2,875 results match your criteria: "Hereditary Spastic Paraplegia"

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients.

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Hereditary spastic paraplegia (HSP) is a group of genetically heterogenous neurodegenerative disorders characterized by progressive spasticity and weakness of lower limbs. We report a novel splicing variant (c.1617-2A>C) of the gene in a heterozygous carrier from an Italian family with autosomal dominant HSP.

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Background: Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Spastic Paraplegia Type 7 (SPG7) are paradigmatic spastic ataxias (SPAX) with suggested white matter (WM) involvement. Aim of this work was to thoroughly disentangle the degree of WM involvement in these conditions, evaluating both macrostructure and microstructure via the analysis of diffusion MRI (dMRI) data.

Material And Methods: In this multi-center prospective study, ARSACS and SPG7 patients and Healthy Controls (HC) were enrolled, all undergoing a standardized dMRI protocol and a clinimetrics evaluation including the Scale for the Assessment and Rating of Ataxia (SARA).

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Decreasing ganglioside synthesis delays motor and cognitive symptom onset in Spg11 knockout mice.

Neurobiol Dis

September 2024

Sorbonne Université, Paris Brain Institute (ICM Institut du Cerveau), INSERM U1127, CNRS UMR 7225, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. Electronic address:

Biallelic variants in the SPG11 gene account for the most common form of autosomal recessive hereditary spastic paraplegia characterized by motor and cognitive impairment, with currently no therapeutic option. We previously observed in a Spg11 knockout mouse that neurodegeneration is associated with accumulation of gangliosides in lysosomes. To test whether a substrate reduction therapy could be a therapeutic option, we downregulated the key enzyme involved in ganglioside biosynthesis using an AAV-PHP.

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Background And Purpose: Hereditary spastic paraplegias (HSPs) comprise a group of inherited neurodegenerative disorders characterized by progressive spasticity and weakness. Botulinum toxin has been approved for lower limb spasticity following stroke and cerebral palsy, but its effects in HSPs remain underexplored. We aimed to characterize the effects of botulinum toxin on clinical, gait, and patient-reported outcomes in HSP patients and explore the potential of mobile digital gait analysis to monitor treatment effects and predict treatment response.

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Atlastin-1 regulates endosomal tubulation and lysosomal proteolysis in human cortical neurons.

Neurobiol Dis

September 2024

Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK; Department of Medical Genetics, University of Cambridge, Cambridge, UK. Electronic address:

Mutation of the ATL1 gene is one of the most common causes of hereditary spastic paraplegia (HSP), a group of genetic neurodegenerative conditions characterised by distal axonal degeneration of the corticospinal tract axons. Atlastin-1, the protein encoded by ATL1, is one of three mammalian atlastins, which are homologous dynamin-like GTPases that control endoplasmic reticulum (ER) morphology by fusing tubules to form the three-way junctions that characterise ER networks. However, it is not clear whether atlastin-1 is required for correct ER morphology in human neurons and if so what the functional consequences of lack of atlastin-1 are.

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Background: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and hereditary spastic paraplegia type 7 (SPG7) represent the most common genotypes of spastic ataxia (SPAX). To date, their magnetic resonance imaging (MRI) features have only been described qualitatively, and a pure neuroradiological differential diagnosis between these two conditions is difficult to achieve.

Objectives: To test the performance of MRI measures to discriminate between ARSACS and SPG7 (as an index of common SPAX disease).

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Disease Progression and Multiparametric Imaging Characteristics of Spinocerebellar Ataxia Type 3 With Spastic Paraplegia.

Neurol Genet

June 2024

From the Department of Neurology and Institute of Neurology of First Affiliated Hospital (Z.-X.Y., H.-L.X., R.-Y.Y., W.L., L.Q., M.L., W.-J.C., N.W., Y.F., S.-R.G.), Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology; Department of Radiology of First Affiliated Hospital (N.-P.C., M.-C.L., J.-P.H.); Department of Rehabilitation Medicine of First Affiliated Hospital (X.-Y.C.); and Department of Neurology (L.Q., M.L., W.-J.C., N.W., Y.F., S.-R.G.), National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.

