Whole-exome sequencing confirms implication of VPS13D as a potential cause of progressive spastic ataxia

Durand, Christelle; Angelini, C.; Michaud, Vincent; Delleci, C.; Coupry, Isabelle; Goizet, Cyril

doi:10.1186/s12883-022-02553-0

Cited by 9 publications

(5 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, oculomotor dysfunction in form of saccadic intrusion [6,17] as well as Leigh-like leukoencephalopathy [7], as present in P1, have likewise been described. While there seems to be no clear genotype-phenotype relation, patients carrying biallelic missense variants [8,12] or non-canonical splice site variants such as P2 seem to have a later age at onset (mean: 30 years) and a less severe phenotype than patients carrying a truncating variant, including canonical splice site variants, in combination with a milder missense or non-canonical splice site change [6][7][8][9][10] such as P1 (mean age at onset: 14 years). However, there are also cases reported who do not fit this pattern [7,11,12].…”

Section: Discussionmentioning

confidence: 98%

“…In all homologs, pathogenic variants have been linked to different neurological disorders [2]: biallelic variants in VPS13A cause choreaacanthocytosis [3] (OMIM: #200150), in VPS13B Cohen syndrome [4] (OMIM: #216550), in VPS13C early-onset parkinsonism [5] (OMIM: # 616840), and in VPS13D, as recently shown, spastic ataxia or spastic paraplegia [6,7] (OMIM: # 607317). However, with 31 published cases [6][7][8][9][10][11][12] of VPS13D-related disorder this form of VPS13-related disorders may be underreported.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Not to Miss: Intronic Variants, Treatment, and Review of the Phenotypic Spectrum in VPS13D-Related Disorder

Pauly

Brüggemann

Efthymiou

et al. 2023

IJMS

View full text Add to dashboard Cite

VPS13D is one of four human homologs of the vacuolar sorting protein 13 gene (VPS13). Biallelic pathogenic variants in the gene are associated with spastic ataxia or spastic paraplegia. Here, we report two patients with intronic pathogenic variants: one patient with early onset severe spastic ataxia and debilitating tremor, which is compound-heterozygous for a canonical (NM_018156.4: c.2237−1G > A) and a non-canonical (NM_018156.4: c.941+3G>A) splice site variant. The second patient carries the same non-canonical splice site variant in the homozygous state and is affected by late-onset spastic paraplegia. We confirmed altered splicing as a result of the intronic variants and demonstrated disturbed mitochondrial integrity. Notably, tremor in the first patient improved significantly by bilateral deep brain stimulation (DBS) in the ventralis intermedius (VIM) nucleus of the thalamus. We also conducted a literature review and summarized the phenotypical spectrum of reported VPS13D-related disorders. Our study underscores that looking for mutations outside the canonical splice sites is important not to miss a genetic diagnosis, especially in disorders with a highly heterogeneous presentation without specific red flags.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Not to Miss: Intronic Variants, Treatment, and Review of the Phenotypic Spectrum in VPS13D-Related Disorder

Pauly

Brüggemann

Efthymiou

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“… 116 In other instances, VPS13D mutations were found in individuals with pure HSP or complex HSP, with variations in the age of onset and symptom complexity associated with the nature of the mutations. 117 , 118 …”

Section: Intersecting Genes and Metabolic Pathways In Diseases Relate...mentioning

confidence: 99%

Hereditary spastic paraplegia: Novel insights into the pathogenesis and management

