The hereditary spastic paraplegias (HSPs) comprise a large group of inherited neurologic disorders. HSP is classified according to the mode of inheritance, the HSP locus when known, and whether the spastic paraplegia syndrome occurs alone or is accompanied by additional neurologic or systemic abnormalities. Analysis of 11 recently discovered HSP genes provides insight into HSP pathogenesis. Hereditary spastic paraplegia is a clinical diagnosis for which laboratory confirmation is sometimes possible, and careful exclusion of alternate and co-existing disorders is an important element in HSP diagnosis. Treatment for HSP is presently limited to symptomatic reduction of muscle spasticity, reduction in urinary urgency, and strength and gait improvement through physical therapy. Prenatal genetic testing in HSP is possible for some individuals with the increasing availability of HSP gene analysis.

https://www.neurologic.theclinics.com/article/S0733-8619(02)00007-5/pdf

Hereditary spastic paraplegia.

https://www.cell.com/cell-reports/pdf/S2211-1247(13)00197-6.pdf

A Conserved Role for Atlastin GTPases in Regulating Lipid Droplet Size

Background: Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurodegenerative disease. The most frequent cause of autosomal dominant HSP is mutation of SPAST ( SPG4 locus), but additional pedigrees remain mutation negative by conventional screening despite linkage to SPG4 . Objective: To determine the frequency of genomic copy number aberrations of SPAST in autosomal dominant HSP. Methods: We developed and validated a multiplex ligation-dependent probe amplification assay targeting SPAST and SPG3A , another gene frequently involved in autosomal dominant HSP. In a multicenter study we subsequently investigated 65 index patients with autosomal dominant HSP, all of whom had previously been screened negative for SPAST mutations. Independent secondary samples, additional family members, and cDNA were analyzed to confirm positive findings. Results: Aberrant MLPA profiles were identified in 12 cases (18%). They exclusively affect SPAST , represent deletions, segregate with the disease, and are largely pedigree specific. Internal SPAST deletions entail expression of correspondingly shortened transcripts, which vary in stability. Age at onset in SPAST deletion carriers does not differ from that associated with other SPAST mutations. Conclusions: Partial SPAST deletions, but not SPAST amplifications and SPG3A copy number aberrations, represent an underestimated cause of autosomal dominant hereditary spastic paraplegia. Partial SPAST deletions are likely to act via haploinsufficiency.

High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia

Hereditary spastic paraplegias (HSP) are a group of degenerative disorders of the spinal cord that lead to a progressive spastic gait disturbance marked by lower limb spasticity and weakness. Genetically, HSPs are among the most heterogeneous Mendelian diseases and can be inherited following autosomal dominant, autosomal recessive, and X-chromosomal modes of inheritance. More than 80 genes and gene loci have been identified so far and require next-generation sequencing approaches for comprehensive genetic testing. In this chapter we discuss clinical aspects of HSP including differential diagnostics, typical presentation of common HSPs, limitations of genotype-phenotype correlation, and overlap with genetic disorders that cause progressive spasticity but are not categorized as HSP-like spastic ataxias, slow variants of amyotrophic lateral sclerosis, spastic variants of peripheral neuropathies, and adult-onset variants of leukodystrophies. In consideration of the complexity of this field, we propose an algorithm for a time- and cost-efficient strategy for genetic diagnostics in HSP.

Genetics of hereditary spastic paraplegias.

Hereditary spastic paraplegias (HSPs), characterized by progressive and bilateral spasticity of the legs, are usually caused by developmental failure or degeneration of motor axons in the corticospinal tract. There are considerable interfamilial and intrafamilial variations in age at onset and severity of spasticity. Genetic studies also showed that there are dozens of genetic loci, on multiple chromosomes, that are responsible for HSPs. Through linkage study of a pedigree of HSP with autosomal-dominant inheritance, we mapped the causative gene to 3q24-q26. Screening of candidate genes revealed that the HSP is caused by a missense mutation in the gene for acetyl-CoA transporter (SLC33A1). It is predicted that the missense mutation, causing the change of the highly conserved serine to arginine at the codon 113 (p. S113R), disrupts the second transmembrane domain in the transporter and reverses the orientation of all of the descending domains. Knockdown of Slc33a1 in zebrafish caused a curve-shaped tail and defective axon outgrowth from the spinal cord. Although the wild-type human SLC33A1 was able to rescue the phenotype caused by Slc33a1 knockdown in zebrafish, the mutant SLC33A1 (p.S113R) was not, suggesting that S113R mutation renders SLC33A1 nonfunctional and one that wild-type allele is not sufficient for sustaining the outgrowth and maintenance of long motor axons in human heterozygotes. Thus, our study illustrated a critical role of acetyl-CoA transporter in motor-neuron development and function.

A Missense Mutation in SLC33A1, which Encodes the Acetyl-CoA Transporter, Causes Autosomal-Dominant Spastic Paraplegia (SPG42)

Hereditary spastic paraplegias (HSP) comprise a genetically and clinically heterogeneous group of neurodegenerative disorders characterised by progressive spasticity and hyperreflexia of the lower limbs. Autosomal dominant hereditary spastic paraplegia linked to the SPG3A locus on chromosome 14q11-21 accounts for approximately 10% of autosomal dominant hereditary spastic paraplegia (ADHSP). It is caused by mutations in the SPG3A gene encoding the protein atlastin. To date, only five disease-causing mutations in the SPG3A gene have been described. We analysed 13 SPG4-negative families for mutations in the SPG3A gene and identified a mutation in 38% (5/13). Two of the mutations are novel, c.481G>C (p.A161P) and c.740A>C (p.H247P). One of the novel mutations was found both in a family with early onset of symptoms and in a late onset family. Furthermore, we report on numerous polymorphisms detected in the SPG3A gene. © 2003 Wiley-Liss, Inc.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/humu.9205

Novel mutations in the Atlastin gene (SPG3A) in families with autosomal dominant hereditary spastic paraplegia and evidence for late onset forms of HSP linked to the SPG3A locus

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Novel mutations in the Atlastin gene (SPG3A) in families with autosomal dominant hereditary spastic paraplegia and evidence for late onset forms of HSP linked to the SPG3A locus