci are associated with autosomal-dominant (AD)-HSP [2,3,4]. Mutations in SPAST are responsible for the largest proportion of both AD-HSPs (15-45%) and sporadic cases (10-15%) [5,6]. Two specific sequence variants resulting in changes in two adjacent amino acids (S44L and P45Q) of spastin, the protein encoded by SPAST , are known to act as modifiers of SPG4 and result in an earlier and more severe phenotype when found in trans with a mutation in SPAST [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in SPAST are responsible for the largest proportion of both AD-HSPs (15-45%) and sporadic cases (10-15%) [5,6]. Two specific sequence variants resulting in changes in two adjacent amino acids (S44L and P45Q) of spastin, the protein encoded by SPAST , are known to act as modifiers of SPG4 and result in an earlier and more severe phenotype when found in trans with a mutation in SPAST [6,7]. In addition, a polymorphism (c.1688G>C/p.G563A) in HSPD1 has been reported to modify the SPG4 phenotype, causing an earlier onset of the disease symptoms [8].…”

Section: Introductionmentioning

confidence: 99%

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Mutation and Clinical Characteristics of Autosomal-Dominant Hereditary Spastic Paraplegias in China

Luo¹,

Chen²,

Zhan³

et al. 2014

Neurodegener Dis

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Background: Hereditary spastic paraplegias constitute a heterogeneous group of inherited neurodegenerative disorders. To date, there has been no systematic mutation and clinical analysis for a large group of autosomal-dominant hereditary spastic paraplegias in China. Objective: The purpose of this study was to investigate the mutation frequencies and the clinical phenotypes of Chinese spastic paraplegia patients. Methods: Direct sequencing and a multiplex ligation-dependent probe amplification assay were applied to detect the mutations of SPAST and ATL1 in 54 autosomal-dominant hereditary spastic paraplegia probands and 66 isolated cases. Next, mutations in NIPA1, KIF5A, REEP1 and SLC33A1 were detected in the negative patients. Subsets of spastic paraplegia patients were genotyped for the modifying variants. Further, detailed clinical data regarding the genetically diagnosed families were analysed. Results: Altogether, 27 families were diagnosed as SPG4, 3 as SPG3A and 1 as SPG6. No mutations in KIF5A, REEP1 or SLC33A1 were found; 9 SPAST mutations were novel. There was no p.S44L or p.P45Q variant in SPAST and no p.G563A variant in HSPD1 in either the 120 spastic paraplegia patients or the 500 controls. There was a remarkable clinical difference between the SPG4 and non-SPG4 patients and even between genders among the SPG4 patients. Non-penetrance and remarkable gender difference were observed in some SPG4 and SPG3A families. Conclusions: Our data confirm that hereditary spastic paraplegias in China represent a heterogeneous group of genetic neurodegenerative disorders in autosomal-dominant and apparently sporadic forms. Novel genotype-phenotype correlations were established.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutation and Clinical Characteristics of Autosomal-Dominant Hereditary Spastic Paraplegias in China

Luo¹,

Chen²,

Zhan³

et al. 2014

Neurodegener Dis

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“…Environmental correlations have not been reported. However, evidence for additional genetic contributions is seen in several independent pedigrees, where single nucleotide polymorphisms encoding missense changes S44L or P45Q in the Spastin protein itself dramatically enhance disease severity when they occur in trans with a mutation affecting Spastin's catalytic domain (Chinnery et al 2004;Svenson et al 2004;Naimi et al 2005;McDermott et al 2006;Schickel et al 2007). …”

mentioning

confidence: 99%

Loss of Drosophila melanogaster p21-activated kinase 3 Suppresses Defects in Synapse Structure and Function Caused by spastin Mutations

et al. 2011

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Microtubules are dynamic structures that must elongate, disassemble, and be cleaved into smaller pieces for proper neuronal development and function. The AAA ATPase Spastin severs microtubules along their lengths and is thought to regulate the balance between long, stable filaments and shorter fragments that seed extension or are transported. In both Drosophila and humans, loss of Spastin function results in reduction of synaptic connections and disabling motor defects. To gain insight into how spastin is regulated, we screened the Drosophila melanogaster genome for deletions that modify a spastin overexpression phenotype, eye size reduction. One suppressor region deleted p21-activated kinase 3 (pak3), which encodes a member of the Pak family of actin-regulatory enzymes, but whose in vivo function is unknown. We show that pak3 mutants have only mild synaptic defects at the larval neuromuscular junction, but exhibit a potent genetic interaction with spastin mutations. Aberrant bouton morphology, microtubule distribution, and synaptic transmission caused by spastin loss of function are all restored to wild type when pak3 is simultaneously reduced. Neuronal overexpression of pak3 induces actin-rich thin projections, suggesting that it functions in vivo to promote filopodia during presynaptic terminal arborization. pak3 therefore regulates synapse development in vivo, and when mutated, suppresses the synaptic defects that result from spastin loss.

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“…Additionally, an SMN gene analysis should be performed in all proximal generalized forms. In contrast to ALS [26, 27] and the pure hereditary spastic paraplegia [28, 29], LMND seem to be monosystemic disorders with isolated damage to the anterior horn cells.…”

Section: Discussionmentioning

confidence: 99%

Classification of Phenotype Characteristics in Adult-Onset Spinal Muscular Atrophy

et al. 2007

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Background/Aims: Degenerative lower motor neuron diseases (LMND) encompass a group of rare clinically and genetically heterogeneous disorders with the hallmark of anterior horn cell degeneration in the spinal cord and brainstem. In a recently proposed classification, LMND were subdivided according to the clinical disease pattern and time course. This study was performed to investigate the clinical practicability of the classification. Methods: In 22 patients with adult LMND (mean disease duration, 24 years), the disease course and detailed clinical, electrophysiological, magnetic resonance imaging, laboratory, and genetic investigations were analyzed. Results: All patients could be assigned to the distinct disease subgroups, i.e. 11 patients to the slowly progressive generalized form (group 1), one to the distal form (group 2), 3 to the segmental distal form (group 3a), and seven to the segmental proximal form (group 3b). Conclusions: The proposed classification was confirmed to be a practicable tool, and additional implications for the classification of LMND could be drawn from the data in our patient sample.

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Clinical features of hereditary spastic paraplegia due to spastin mutation

Cited by 120 publications

References 26 publications

Mutation and Clinical Characteristics of Autosomal-Dominant Hereditary Spastic Paraplegias in China

Mutation and Clinical Characteristics of Autosomal-Dominant Hereditary Spastic Paraplegias in China

Loss of Drosophila melanogaster p21-activated kinase 3 Suppresses Defects in Synapse Structure and Function Caused by spastin Mutations

Classification of Phenotype Characteristics in Adult-Onset Spinal Muscular Atrophy

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