Genotype–phenotype associations in hereditary spastic paraplegia: a systematic review and meta-analysis on 13,570 patients

Omidvar, Maryam; Torkamandi, Shahram; Rezaei, Somaye; Alipoor, Behnam; Omrani, Mir Davood; Darvish, Hossein; Ghaedi, Hamid

doi:10.1007/s00415-019-09633-1

Cited by 67 publications

(77 citation statements)

References 108 publications

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“…12,17 Of note, the detected genetic variants were on different genes, as in adult HSP cohorts, as reported in the literature. 2,13,[20][21][22][23] In adult cohorts, pathogenic variants in SPG4 are most common, 2,16,20,21 while SPG3A variants prevailed in our paediatric cohort. This may reflect the fact that SPG4 pathogenic variants commonly present in later age.…”

Section: Discussionmentioning

confidence: 77%

Paediatric‐onset hereditary spastic paraplegias: a retrospective cohort study

Schiavoni

Spagnoli

Rizzi

et al. 2020

Develop Med Child Neuro

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Aim To describe the clinical and neurogenetic spectrum of paediatric‐onset hereditary spastic paraplegias (HSPs) diagnosed in our unit. Method We report on 47 patients (30 males, 17 females; mean [SD] age 12y 7mo [6y 2mo], range 4–34y) clinically diagnosed with an HSP at the Child Neurology Unit, IRCCS‐ASMN (Reggio Emilia, Italy) between 1990 and 2018, who were genetically investigated by means of single‐gene direct sequencing and/or next‐generation sequencing technologies (targeted panels, whole‐exome sequencing [WES]). Results Complex forms prevailed slightly (n=26), autosomal dominant being the main inheritance pattern (n=11), followed by recessive (n=5) and X‐linked (n=1). A definite genetic diagnosis was achieved in 17 patients. Spastic paraplegia 3A (n=4) was the most frequent cause of autosomal dominant HSP in our cohort, while no genetic variant prevailed in autosomal recessive forms and pathogenic/likely pathogenic variants were disclosed in a wide range of different genes. Interpretation We found wide phenotypic and genetic heterogeneity. With increasing accessibility to WES, a higher number of patients receive a diagnosis, allowing detection of variants in ultra‐rare disease‐causing genes and refining genotype–phenotype correlations. What this paper adds A genetic diagnosis of paediatric‐onset hereditary spastic paraplegia was achieved in one‐third of patients. Pathogenic/likely pathogenic variants in rare genes were found. Genotypic and phenotypic heterogeneity favours targeted panel/whole‐exome sequencing for diagnosis.

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Section: Discussionmentioning

confidence: 77%

Paediatric‐onset hereditary spastic paraplegias: a retrospective cohort study

Schiavoni

Spagnoli

Rizzi

et al. 2020

Develop Med Child Neuro

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“…Most of these identifications have been made within the past two decades, particularly after the advent of whole exome sequencing (WES), and they encompass all types of inheritances. 2 Over 60 genes have now been identified as causative, with the mutated gene products predicted to coalesce into a relatively small number of common cellular pathogenic themes that are guiding new therapeutic investigations. 1 Historically, HSPs have been underdiagnosed, though as genetic testing has become more affordable and widely employed, diagnostic accuracy has improved.…”

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confidence: 99%

Early‐onset hereditary spastic paraplegia: the possibility of a genetic diagnosis

Blackstone

2020

Develop Med Child Neuro

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“…Hereditary Spastic Paraplegias (HSPs) are a class of inherited neurodegenerative disorders characterized by progressive gait abnormalities due to muscle weakness and stiffness in the lower limbs, usually associated with degeneration of corticospinal tract motor neurons [1,2]. HSPs can be classified as either "uncomplicated" or "complicated": characteristic symptoms of uncomplicated HSPs are lower limb spastic weakness and urinary urgency, while complicated HSPs have additional features, such as ataxia and seizures [1,2]. These additional features often makes it difficult to differentiate complicated HSPs from other neurological diseases.…”

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confidence: 99%

“…These additional features often makes it difficult to differentiate complicated HSPs from other neurological diseases. Interestingly, most uncomplicated HSPs are autosomal dominant, while most complicated HSPs are autosomal recessive, and often linked to inbreeding [1]. Currently, there are more than 80 known HSP-linked genes, but still many HSP cases are without a defined genetic cause [1,2].…”

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confidence: 99%