更新于：2024-11-01

Hereditary Spastic Paralysis, Infantile Onset Ascending

遗传性痉挛性瘫痪，婴儿期起病

更新于：2024-11-01

基本信息

别名

Hereditary spastic paralysis, infantile onset ascending、IAHSP、IAHSP - infantile onset ascending hereditary spastic paralysis

+ [9]

简介

Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a very rare motor neuron disease characterized by severe spasticity of the lower limbs in early life, progression of spasticity to the upper limbs in late childhood, and dysarthria.

关联

项与遗传性痉挛性瘫痪，婴儿期起病相关的药物

Baclofen

巴氯芬

靶点

GABAB receptor

作用机制

GABAB receptor激动剂

在研机构

Sun Pharma Japan Ltd. [+7]

原研机构

Novartis Pharma AG

在研适应症

多发性硬化症 [+4]

非在研适应症

酗酒 [+1]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期1977-11-22

100 项与遗传性痉挛性瘫痪，婴儿期起病相关的临床结果

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100 项与遗传性痉挛性瘫痪，婴儿期起病相关的转化医学

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0 项与遗传性痉挛性瘫痪，婴儿期起病相关的专利（医药）

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项与遗传性痉挛性瘫痪，婴儿期起病相关的文献（医药）

2024-11-01·Proteins: Structure, Function, and Bioinformatics

Conformational Dynamics and Molecular Characterization of Alsin MORN Monomer and Dimeric Assemblies

Article

作者: Pallante, Lorenzo ; Cannariato, Marco ; Deriu, Marco A. ; Zizzi, Eric A. ; Tortarolo, Riccardo ; Miceli, Marcello

ABSTRACTDespite the ubiquity of membrane occupation recognition nexus (MORN) motifs across diverse species in both eukaryotic and prokaryotic organisms, these protein domains remain poorly characterized. Their significance is underscored in the context of the Alsin protein, implicated in the debilitating condition known as infantile‐onset ascending hereditary spastic paralysis (IAHSP). Recent investigations have proposed that mutations within the Alsin MORN domain disrupt proper protein assembly, precluding the formation of the requisite tetrameric configuration essential for the protein's inherent biological activity. However, a comprehensive understanding of the relationship between the biological functions of Alsin and its three‐dimensional molecular structure is hindered by the lack of available experimental structures. In this study, we employed and compared several protein structure prediction algorithms to identify a three‐dimensional structure for the putative MORN of Alsin. Furthermore, inspired by experimental pieces of evidence from previous studies, we employed the developed models to predict and investigate two homo‐dimeric assemblies, characterizing their stability. This study's insights into the three‐dimensional structure of the Alsin MORN domain and the stability dynamics of its homo‐dimeric assemblies suggest an antiparallel linear configuration stabilized by a noncovalent interaction network.

2024-03-01·Pediatric Neurology

A Retrospective Review of 18 Patients With Childhood-Onset Hereditary Spastic Paraplegia, Nine With Novel Variants

Article

作者: Kara, Bulent ; Genc, Hulya Maras ; Akbas, Sinan ; Avci, Ridvan ; Coskun, Orhan ; Kilic, Mehmet Akif ; Deniz, Adnan ; Kurekci, Fulya ; Yesil, Gozde ; Yesilyurt, Ahmet ; Yildiz, Edibe Pembegul

BACKGROUNDHereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative disorders. Our objective was to determine the clinical and molecular characteristics of patients with genetically confirmed childhood-onset HSPs and to expand the genetic spectrum for some rare subtypes of HSP.METHODSWe reviewed the charts of subjects with genetically confirmed childhood-onset HSP. The age at the disease onset was defined as the point at which the delayed motor milestones were observed. Delayed motor milestones were defined as being unable to hold the head up by four months, sitting unassisted by nine months, and walking independently by 17 months. If there were no delayed motor milestones, age at disease onset was determined by leg stiffness, frequent falls, or unsteady gait. Genetic testing was performed based on delayed motor milestones, progressive leg spasticity, and gait difficulty. The variant classification was determined based on the American College of Medical Genetics standard guidelines for variant interpretation. Variants of uncertain significance (VUS) were considered disease-associated when clinical findings were consistent with the previously described disease phenotypes for pathogenic variants. In addition, in the absence of another pathogenic, likely pathogenic, or VUS variant that could explain the phenotype of our cases, we concluded that the disease is associated with VUS in the HSP-causing gene. Segregation analysis was also performed on the parents of some patients to demonstrate the inheritance model.RESULTSThere were a total of 18 patients from 17 families. The median age of symptom onset was 18 months (2 to 84 months). The mean delay between symptom onset and genetic diagnosis was 5.8 years (5 months to 17 years). All patients had gait difficulty caused by progressive leg spasticity and weakness. Independent walking was not achieved at 17 months for 67% of patients (n = 12). In our cohort, there were two subjects each with SPG11, SPG46, and SPG 50 followed by single subject each with SPG3A, SPG4, SPG7, SPG8, SPG30, SPG35, SPG43, SPG44, SPG57, SPG62, infantile-onset ascending spastic paralysis (IAHSP), and spastic paraplegia and psychomotor retardation with or without seizures (SPPRS). Eight novel variants in nine patients were described. Two affected siblings had a novel variant in the GBA2 gene (SPG46), and one subject each had a novel variant in WASHC5 (SPG8), SPG11 (SPG11), KIF1A (SPG30), GJC2 (SPG44), ERLIN1 (SPG62), ALS2 (IAHSP), and HACE1 (SPPRS). Among the novel variants, the variant in the SPG11 was pathogenic and the variants in the KIF1A, GJC2, and HACE1 were likely pathogenic. The variants in the GBA2, ALS2, ERLIN1, and WASHC5 were classified as VUS.CONCLUSIONSThere was a significant delay between symptom onset and genetic diagnosis of HSP. An early diagnosis may be possible by examining patients with delayed motor milestones, progressive spasticity, gait difficulties, and neuromuscular weakness in the context of HSP. Eight novel variants in nine patients were described, clinically similar to the previously described disease phenotype associated with pathogenic variants. This study contributes to expanding the genetic spectrum of some rare subtypes of HSP.

2023-08-01·Clinical Genetics

Clinical and molecular spectrum of a large Egyptian cohort with ALS2‐related disorders of infantile‐onset of clinical continuum IAHSP/JPLS

Article

作者: Abdel-Hamid, Mohamed S ; Elkhateeb, Nour ; Gleeson, Joseph G ; Rafat, Karima ; Noureldeen, Mahmoud M ; Essawi, Mona L ; Sadek, Abdelrahim A ; Sharaf-Eldin, Wessam E ; Murphy, David ; Zaki, Maha S ; Holuden, Henry ; Abdeltawab, Mohamed A ; Issa, Mahmoud Y ; Elbendary, Hasnaa M ; Kamel, Mona ; Lau, Tracy

AbstractThis study presents 46 patients from 23 unrelated Egyptian families with ALS2‐related disorders without evidence of lower motor neuron involvement. Age at onset ranged from 10 months to 2.5 years, featuring progressive upper motor neuron signs. Detailed clinical phenotypes demonstrated inter‐ and intrafamilial variability. We identified 16 homozygous disease‐causing ALS2 variants; sorted as splice‐site, missense, frameshift, nonsense and in‐frame in eight, seven, four, three, and one families, respectively. Seven of these variants were novel, expanding the mutational spectrum of the ALS2 gene. As expected, clinical severity was positively correlated with disease onset (p = 0.004). This work provides clinical and molecular profiles of a large single ethnic cohort of patients with ALS2 mutations, and suggests that infantile ascending hereditary spastic paralysis (IAHSP) and juvenile primary lateral sclerosis (JPLS) are belonged to one entity with no phenotype–genotype correlation.