Article Synopsis
  • Spinocerebellar ataxia type 3 (SCA3) is a hereditary condition with varied clinical patterns, including one form marked by spastic paraplegia, leading researchers to examine its features and progression.
  • A study involving 249 SCA3 patients was conducted, focusing on two groups: those with spastic paraplegia (SCA3-SP) and those without (SCA3-NSP), using advanced brain imaging techniques to analyze differences.
  • The results indicated that SCA3-SP patients were younger and had more severe symptoms, as shown by higher clinical scores and larger genetic markers, compared to the SCA3-NSP group, highlighting differences in disease progression between the two subtypes
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Article Synopsis
  • - The study investigates TFG mutations in Taiwanese patients with hereditary spastic paraplegia (HSP), specifically focusing on new variants and their effects.
  • - Researchers identified a novel TFG variant (c.177A>C, p.(Lys59Asn)) linked to a pure form of HSP, which negatively impacts protein function and cellular health.
  • - The findings demonstrate that this variant contributes to the understanding of TFG-related diseases, emphasizing the importance of TFG mutations in the pathology of HSP.
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Article Synopsis
  • Motor neuron disorders are a diverse group of diseases that involve the progressive degeneration of motor neurons, affecting both upper and lower motor neurons and can be either sporadic or hereditary.
  • Hereditary forms of these disorders are complex and often overlap in clinical and genetic features, making diagnosis challenging.
  • This review outlines the main types of inherited motor neuron disorders, their historical descriptions, clinical characteristics, and updates on the genes associated with conditions like spinal muscular atrophy and familial amyotrophic lateral sclerosis.
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Motor neuron diseases and peripheral neuropathies are heterogeneous groups of neurodegenerative disorders that manifest with distinct symptoms due to progressive dysfunction or loss of specific neuronal subpopulations during different stages of development. A few monogenic, neurodegenerative diseases associated with primary metabolic disruptions of sphingolipid biosynthesis have been recently discovered. Sphingolipids are a subclass of lipids that form critical building blocks of all cellular and subcellular organelle membranes including the membrane components of the nervous system cells.

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Complexes of ERLIN1 and ERLIN2 (ER lipid raft-associated 1 and 2) form large ring-like cup-shaped structures on the endoplasmic reticulum (ER) membrane and serve as platforms to bind cholesterol and E3 ubiquitin ligases, potentially defining functional nanodomains. Here, we show that ERLIN scaffolds mediate the interaction between the full-length isoform of TMUB1 (transmembrane and ubiquitin-like domain-containing 1) and RNF170 (RING finger protein 170). We identify a luminal N-terminal conserved region in TMUB1 and RNF170, which is required for this interaction.

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AP2A2 mutation and defective endocytosis in a Malian family with hereditary spastic paraplegia.

Neurobiol Dis

August 2024

Neurogenetics Branch, NINDS, NIH, Bethesda, MD, United States. Electronic address:

Hereditary spastic paraplegia (HSP) comprises a large group of neurogenetic disorders characterized by progressive lower extremity spasticity. Neurological evaluation and genetic testing were completed in a Malian family with early-onset HSP. Three children with unaffected consanguineous parents presented with symptoms consistent with childhood-onset complicated HSP.

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DEAD-box helicase 53 (DDX53) is a member of the DEAD-box protein family of RNA helicases. Unlike other family members that are responsible for RNA metabolism, the biological function of DDX53 and its impact on the human condition are unclear. Herein, we found a full-length DDX53 deletion mutation in a hereditary spastic paraplegia-like (HSP-like) patient with lower extremity spasticity, walking disorder, visual impairment, and lateral ventricular white matter lesions.

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Hereditary spastic paraplegia: Manifestations and treatment challenges.

Asian J Surg

September 2024

Department of Neurology, Ganzhou People's Hospital, Jiangxi Medical College, Nanchang University, Ganzhou, Jiangxi, China. Electronic address:

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The most common form of hereditary spastic paraplegia (HSP), SPG4 is caused by single nucleotide variants and microrearrangements in the gene. The high percentage of multi-exonic deletions or duplications observed in SPG4 patients is predisposed by the presence of a high frequency of sequences in the gene sequence. In the present study, we analyzed DNA and RNA samples collected from patients with different microrearrangements in to map gene breakpoints and evaluate the mutation mechanism.

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Article Synopsis
  • Rare diseases are mostly genetic and often have neurological symptoms, making their diagnosis and treatment complicated due to their rarity and low prevalence.
  • A national registry has been established in Korea to focus on three specific rare diseases that cause gait disturbances, collecting clinical data and biological materials from patients.
  • The registry aims to identify genetic variants specific to Korean patients and discover biomarkers to improve early diagnosis and treatment development for these conditions.
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Large-Scale Whole-Genome Analysis of HTLV-1-Associated Myelopathy Identified Hereditary Spastic Paraplegias.