Awuah,

Tan,

Shkodina

et al. 2023

SAGE Open Medicine

View full text Add to dashboard Cite

Hereditary spastic paraplegia is a genetically heterogeneous neurodegenerative disorder characterised primarily by muscle stiffness in the lower limbs. Neurodegenerative disorders are conditions that result from cellular and metabolic abnormalities, many of which have strong genetic ties. While ageing is a known contributor to these changes, certain neurodegenerative disorders can manifest early in life, progressively affecting a person’s quality of life. Hereditary spastic paraplegia is one such condition that can appear in individuals of any age. In hereditary spastic paraplegia, a distinctive feature is the degeneration of long nerve fibres in the corticospinal tract of the lower limbs. This degeneration is linked to various cellular and metabolic processes, including mitochondrial dysfunction, remodelling of the endoplasmic reticulum membrane, autophagy, abnormal myelination processes and alterations in lipid metabolism. Additionally, hereditary spastic paraplegia affects processes like endosome membrane trafficking, oxidative stress and mitochondrial DNA polymorphisms. Disease-causing genetic loci and associated genes influence the progression and severity of hereditary spastic paraplegia, potentially affecting various cellular and metabolic functions. Although hereditary spastic paraplegia does not reduce a person’s lifespan, it significantly impairs their quality of life as they age, particularly with more severe symptoms. Regrettably, there are currently no treatments available to halt or reverse the pathological progression of hereditary spastic paraplegia. This review aims to explore the metabolic mechanisms underlying the pathophysiology of hereditary spastic paraplegia, emphasising the interactions of various genes identified in recent network studies. By comprehending these associations, targeted molecular therapies that address these biochemical processes can be developed to enhance treatment strategies for hereditary spastic paraplegia and guide clinical practice effectively.

show abstract

“…Constitutive, pan-neuronal knockdown of Vps13D caused strong developmental lethality during pupal stages ( Seong et al, 2018 ; Insolera et al, 2021 ), limiting the ability to investigate the chronic effects of accumulating damaged mitochondria in neurons. We hypothesized that bypassing this developmental lethality with genetic tools that permit adult-onset Vps13D RNAi expression would provide a more accurate model of the progressive neurodegenerative phenotypes of patients with mutations in VPS13D ( Gauthier et al, 2018 ; Seong et al, 2018 ; Koh et al, 2020 ; Durand et al, 2022 ; Huang and Fan, 2022 ; Pauly et al, 2023 ). To this end, we examined two temporally-controlled Gal4 tools for adult-onset knockdown of Vps13D .…”

Section: Introductionmentioning

confidence: 99%

An optimized temporally controlled Gal4 system in Drosophila reveals degeneration caused by adult-onset neuronal Vps13D knockdown

Rozich,

Randolph,

Insolera

2023

Front. Neurosci.

View full text Add to dashboard Cite

Mutations in the human gene VPS13D cause the adult-onset neurodegenerative disease ataxia. Our previous work showed that disruptions in the Vps13D gene in Drosophila neurons causes mitochondrial defects. However, developmental lethality caused by Vps13D loss limited our understanding of the long-term physiological effects of Vps13D perturbation in neurons. Here, we optimized a previously generated system to temporally knock down Vps13D expression precisely in adult Drosophila neurons using a modification to the Gal4/UAS system. Adult-onset activation of Gal4 was enacted using the chemically-inducible tool which fuses a destabilization-domain to the Gal4 repressor Gal80 (Gal80-DD). Optimization of the Gal80-DD tool shows that feeding animals the DD-stabilizing drug trimethoprim (TMP) during development and rearing at a reduced temperature maximally represses Gal4 activity. Temperature shift and removal of TMP from the food after eclosion robustly activates Gal4 expression in adult neurons. Using the optimized Gal80-DD system, we find that adult-onset Vps13D RNAi expression in neurons causes the accumulation of mitophagy intermediates, progressive deficits in locomotor activity, early lethality, and brain vacuolization characteristic of neurodegeneration. The development of this optimized system allows us to more precisely examine the degenerative phenotypes caused by Vps13D disruption, and can likely be utilized in the future for other genes associated with neurological diseases whose manipulation causes developmental lethality in Drosophila.

show abstract

Whole-exome sequencing confirms implication of VPS13D as a potential cause of progressive spastic ataxia

Cited by 9 publications

References 19 publications

Not to Miss: Intronic Variants, Treatment, and Review of the Phenotypic Spectrum in VPS13D-Related Disorder

Not to Miss: Intronic Variants, Treatment, and Review of the Phenotypic Spectrum in VPS13D-Related Disorder

Hereditary spastic paraplegia: Novel insights into the pathogenesis and management

An optimized temporally controlled Gal4 system in Drosophila reveals degeneration caused by adult-onset neuronal Vps13D knockdown

Contact Info

Product

Resources

About