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Last update 08 May 2025

Spastic Paraplegia 4, Autosomal Dominant

Last update 08 May 2025

Basic Info

Synonyms

Autosomal dominant spastic paraplegia type 4, Autosomal dominant spastic paraplegia type 4 (diagnosis), Autosomal dominant spastic paraplegia type 4 (disorder)

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Introduction

A form of hereditary spastic paraplegia with high intrafamilial clinical variability. Characterized in most cases as a pure phenotype with an adult onset (mainly the third to fifth decade of life, but that can present at any age) with progressive gait impairment due to bilateral lower-limb spasticity and weakness as well as very mild proximal weakness and urinary urgency. In some cases, a complex phenotype is also reported with additional manifestations including cognitive impairment, cerebellar ataxia, epilepsy and neuropathy. A faster disease progression is noted in patients with a later age of onset. Caused by mutations in the SPAST gene (2p24-p21), encoding spastin.

Clinical Trials associated with Spastic Paraplegia 4, Autosomal Dominant

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]

NCT06229626

/ RecruitingNot ApplicableIIT

Evaluation of an Intensive Training Program for Patients with Hereditary Spastic Paraparesis SPG4/Spast

Hereditary spastic paraparesis is a group of inherited neurological diseases. Only symptomatic treatments exist for the moment. The Modifspa study (cf citation) carried out by the team showed that patients perceived a feeling of effectiveness of physiotherapy on lower limb spasticity. The aim of the Walk-up study is to objectivize this feeling of efficacy on gait disorders in these patients.
This is an interventional study using physical training. The study is prospective, open, randomized in 2 parallel groups, one of which is a control group. Analyses will be comparative between the 2 groups during the course of the study.

Start Date04 Apr 2024

Sponsor / Collaborator

Assistance Publique des Hôpitaux de Paris SA

NCT04712812

/ RecruitingNot ApplicableIIT

Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia (HSP)

The Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia (HSP) is focused on gathering longitudinal clinical data as well as biological samples (skin and/or blood and/or saliva) from male and female patients, under the age of 30, who exhibited early onset symptoms of HSP with (1) a clinical diagnosis of hereditary spastic paraplegia and (2) the presence of variants in HSP related genes and/or be a relative of a person with such a diagnosis. Currently, the treatment for this disorder is generally symptomatic and available therapies improve quality of life, but are grossly inefficient in slowing the disease progression. Access to the registry information will be limited to the study staff who are responsible for recruitment and maintenance of the registry. We hope that recruitment into the registry for studies will advance knowledge of the causes, clinical course, diagnosis, and treatment of these conditions.

Start Date27 Apr 2020

Sponsor / Collaborator

The Children's Hospital Corp.

100 Clinical Results associated with Spastic Paraplegia 4, Autosomal Dominant

100 Translational Medicine associated with Spastic Paraplegia 4, Autosomal Dominant

0 Patents (Medical) associated with Spastic Paraplegia 4, Autosomal Dominant

126

Literatures (Medical) associated with Spastic Paraplegia 4, Autosomal Dominant

01 Mar 2025·Movement Disorders

Unraveling Isoform Complexity: The Roles of M1‐ and M87‐Spastin in Spastic Paraplegia 4 (SPG4)

Review

Author: Ramakrishnan, Skandha ; Mohan, Neha ; Qiang, Liang ; Dong, Zhangji ; Liu, Mei

