scholarly journals GCH1 mutations in hereditary spastic paraplegia

2021 ◽  
Author(s):  
Parizad Varghaei ◽  
Grace Yoon ◽  
Mehrdad A Estiar ◽  
Simon Veyron ◽  
Nicolas Dupre ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Monozygotic Twins ◽  
Enrichment Analysis ◽  
Lower Limbs ◽  
Pathway Enrichment Analysis ◽  
Disruptive Effect ◽  
Spastic Paraplegia ◽  
Phenotypic Differences ◽  
Whole Exome ◽  
Hsp Genes

AbstractGCH1 mutations have been associated with dopa-responsive dystonia (DRD), Parkinson’s disease (PD) and tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia B. Recently, GCH1 mutations have also been reported in five patients with hereditary spastic paraplegia (HSP). In this study, a total of 400 HSP patients (291 families) from different centers across Canada were analyzed by whole exome sequencing (WES). Three patients with GCH1 variants were identified: monozygotic twins with a p.(Ser77_Leu82del) variant, and a patient with a p.(Val205Glu) variant. Both variants were predicted to be likely pathogenic. The three patients presented with childhood-onset spasticity in the lower limbs, hyperreflexia and abnormal plantar responses. Only one of the patients had diurnal fluctuations, and none had parkinsonism or dystonia. Phenotypic differences between the monozygotic twins were observed, and they responded well to levodopa treatment. Pathway enrichment analysis suggested that GCH1 shares similar processes and pathways with other HSP-associated genes, and structural analysis of the variants suggested a disruptive effect. In conclusion, GCH1 mutations may also cause HSP; therefore, we suggest including GCH1 in the screening panels of HSP genes. Clinical differences between monozygotic twins suggest that environmental factors could play a role in the clinical presentation of the disease.

scholarly journals A Japanese hereditary spastic paraplegia family with a rare nonsynonymous variant in the SPAST gene

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Takuya Morikawa ◽  
Shiroh Miura ◽  
Takahisa Tateishi ◽  
Kazuhito Noda ◽  
Hiroki Shibata
Keyword(s):  
Molecular Diagnosis ◽  
Hereditary Spastic Paraplegia ◽  
Autosomal Dominant ◽  
Family Members ◽  
Pathogenic Variant ◽  
Lower Limbs ◽  
Spastic Paraplegia ◽  
Nonsynonymous Variant ◽  
Japanese Family ◽  
Functional Variants

AbstractSpastic paraplegia (SPG) type 4 is an autosomal dominant SPG caused by functional variants in the SPAST gene. We examined a Japanese family with three autosomal dominant SPG patients. These patients presented with typical symptoms of SPG, such as spasticity of the lower limbs. We identified a rare nonsynonymous variant, NM_014946.4:c.1252G>A [p.Glu418Lys], in all three family members. This variant has previously been reported in a Russian SPG family as a “likely pathogenic” variant.5 Ascertainment of additional patients carrying this variant in an unrelated Japanese SPG family further supports its pathogenicity. Molecular diagnosis of SPG4 in this family with hereditary spastic paraplegia is confirmed.

scholarly journals Current Knowledge of Endolysosomal and Autophagy Defects in Hereditary Spastic Paraplegia

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1678
Author(s):  
Liriopé Toupenet Marchesi ◽  
Marion Leblanc ◽  
Giovanni Stevanin
Keyword(s):  
Nervous System ◽  
Motor Neurons ◽  
Neurological Disorders ◽  
Hereditary Spastic Paraplegia ◽  
Current Knowledge ◽  
Spastic Paraplegia ◽  
Functional Convergence ◽  
The Common ◽  
Hsp Genes

Hereditary spastic paraplegia (HSP) refers to a group of neurological disorders involving the degeneration of motor neurons. Due to their clinical and genetic heterogeneity, finding common effective therapeutics is difficult. Therefore, a better understanding of the common pathological mechanisms is necessary. The role of several HSP genes/proteins is linked to the endolysosomal and autophagic pathways, suggesting a functional convergence. Furthermore, impairment of these pathways is particularly interesting since it has been linked to other neurodegenerative diseases, which would suggest that the nervous system is particularly sensitive to the disruption of the endolysosomal and autophagic systems. In this review, we will summarize the involvement of HSP proteins in the endolysosomal and autophagic pathways in order to clarify their functioning and decipher some of the pathological mechanisms leading to HSP.

scholarly journals A novel SPAST gene mutation identified in a Chinese family with hereditary spastic paraplegia