Neurol Genet

February 2024

From the Department of Neurology (N.T., J.Y., T.S., S.M., Y.Y.); Department of Rare Diseases Research (N.Y., N.A., S.A., J.Y., K. Takahashi, Y. Kunitomo, T.S., Y.Y.), Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki; Advanced Business Promotion Department (S.A.), Business Development Segment, LSI Medience Corporation, Tokyo; Department of Clinical Neuroscience and Therapeutics Hiroshima University Graduate School of Biomedical and Health Sciences (M.N.); Genome Medical Science Project (Y. Kawai, Y.O., K. Tokunaga), National Center for Global Health and Medicine, Tokyo; and Center for Genomic Medicine (F.M.), Kyoto University Graduate School of Medicine, Japan.

Objectives: Distinguishing human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy from hereditary spastic paraplegia in patients infected with HTLV-1 is challenging due to overlapping clinical symptoms. The aim of this study was to explore the possibility that hereditary spastic paraplegia is inherently present in patients diagnosed with HTLV-1-associated myelopathy.

Methods: We performed whole-genome sequencing on 315 unrelated patients registered in the HTLV-1-Associated Myelopathy patient registry "HAM-net," from 2013 to 2022 in Japan.

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Objectives: The aim of our study was to examine the genetic variants already described in hereditary spastic paraplegia in a family where 2 members had spasticity, dysregulation of sphincter function, and dyspraxia in the proband.

Methods: The study included 2 members of a non-consanguineous family with spastic gait, sphincter abnormalities, and neuropsychological characteristics. Whole-exome sequencing was used in the proband and his mother, both diagnosed with hereditary spastic paraplegia, to identify the underlying genetic cause.

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Distal hereditary motor neuropathies.

Rev Neurol (Paris)

December 2024

Neurosciences Laboratory, University Benyoucef Benkhedda, Algiers, Algeria; Department of Neurology, EHS El Maham, Cherchell,Tipaza, Algeria.

Distal hereditary motor neuropathies (dHMN) are a group of heterogeneous hereditary disorders characterized by a slowly progressive distal pure motor neuropathy. Electrophysiology, with normal motor and sensory conduction velocities, can suggest the diagnosis of dHMN and guide the genetic study. More than thirty genes are currently associated with HMNs, but around 60 to 70% of cases of dHMN remain uncharacterized genetically.

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Introduction/aims: The frequency and distribution of upper motor neuron (UMN) signs in primary lateral sclerosis (PLS) are unknown. We aimed to study the spectrum of UMN signs in PLS and compare it with hereditary spastic paraplegia (HSP).

Methods: We retrospectively analyzed the frequency of different UMN signs, including hyperreflexia (limbs and jaw), limb and tongue spasticity, Babinski, and Hoffman signs, in PLS patients at first observation and compared this respect to onset region and symptom duration.

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Two Novel Variants in in a Family Presenting With Hereditary Spastic Paraparesis: A Case Report.

Neurol Genet

June 2024

From the Rare Disease Genetics and Functional Genomics Group (J.M.P., E.L.M., A.R., G.R.), Centre for Medical Research, University of Western Australia; Harry Perkins Institute of Medical Research (J.M.P., E.L.M., A.R., G.R.), Nedlands; Royal Perth Hospital (P.J.L.); Sydney Medical School (K.R.K., P.L.C.), Faculty of Medicine and Health, University of Sydney, Camperdown; Garvan Institute of Medical Research (K.R.K.), Darlinghurst; Molecular Medicine Laboratory (K.R.K., M.S., P.L.C.), Concord Repatriation General Hospital, NSW Health Pathology; Department of Neurology (K.R.K.), Concord Repatriation General Hospital; and School of Medical Sciences (M.S.), University of Sydney, Camperdown, Australia.

Article Synopsis
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Emerging therapies for childhood-onset movement disorders.

Curr Opin Pediatr

June 2024

Movement Disorders Program, Department of Neurology.

Purpose Of Review: We highlight novel and emerging therapies in the treatment of childhood-onset movement disorders. We structured this review by therapeutic entity (small molecule drugs, RNA-targeted therapeutics, gene replacement therapy, and neuromodulation), recognizing that there are two main approaches to treatment: symptomatic (based on phenomenology) and molecular mechanism-based therapy or 'precision medicine' (which is disease-modifying).

Recent Findings: We highlight reports of new small molecule drugs for Tourette syndrome, Friedreich's ataxia and Rett syndrome.

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