A total of 220 patients with autosomal dominant spastic paraplegia do not display mutations in the SLC33A1 gene (SPG42).
The most frequent causes of autosomal dominant (AD) hereditary spastic paraplegias (HSP) (ADHSP) are mutations in the SPAST gene (SPG4 locus). However, roughly 60% of patients are negative for SPAST mutations, despite their family history being compatible with AD inheritance. A mutation in the gene for an acetyl-CoA transporter (SLC33A1) has recently been reported in one Chinese family to cause ADHSP-type SPG42. In this study, we screened 220 independent SPAST mutation-negative ADHSP samples for mutations in the SLC33A1 gene by high-resolution melting curve analysis. Conspicuous samples were validated by direct sequencing. Moreover, copy number variations affecting SLC33A1 were screened by …
Frequency and phenotype of SPG11 and SPG15 in complicated hereditary spastic paraplegia
Background: Hereditary spastic paraplegias (HSP) are clinically and genetically highly heterogeneous. Recently, two novel genes, SPG11 ( spatacsin ) and SPG15 ( spastizin ), associated with autosomal recessive HSP, were identified. Clinically, both are characterised by complicated HSP and a rather similar phenotype consisting of early onset spastic paraplegia, cognitive deficits, thin corpus callosum (TCC), peripheral neuropathy and mild cerebellar ataxia. Objective: To compare the frequency of SPG11 and SPG15 in patients with early onset complicated HSP and to further characterise the phenotype of SPG11 and SPG15. Results: A sample of 36 index patients with early onset complicated HSP and …
SPG10 is a rare cause of spastic paraplegia in European families.
Contains fulltext : 71099.pdf (Publisher’s version ) (Closed access) BACKGROUND: SPG10 is an autosomal dominant form of hereditary spastic paraplegia (HSP), which is caused by mutations in the neural kinesin heavy chain KIF5A gene, the neuronal motor of fast anterograde axonal transport. Only four mutations have been identified to date. OBJECTIVE: To determine the frequency of SPG10 in European families with HSP and to specify the SPG10 phenotype. PATIENTS AND METHODS: 80 index patients from families with autosomal dominant HSP were investigated for SPG10 mutations by direct sequencing of the KIF5A motor domain. Additionally, the whole gene was sequenced in 20 of these families. RESULTS: Th…
REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31.
Contains fulltext : 71291.pdf (Publisher’s version ) (Closed access) Mutations in the receptor expression enhancing protein 1 (REEP1) have recently been reported to cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG31. In a large collaborative effort, we screened a sample of 535 unrelated HSP patients for REEP1 mutations and copy number variations. We identified 13 novel and 2 known REEP1 mutations in 16 familial and sporadic patients by direct sequencing analysis. Twelve out of 16 mutations were small insertions, deletions or splice site mutations. These changes would result in shifts of the open-reading-frame followed by premature termination of translation and haploins…
Disease severity affects quality of life of hereditary spastic paraplegia patients
Background and purpose: Hereditary spastic paraplegia (HSP) causes progressive gait disturbance because of degeneration of the corticospinal tract. To assess its impact on Health-Related Quality of Life (HRQoL), we analyzed the correlation of HRQoL with disease severity and clinical symptoms in HSP. Methods: HRQoL was assessed by the Short-Form 36 (SF-36) Mental and Physical Component summary scores (MCS and PCS) in 143 German patients with HSP. Disease severity was assessed by the Spastic Paraplegia Rating Scale (SPRS) and landmarks of walking ability. Patients with ! pure" or ! complicated" HSP were compared. Results: Higher SPRS scores indicating higher disease severity correlated signif…
AP5Z1/SPG4 8 frequency in autosomal recessive and sporadic spastic paraplegia
Hereditary spastic paraplegias (HSP) constitute a rare and highly heterogeneous group of neurodegenerative disorders, defined clinically by progressive lower limb spasticity and pyramidal weakness. Autosomal recessive HSP as well as sporadic cases present a significant diagnostic challenge. Mutations in AP5Z1, a gene playing a role in intracellular membrane trafficking, have been recently reported to be associated with spastic paraplegia type 48 (SPG48). Our objective was to determine the relative frequency and clinical relevance of AP5Z1 mutations in a large cohort of 127 HSP patients. We applied a targeted next-generation sequencing approach to analyze all coding exons of the AP5Z1 gene. …
Amplicon-based high-throughput pooled sequencing identifies mutations in CYP7B1 and SPG7 in sporadic spastic paraplegia patients
Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder defined clinically by progressive lower limb spasticity and weakness. HSP is a genetically highly heterogeneous condition with at least 46 gene loci identified so far, involving X-linked, autosomal recessive (AR) and autosomal dominant inheritance. For correct diagnosis, molecular testing is essential because clinical parameters by themselves are not reliable to differentiate HSP forms. The purpose of this study was to establish amplicon-based high-throughput genotyping for AR-HSP. A sample of 187 index cases with apparently sporadic or recessive spastic paraplegia were analyzed by applying an array-based amplification stra…
Screening of hereditary spastic paraplegia patients for alterations at NIPA1 mutational hotspots.
Item does not contain fulltext Mutations in NIPA1 cause hereditary spastic paraplegia type 6 (SPG6 HSP). Sequencing of the whole gene has revealed alterations of either of two nucleotides in eight of nine SPG6 HSP families reported to date. By analysing CpG methylation, we provide a mechanistic explanation for a mutational hotspot to underlie frequent alteration of one of these nucleotides. We also developed PCR RFLP assays to detect recurrent NIPA1 changes and screened 101 independent HSP patients, including 45 index patients of autosomal dominant HSP families. Our negative finding in this cohort for which several other causes of HSP had been excluded suggests NIPA1 alterations at mutation…