2020 ◽  
Author(s):  
Weiwei Yu ◽  
Haiqiang Jin ◽  
Jianwen Deng ◽  
Ding Nan ◽  
Yining Huang
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Hereditary Spastic Paraplegia ◽  
Dna Isolation ◽  
Tertiary Structure ◽  
Novel Mutation ◽  
Chinese Family ◽  
Spastic Paraplegia ◽  
Whole Exome ◽  
And Function

Abstract Background: Hereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder. Hereditary spastic paraplegia can be inherited in various ways, and all modes of inheritance are associated with multiple genes or loci. At present, more than 76 disease-causing loci have been identified in hereditary spastic paraplegia patients. Here, we report a novel mutation in SPAST gene associated with hereditary spastic paraplegia in a Chinese family, further enriching the hereditary spastic paraplegia spectrum. Methods: Whole genomic DNA was extracted from peripheral blood of the 15 subjects from a Chinese family using DNA Isolation Kit. The Whole Exome Sequencing of the proband was analyzed and the result was identified in the rest individuals. RaptorX prediction tool and Protein Variation Effect Analyzer were used to predict the effects of the mutation on protein tertiary structure and function.Results: Spastic paraplegia has been inherited across at least four generations in this family, during which only four HSP patients were alive. The results obtained by analyzing the Whole Exome Sequencing of the proband exhibited a novel disease-associated in-frame deletion in the SPAST gene, and the this mutation also existed in the rest three HSP patients in this family. This in-frame deletion consists of three nucleotides deletion (c.1710_1712delGAA) within the exon 16, resulting in lysine deficiency at the position 570 of the protein (p.K570del). This novel mutation was also predicted to result in the synthesis of misfolded SPAST protein and have the deleterious effect on the function of SPAST protein.Conclusion: In this case, we reported a novel mutation in the known SPAST gene that segregated with HSP disease, which can be inherited in each generation. Simultaneously, this novel discovery significantly enriches the mutation spectrum, which provides an opportunity for further investigation of genetic pathogenesis of HSP.

scholarly journals Hereditary Spastic Paraplegia: From Genes, Cells and Networks to Novel Pathways for Drug Discovery

2021 ◽  
Vol 11 (3) ◽  
pp. 403
Author(s):  
Alan Mackay-Sim
Keyword(s):  
Motor Neurons ◽  
Hereditary Spastic Paraplegia ◽  
Genetic Disorders ◽  
Spastic Paraplegia ◽  
Cellular Mechanisms ◽  
Causative Gene ◽  
Cell Functions ◽  
Daunting Task ◽  
Future Drug ◽  
Hsp Genes

Hereditary spastic paraplegia (HSP) is a diverse group of Mendelian genetic disorders affecting the upper motor neurons, specifically degeneration of their distal axons in the corticospinal tract. Currently, there are 80 genes or genomic loci (genomic regions for which the causative gene has not been identified) associated with HSP diagnosis. HSP is therefore genetically very heterogeneous. Finding treatments for the HSPs is a daunting task: a rare disease made rarer by so many causative genes and many potential mutations in those genes in individual patients. Personalized medicine through genetic correction may be possible, but impractical as a generalized treatment strategy. The ideal treatments would be small molecules that are effective for people with different causative mutations. This requires identification of disease-associated cell dysfunctions shared across genotypes despite the large number of HSP genes that suggest a wide diversity of molecular and cellular mechanisms. This review highlights the shared dysfunctional phenotypes in patient-derived cells from patients with different causative mutations and uses bioinformatic analyses of the HSP genes to identify novel cell functions as potential targets for future drug treatments for multiple genotypes.

scholarly journals Hereditary spastic paraplegia: An “ears of the lynx” magnetic resonance imaging sign in a patient with recessive genetic type 11

2020 ◽  
pp. 197140092095382
Author(s):  
Emiliano Ruiz Romagnoli ◽  
Manuel Perez Akly ◽  
Luis A Miquelini ◽  
Jorge A Funes ◽  
Cristina H Besada
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Corpus Callosum ◽  
Hereditary Spastic Paraplegia ◽  
Brain Magnetic Resonance Imaging ◽  
Lower Limbs ◽  
Spastic Paraplegia ◽  
Resonance Imaging ◽  
Hereditary Spastic Paraplegias ◽  
Monogenic Diseases

