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Last update 08 May 2025

Spastic Paraplegia Type 4

Last update 08 May 2025

Basic Info

Synonyms

SPASTIC PARAPLEGIA 4, Spastic Paraplegia 4, Spastic Paraplegia Type 4

+ [1]

Introduction

An autosomal dominant condition caused by mutation(s) in the SPAST gene, encoding spastin. It is characterized by progressive lower extremity spasticity and weakness.

Drugs associated with Spastic Paraplegia Type 4

Spastic Paraplegia Type 4(UMass Chan Medical School)

Target

spastin

Mechanism

spastin modulators

Active Org.

UMass Chan Medical School

Originator Org.

UMass Chan Medical School

Active Indication

Spastic Paraplegia Type 4

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with Spastic Paraplegia Type 4

NCT06553976

/ RecruitingNot ApplicableIIT

Spastic Paraplegia - Centers of Excellence Research Network (SP-CERN) - Natural History Study Pilot

The Spastic Paraplegia - Centers of Excellence Research Network (SP-CERN) is a collaborative research consortium dedicated to advancing the understanding, diagnosis, and treatment of hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS). Aims of the consortium are to a) perform natural history studies of HSP subtypes, b) discover and validate biomarkers and clinician- and patient-reported outcome measures, c) uncover HSP's molecular pathophysiology and develop rational therapeutic targets, and d) perform sufficiently powered clinical trials. The current pilot study is aimed at enrolling 100 individuals with hereditary spastic paraplegia type 4 (SPG4) or hereditary spastic paraplegia type 5A (SPG5A).

Start Date04 Jun 2024

Sponsor / Collaborator

The Children's Hospital Corp.

[+10]

NCT06260982

/ RecruitingNot ApplicableIIT

Cognitive Disorders and Metabolism in 18-FDG- PET in Hereditary Spastic Paraplegia Type 4 (SPG4)

Hereditary spastic paraplegia type 4 is the most frequent mutation of hereditary spastic paraplegias. It is commonly described as pure, with progressive weakness of the lower limbs, pyramidal syndrome and vesico-sphincter disorders. However, cognitive disorders have been reported for over 20 years, but remain poorly characterized.

Start Date01 Jan 2022

Sponsor / Collaborator

Centre Hospitalier Regional de Nancy

NCT03206190

/ RecruitingNot ApplicableIIT

Studying the Prodromal and Early Phase of Hereditary Spastic Paraplegia Type 4 (SPG4)

Study goals
Prospective longitudinal data on progression in the natural course of SPG4 in presymptomatic mutation carriers prior to clinical disease onset and in early stages of disease
Biomarkers providing objective measures of disease activity

Start Date01 Jul 2018

Sponsor / Collaborator

University Hospital Tübingen

100 Clinical Results associated with Spastic Paraplegia Type 4

100 Translational Medicine associated with Spastic Paraplegia Type 4

0 Patents (Medical) associated with Spastic Paraplegia Type 4

Literatures (Medical) associated with Spastic Paraplegia Type 4

01 Aug 2024·European Journal of Neurology

Relationship between brain white matter damage and grey matter atrophy in hereditary spastic paraplegia types 4 and 5

Article

Author: Li, Mengcheng ; Fu, Ying ; Tu, Yuqing ; Zhang, Fan ; Weng, Jiaqi ; Fan, Shuping ; Hu, Jianping ; Liu, Ying

