SCA1 patients may present as hereditary spastic paraplegia and must be included in spastic-ataxias group

Pedroso, José Luiz; Souza, Paulo Victor Sgobbi de; Pinto, Wladimir Bocca Vieira de Rezende; Braga‐Neto, Pedro; Albuquerque, Marcus Vinicius Cristino; Saraiva-Pereira, Maria Luiza; Jardim, Laura Bannach; Barsottini, Orlando Graziani Póvoas

doi:10.1016/j.parkreldis.2015.07.015

Cited by 15 publications

(11 citation statements)

References 10 publications

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“…[46][47][48][49][50][51][52][53] Several of the diseases in these groups, such as SCA1 (ATXN1), SCA3 (ATXN3), and Friedreich's ataxia (FXN) are triplet repeat disorders and may not therefore be covered by gene panels, even if they are extended to include wider groups of monogenic diseases associated with spasticity. [54][55][56] Particular attention should however be given to atypical presentations of treatable diseases in which lower limb spasticity occurs, often in the context of other clinical features, in the absence of T2-weighted imaging abnormalities in the spinal cord. These include adrenoleukodystophy (ABCD1), 57 arginase deficiency (ARG1), 58 cerebrotendinous xanthomatosis (CYP27A1), 59 dopa-responsive dystonia (GCH1, TH, and other genes), 60 phenylketonuria (PAH), 61 biotinidase deficiency (BTD), 62 cobalamin-related remethylation disorders, 63 methylenetetrahydrofolate reductase deficiency (MTHFR), 64 and primary coenzyme Q10 deficiencies.…”

Section: Genetic Testingmentioning

confidence: 99%

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

Shribman

Reid

Crosby

et al. 2019

The Lancet Neurology

215

207

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Hereditary spastic paraplegia (HSP) describes a heterogeneous group of genetic neurodegenerative diseases characterised by progressive spasticity of the lower limbs. The pathogenic mechanism, associated clinical features and imaging abnormalities vary significantly according to the affected gene. Here, we describe the clinical and imaging characteristics of the more common forms of HSP. We discuss how to approach the diagnosis and management of a suspected case of HSP in the era of next generation sequencing, before discussing treatment and the potential of emerging therapeutic options for specific causes of HSP based on their underlying molecular mechanism.

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Section: Genetic Testingmentioning

confidence: 99%

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

Shribman

Reid

Crosby

et al. 2019

The Lancet Neurology

215

207

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“…Moreover, the HSPs are among the most genetically diverse neurologic disorders, with well over 70 distinct genetic loci, for which about 60 mutated genes have already been identified (Blackstone, 2018). The diagnosis of HSP is based on the presence of a clinical history of progressive spastic paraparesis in a pure form or associated with other neurological and systemic manifestations (with or without familial history), evidence of a genetic mutation in a locus related to a phenotype of HSP previously described in the literature, and exclusion of structural disorders or other genetic or acquired conditions that explain the clinical picture (Sedel et al, 2007;De Bot et al, 2010;Lo Giudice et al, 2014;Klebe et al, 2015;Pedroso et al, 2015;Souza et al, 2015). Generally, the clinical picture of an HSP is characterized by a subtle onset and slowly progressive course of spastic paraparesis described by patients as abnormal gait, leg stiffness, or gait instability.…”

Section: Introductionmentioning

confidence: 99%

“…Generally, the clinical picture of an HSP is characterized by a subtle onset and slowly progressive course of spastic paraparesis described by patients as abnormal gait, leg stiffness, or gait instability. It is very difficult to HSP because the other neurological and systemic features that characterize complicated forms may precede the onset of spastic paraparesis (Harding, 1993;Sedel et al, 2007;Salinas et al, 2008;De Bot et al, 2010;Pedroso et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Exome Analysis Identified Novel Homozygous Splice Site Donor Alteration in NT5C2 Gene in a Saudi Family Associated With Spastic Diplegia Cerebral Palsy, Developmental Delay, and Intellectual Disability

et al. 2020

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Hereditary spastic paraplegias (HSPs) is a rare heterogeneous group of neurodegenerative diseases, with upper and lower limb spasticity motor neuron disintegration leading to paraplegias. NT5C2 gene (OMIM: 600417) encode a hydrolase enzyme 5'-nucleotidase, cytosolic II play an important role in maintaining the balance of purine nucleotides and free nucleobases in the spinal cord and brain. In this study we have identified a large consanguineous Saudi family segregating a novel homozygous splice site donor alteration in NT5C2 gene leading to spastic diplegia cerebral palsy, developmental delay and microcephaly. Whole exome sequencing (WES) was performed for the affected members of the family to study the novel mutation. WES data analysis, confirmed by Sanger sequencing analysis, identifies a homozygous splice site donor alteration of possible interest in NT5C2 (ENST00000343289: c.539+1G > T) at the sixth exon/intron boundaries. The mutation was further ruled out in 100 healthy control from normal population. The novel homozygous mutation observed in this study has not been reported in the literature or variant databases. The identified splicing alteration broadens the mutation spectrum of NT5C2 gene in neurodevelopmental disorders. To the best of our knowledge this is the first report from Saudi Arabia.

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“…There is significant overlap in clinical features of the two syndromes that makes diagnosis based on phenotype alone difficult. For example, patients with SCA1 may present initially with spastic paraplegia before development of cerebellar ataxia, and thus be misdiagnosed with HSP [ 4 ]. Conversely, patients with the HSP subtypes SPG4, SPG6, SPG31 and SPG37 may present with cerebellar atrophy [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review

Pang

Teo

Hsu

et al. 2017

Transl Neurodegener

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The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping symptoms. It does not take into account the disease etiology or the highly variable clinical course even amongst patients diagnosed with the same disorder. The advent of next generation sequencing (NGS) has allowed for a system-wide, unbiased approach to identify all gene variants in the genome simultaneously. With the plethora of new genes being identified, genetic rather than phenotype-based classification of Mendelian diseases such as spinocerebellar ataxia (SCA), hereditary spastic paraplegia (HSP) and Charcot-Marie-Tooth disease (CMT) has become widely accepted. It has also become clear that gene variants play a role in common and predominantly sporadic neurodegenerative diseases such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). The observation of pleiotropy has emerged, with mutations in the same gene giving rise to diverse phenotypes, which further increases the complexity of phenotype-genotype correlation. Possible mechanisms of pleiotropy include different downstream effects of different mutations in the same gene, presence of modifier genes, and oligogenic inheritance. Future directions include development of bioinformatics tools and establishment of more extensive public genotype/phenotype databases to better distinguish deleterious gene variants from benign polymorphisms, translation of genetic findings into pathogenic mechanisms through in-vitro and in-vivo studies, and ultimately finding disease-modifying therapies for neurodegenerative disorders.

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SCA1 patients may present as hereditary spastic paraplegia and must be included in spastic-ataxias group

Cited by 15 publications

References 10 publications

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

Exome Analysis Identified Novel Homozygous Splice Site Donor Alteration in NT5C2 Gene in a Saudi Family Associated With Spastic Diplegia Cerebral Palsy, Developmental Delay, and Intellectual Disability

The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review

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