AbstractSpastic Paraplegia 4 (SPG4) is a debilitating neurodegenerative disorder characterized by progressive muscle weakness and spasticity in the lower limbs, often leading to gait impairment. Central to SPG4 pathology is the die‐back degeneration of corticospinal tracts, primarily driven by mutations in the spastin protein encoded by the SPAST gene. SPAST gives rise to two major spastin isoforms, M1‐ and M87‐spastin, which are generated from distinct translation initiation sites. Although spastin is implicated in various cellular functions, the specific roles of each isoform in the pathogenesis of SPG4 remain poorly understood. This review offers an overview of the genetic and structural organization of the M1‐ and M87‐spastin isoforms, highlighting their distinct and overlapping functions, and exploring their potential roles in the haploinsufficiency and gain‐of‐toxicity mechanisms underlying SPG4. We also present a novel perspective on the evolutionary emergence of M1‐spastin and its potential unique involvement in the pathogenesis of SPG4. Drawing upon the latest research, we propose an intriguing hypothesis regarding the hetero‐oligomerization of M1‐ and M87‐spastin, exploring how their interaction may drive disease progression and open new avenues for therapeutic intervention. By integrating the current research with these fresh insights, we seek to illuminate the complex molecular mechanisms driving SPG4 and foster the development of innovative therapeutic strategies. This review not only incorporates existing knowledge but also lays the groundwork for future studies aimed at uncovering the isoform‐specific roles of spastin in SPG4, with the ultimate goal of advancing targeted treatments for this challenging neurodegenerative disorder. © 2024 International Parkinson and Movement Disorder Society.

01 Jan 2025·European Journal of Neurology

From spastic paraplegia to infantile neurodegenerative disorder: Expanding the phenotypic spectrum associated with biallelic SPAST variants

Article

Author: Boulariah‐Hadjou, Razika ; Lefeuvre, Claire ; Angelini, Chloé ; Ewenczyk, Claire ; Suchowersky, Oksana ; Gan‐Or, Ziv ; Degoutin, Manon ; Lacombe, Didier ; Barnerias, Christine ; Guillaud‐Bataille, Marine ; Narayanan, Dhanya Lakshmi ; Rouleau, Guy A. ; Estiar, Mehrdad A. ; El Khedoud, Wahiba Amer ; Messaoud‐Khelifi, Mouna ; Shukla, Anju ; Goizet, Cyril ; Stevanin, Giovanni ; Majethia, Purvi ; Bar, Claire

AbstractPurposeHeterozygous pathogenic variants in SPAST are known to cause Hereditary Spastic Paraplegia 4 (SPG4), the most common form of HSP, characterized by progressive bilateral lower limbs spasticity with frequent sphincter disorders. However, there are very few descriptions in the literature of patients carrying biallelic variants in SPAST.MethodsTargeted Sanger sequencing, panel sequencing and exome sequencing were used to identify the genetic causes in 9 patients from 6 unrelated families with symptoms of HSP or infantile neurodegenerative disorder.ResultsWe describe 5 patients with pure HSP with a variable age of onset, mostly in infancy, and 4 patients with profound intellectual disability and progressively worsening tetrapyramidal syndrome. The patients' parents, heterozygous carriers of pathogenic SPAST variants, included both asymptomatic carriers and patients with classic forms of SPG4.ConclusionBiallelic variants of SPAST may explain cases of hereditary spastic paraplegia with autosomal recessive inheritance. Furthermore, some biallelic variants may also cause psychomotor regression with an infantile neurodegenerative disorder, associated with a tetrapyramidal syndrome, a new phenotype associated with the SPAST gene.

01 Jan 2025·Journal of Investigative Medicine High Impact Case Reports

Novel SPAST Deletion Mutation in an American Family With Hereditary Spastic Paraplegia: A Case Report

Article

Author: Bhopatkar, Sydney B. ; Huang, Juebin

The diverse group of neurodegenerative disorders known as hereditary spastic paraplegia (HSP) is characterized by spasticity and weakness of the bilateral lower extremity due to degeneration of the corticospinal tract. The pathogenesis of HSP is broad, with autosomal dominant, autosomal recessive, X-linked recessive, mitochondrial inheritance, and de novo mutations reported, along with remarkable heterogeneity of mutations and clinical presentation. Of these, the most common subtype of HSP is HSP type 4 (HSP- SPG4), a result of mutations in the SPAST gene (chromosome 2p22.3) that leads to impaired activity of the microtubule-severing protein spastin. Typically presenting as an uncomplicated, autosomal dominant form of the disease, HSP- SPG4 has been documented worldwide with vast genomic variance across the SPAST gene. Despite common features in clinical phenotypes, a clear link between SPAST gene variants and disease presentation remains vague. Here, we report a novel 26.1 kb deletion in the SPAST gene (del exons 4-7) in a US family with previously undiagnosed HSP- SPG4.

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Spastic Paraplegia 4, Autosomal Dominant

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