AbstractBackground and purposeWhite matter (WM) damage is the main target of hereditary spastic paraplegia (HSP), but mounting evidence indicates that genotype‐specific grey matter (GM) damage is not uncommon. Our aim was to identify and compare brain GM and WM damage patterns in HSP subtypes and investigate how gene expression contributes to these patterns, and explore the relationship between GM and WM damage.MethodsIn this prospective single‐centre cohort study from 2019 to 2022, HSP patients and controls underwent magnetic resonance imaging evaluations. The alterations of GM and WM patterns were compared between groups by applying a source‐based morphometry approach. Spearman rank correlation was used to explore the associations between gene expression and GM atrophy patterns in HSP subtypes. Mediation analysis was conducted to investigate the interplay between GM and WM damage.ResultsTwenty‐one spastic paraplegia type 4 (SPG4) patients (mean age 50.7 years ± 12.0 SD, 15 men), 21 spastic paraplegia type 5 (SPG5) patients (mean age 29.1 years ± 12.8 SD, 14 men) and 42 controls (sex‐ and age‐matched) were evaluated. Compared to controls, SPG4 and SPG5 showed similar WM damage but different GM atrophy patterns. GM atrophy patterns in SPG4 and SPG5 were correlated with corresponding gene expression (ρ = 0.30, p = 0.008, ρ = 0.40, p < 0.001, respectively). Mediation analysis indicated that GM atrophy patterns were mediated by WM damage in HSP.ConclusionsGrey matter atrophy patterns were distinct between SPG4 and SPG5 and were not only secondary to WM damage but also associated with disease‐related gene expression.Clinical trial registration no. NCT04006418.

01 Aug 2024·Journal of Sleep Research

A case of monozygotic twins with hereditary spastic paraplegia type 4 and epilepsy, of whom only one developed narcolepsy type 1

Article

Author: Uehara, Taira ; Isobe, Noriko ; Koh, Kishin ; Kira, Jun‐ichi ; Takiyama, Yoshihisa ; Shigeto, Hiroshi ; Okadome, Toshiki ; Nakamura, Yuri ; Mizuno, Yuri ; Kanbayashi, Takashi ; Mukaino, Takahiko ; Murai, Hiroyuki

SummaryWe report a case of monozygotic twin sisters with hereditary spastic paraplegia type 4 (SPG4) and epilepsy, only one of whom had a diagnosis of narcolepsy type 1 (NT1). The older sister with NT1 exhibited excessive daytime sleepiness, cataplexy, sleep‐onset rapid eye movement period in the multiple sleep latency test, and decreased orexin levels in cerebrospinal fluid. Both sisters had HLA‐DRB1*15:01‐DQB1*06:02 and were further identified to have a novel missense mutation (c.1156A > C, p.Asn386His) in the coding exon of the spastin (SPAST) gene. The novel missense mutation might be involved in the development of epilepsy. This case is characterised by a combined diagnosis of SPG4 and epilepsy, and it is the first report of NT1 combined with epilepsy and genetically confirmed SPG4. The fact that only one of the twins has NT1 suggests that acquired and environmental factors are important in the pathogenesis of NT1.

01 Jul 2024·Clinical Genetics

Clinical and genetic characteristics in a Chinese cohort of complex spastic paraplegia type 4

Article

Author: Huang, Xiaojun ; Zhang, Chao ; Cao, Yuwen ; Yao, Li ; Tian, Wotu ; Cao, Li

AbstractSpastic paraplegia type 4 (SPG4), caused by SPAST mutations, is the most predominant subtype of hereditary spastic paraplegia. Most documented SPG4 patients present as pure form, with the complex form rarely reported. We described the clinical and genetic features of 20 patients with complex phenotypes of SPG4 and further explored the genotype–phenotype correlations. We collected detailed clinical data of all SPG4 patients and assessed their phenotypes. SPAST gene mutations were identified by Multiplex ligation‐dependent probe amplification in combination with whole exome sequencing. We further performed statistical analysis in genotype and phenotype among patients with various manifestations and different variants. Out of 90 SPG4 patients, 20 patients (male:female = 16:4) with additional neurologic deficits, namely complex form, were included in our study. The bimodal distribution of age of onset at 0–10 and 21–40 years old is concluded. On cranial MRI, obvious white matter lesions can be observed in five patients. We identified 9 novel and 8 reported SPAST mutations, of which 11 mutations were located in AAA (ATPase associated with various cellular activities) domain. The AAA cassette of spastin is the hottest mutated region among complex SPG4. All patients with cognitive impairment (CI) are males (n = 9/9). Additionally, 80% patients with ataxia are due to frameshift mutations (n = 4/5). Overall, our study summarized and analyzed the genetic and phenotypic characteristics of complex SPG4, making up over 1/5 of in‐house SPG4 cohort, among which CI and ataxia are the most common features. Further studies are expected to explore the underlying mechanisms.

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