New biallelic GBA2 variant in a patient with SPG46

Spagnoli, Carlotta; Schiavoni, Silvia; Rizzi, Susanna; Salerno, Grazia Gabriella; Frattini, Daniele; Fusco, Carlo

doi:10.1016/j.clineuro.2020.105676

Cited by 9 publications

(8 citation statements)

References 4 publications

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“…This gene encodes for a member of the CWF19 protein family (CWF19-like cell cycle control factor 1), associated with autosomal recessive spinocerebellar ataxia and mild cognitive disability (spinocerebellar ataxia type 17). [31][32][33][34] As no reports of pathogenic variants in CWF19L1 in patients without ataxia have been so far described and our variant is a VUS, we cannot definitely conclude on its role in our patient's phenotype, even though it cannot be completely excluded that the absence of ataxia might be linked to his young age. Moreover, our findings might also be interpreted in light of the well-known phenotypic and genetic overlap between HSPs and hereditary cerebellar ataxias, 19,35 as well as other neurodegenerative conditions.…”

Section: Discussionmentioning

confidence: 80%

“…The second patient (patient 2, Table S2) had a cHSP phenotype (SPG and ataxia) and harboured a VUS in GBA2 , which is the cause of SPG46, a complex form of HSP associating HSP with ataxia. In this case there was strong consistency between the detected variant and the patient's phenotype, although according to the ACMG guidelines, there is not enough evidence to classify this previously undescribed variant as pathogenic 32 …”

Section: Discussionmentioning

confidence: 84%

“…In the 5‐year‐old patient 3 (Table S2) with progressive cHSP, we diagnosed a homozygous VUS in CWF19L1 . This gene encodes for a member of the CWF19 protein family (CWF19‐like cell cycle control factor 1), associated with autosomal recessive spinocerebellar ataxia and mild cognitive disability (spinocerebellar ataxia type 17) 31–34 . As no reports of pathogenic variants in CWF19L1 in patients without ataxia have been so far described and our variant is a VUS, we cannot definitely conclude on its role in our patient’s phenotype, even though it cannot be completely excluded that the absence of ataxia might be linked to his young age.…”

Section: Discussionmentioning

confidence: 86%

“…In this case there was strong consistency between the detected variant and the patient's phenotype, although according to the ACMG guidelines, there is not enough evidence to classify this previously undescribed variant as pathogenic. 32 Moreover, we describe two patients harbouring variants in genes associated with spinocerebellar ataxia. The first patient (patient 11, Table S1) harboured a likely pathogenic variant in ITPR1.…”

Section: Discussionmentioning

confidence: 99%

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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: 80%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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Paediatric‐onset hereditary spastic paraplegias: a retrospective cohort study

Schiavoni

Spagnoli

Rizzi

et al. 2020

Develop Med Child Neuro

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“…Subcellularly, GBA2 is localized in the ER and Golgi membranes with its N and C termini facing the cytoplasm [134]. GBA2 depletion can cause strong or mild locomotor defects in mice [137], while in humans, its mutations are associated with hereditary spastic paraplegia/cerebellar ataxia (SPG46) and Marinesco-Sjögren-like syndrome, both characterized by cerebellar ataxia [138][139][140][141][142].…”

Section: β-Glucosidase 2 (Gba2)mentioning

confidence: 99%

Lipid Dyshomeostasis and Inherited Cerebellar Ataxia

Zhao

Zhang

Fan

et al. 2021

Preprint

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Cerebellar ataxia is a neurological disorder originating in the cerebellum and can be divided into different subtypes. The etiology of these disorders is complicated, especially in inherited disorders. Currently, nearly all disorders remain incurable. To precisely diagnose and treat these diseases, studies on their molecular mechanisms have been conducted extensively in the past. Accumulating evidence has demonstrated that some common pathogenic mechanisms exist within each subtype of inherited ataxia. However, no reports have indicated whether there is a common mechanism among the different subtypes of cerebellar ataxia. In this review, we summarize the available references and databases on neurological disorders characterized by cerebellar ataxia and show that a subset of genes involved in lipid homeostasis form a new group that may cause ataxic disorders through a common mechanism. This common signaling pathway can provide a valuable reference for future diagnosis and treatment of ataxic disorders.

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Hereditary spastic paraparesis type 46 (SPG46): new GBA2 variants in a large Italian case series and review of the literature

Cioffi,

Coppola,

Musumeci

et al. 2024

Neurogenetics

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Hereditary spastic paraparesis (HSP) is a group of central nervous system diseases primarily affecting the spinal upper motor neurons, with different inheritance patterns and phenotypes. SPG46 is a rare, early-onset and autosomal recessive HSP, linked to biallelic GBA2 mutations. About thirty families have been described worldwide, with different phenotypes like complicated HSP, recessive cerebellar ataxia or Marinesco-Sjögren Syndrome. Herein, we report five SPG46 patients harbouring five novel GBA2 mutations, the largest series described in Italy so far. Probands were enrolled in five different centres and underwent neurological examination, clinical cognitive assessment, column imaging for scoliosis assessment, ophthalmologic examination, brain imaging, GBA2 activity in peripheral blood cells and genetic testing. Their phenotype was consistent with HSP, with notable features like upper gaze palsy and movement disorders. We review demographic, genetic, biochemical and clinical information from all documented cases in the existing literature, focusing on the global distribution of cases, the features of the syndrome, its variable presentation, new potential identifying features and the significance of measuring GBA2 enzyme activity.

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New biallelic GBA2 variant in a patient with SPG46

Cited by 9 publications

References 4 publications

Paediatric‐onset hereditary spastic paraplegias: a retrospective cohort study

Paediatric‐onset hereditary spastic paraplegias: a retrospective cohort study

Lipid Dyshomeostasis and Inherited Cerebellar Ataxia

Hereditary spastic paraparesis type 46 (SPG46): new GBA2 variants in a large Italian case series and review of the literature

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