Hereditary spastic paraplegias are an uncommon group of monogenic diseases that include 79 types of genetic disorders. The most frequent cause of recessive hereditary spastic paraplegia is a mutation in the spastic paraplegia gene type 11 followed by type 15. This group is usually associated with non-specific clinical features like cognitive decline and may precede the progressive weakness and spasticity of lower limbs. The magnetic resonance imaging hallmark of hereditary spastic paraplegia is thinning of the spinal cord. However, brain magnetic resonance imaging may provide relevant clues for specific hereditary spastic paraplegia subtypes, and thinning of the corpus callosum has been described as the most frequent abnormality in almost one-third of recessive hereditary spastic paraplegias. Moreover, a characteristic abnormality affecting the forceps minor of the corpus callosum has been recently reported as the “ears of the lynx” sign and is highly suggestive of type 11 and 15 hereditary spastic paraplegias. We report a patient who was diagnosed with hereditary spastic paraplegia type 11 by exome genetic testing, presenting the ears of the lynx sign in the first magnetic resonance imaging assessment.

scholarly journals Clinical features and management of hereditary spastic paraplegia

2014 ◽  
Vol 72 (3) ◽  
pp. 219-226 ◽  
Author(s):  
Ingrid Faber ◽  
Katiane R. Servelhere ◽  
Alberto R. M. Martinez ◽  
Anelyssa D?Abreu ◽  
Iscia Lopes-Cendes ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Significant Proportion ◽  
Clinical Problem ◽  
Sporadic Case ◽  
Lower Limbs ◽  
Spastic Paraplegia ◽  
Diagnostic Features ◽  
Recent Advances ◽  
Wide Range ◽  
The Central Nervous System

Hereditary spastic paraplegia (HSP) is a group of genetically-determined disorders characterized by progressive spasticity and weakness of lower limbs. An apparently sporadic case of adult-onset spastic paraplegia is a frequent clinical problem and a significant proportion of cases are likely to be of genetic origin. HSP is clinically divided into pure and complicated forms. The later present with a wide range of additional neurological and systemic features. To date, there are up to 60 genetic subtypes described. All modes of monogenic inheritance have been described: autosomal dominant, autosomal recessive, X-linked and mitochondrial traits. Recent advances point to abnormal axonal transport as a key mechanism leading to the degeneration of the long motor neuron axons in the central nervous system in HSP. In this review we aim to address recent advances in the field, placing emphasis on key diagnostic features that will help practicing neurologists to identify and manage these conditions.

Identification of a novel homozygous SPG7 mutation by whole exome sequencing in a Greek family with a complicated form of hereditary spastic paraplegia

2015 ◽  
Vol 58 (11) ◽  
pp. 573-577 ◽  
Author(s):  
Hussein Daoud ◽  
Eleni Merkouri Papadima ◽  
Bouchra Ouled Amar Bencheikh ◽  
Theodora Katsila ◽  
Alexandre Dionne-Laporte ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia ◽  
Whole Exome ◽  
Complicated Form

scholarly journals Novel Type of Complicated Autosomal Dominant Hereditary Spastic Paraplegia Associated with Congenital Distal Arthrogryposis Type I

2018 ◽  
Vol 8 (7) ◽  
pp. 136
Author(s):  
Peter Hedera ◽  
Paolo Moretti ◽  
Jane Howard ◽  
Jiali Zhao
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Autosomal Dominant ◽  
Spastic Paraparesis ◽  
Clinical Signs ◽  
Type I ◽  
Spastic Paraplegia ◽  
Distal Arthrogryposis ◽  
Skeletal Abnormalities ◽  
Whole Exome ◽  
Present Complex

Hereditary spastic paraplegia (HSP) is one of the most genetically heterogeneous neurological disorders. HSP is classified as pure when only a spastic weakness of the lower extremities is present. Complex HSP comes with additional neurological or systemic abnormalities. Complex HSP with skeletal abnormalities is rare and mostly seen in autosomal recessive HSP. Autosomal dominant (AD) complex HSP with skeletal abnormalities are consistently seen only in SPG9 (spastic gait type 9). In this paper, we report a kindred condition with AD HSP among four living affected individuals who had progressive, adult onset spastic paraparesis that was associated with a distal arthrogryposis (DA) in every affected individual. They also had episodes of rhabdomyolysis without any clinical signs of myopathy. Exhaustive genetic analysis including targeted sequencing of known HSP and DA genes and whole exome sequencing did not identify the disease-causing gene. It excluded all known HSP and DA genes. We propose that this is a novel genetic type of complex AD HSP. Elucidation of a genetic cause of this type of HSP will further contribute to our understanding of axonal degeneration and skeletal abnormalities.

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