The GM2 gangliosidoses: Unlocking the mysteries of pathogenesis and treatment

Toro, Camilo; Zainab, Mosufa; Tifft, Cynthia J.

doi:10.1016/j.neulet.2021.136195

Cited by 29 publications

(45 citation statements)

References 157 publications

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“…The role of TREM2 and SORL1 is well known in AD 9 , 11 , 21 and the loss of significance of TOMM40 after condition on APOE ε4 alleles suggests that the association of TOMM40 is connected to the well-established APOE locus. HEXA is a known risk gene for a rare neurodegenerative disease (Tay-Sachs disease) 25 . However, neither HEXA nor the highlighted variant were nominally associated with proxy AD/dementia in the replication dataset, which suggests that HEXA is not a gene associated with AD/dementia.…”

Section: Discussionmentioning

confidence: 99%

Rare variant aggregation in 148,508 exomes identifies genes associated with proxy dementia

Wightman

Savage

Leeuw

et al. 2023

Sci Rep

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Proxy phenotypes allow for the utilization of genetic data from large population cohorts to analyze late-onset diseases by using parental diagnoses as a proxy for genetic disease risk. Proxy phenotypes based on parental diagnosis status have been used in previous studies to identify common variants associated with Alzheimer’s disease. As of yet, proxy phenotypes have not been used to identify genes associated with Alzheimer’s disease through rare variants. Here we show that a proxy Alzheimer’s disease/dementia phenotype can capture known Alzheimer’s disease risk genes through rare variant aggregation. We generated a proxy Alzheimer’s disease/dementia phenotype for 148,508 unrelated individuals of European ancestry in the UK biobank in order to perform exome-wide rare variant aggregation analyses to identify genes associated with proxy Alzheimer’s disease/dementia. We identified four genes significantly associated with the proxy phenotype, three of which were significantly associated with proxy Alzheimer’s disease/dementia in an independent replication cohort consisting of 197,506 unrelated individuals of European ancestry in the UK biobank. All three of the replicated genes have been previously associated with clinically diagnosed Alzheimer’s disease (SORL1, TREM2, and TOMM40/APOE). We show that proxy Alzheimer’s disease/dementia can be used to identify genes associated with Alzheimer’s disease through rare variant aggregation.

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Section: Discussionmentioning

confidence: 99%

Rare variant aggregation in 148,508 exomes identifies genes associated with proxy dementia

Wightman

Savage

Leeuw

et al. 2023

Sci Rep

View full text Add to dashboard Cite

show abstract

“…The role of TREM2 and SORL1 is well known in AD 9,11,18 and the loss of significance of TOMM40 after condition on APOE ε4 alleles suggests that the association of TOMM40 is connected to the well-established APOE locus. HEXA is a known risk gene for a rare neurodegenerative disease (Tay-Sachs disease) 22 . However, neither HEXA nor the highlighted variant were nominally associated with proxy AD/dementia in the replication dataset, which suggests that HEXA is not a gene associated with AD/dementia.…”

Section: Discussionmentioning

confidence: 99%

Rare Variant Aggregation in 148,508 Exomes Identifies Genes Associated with Proxy Alzheimer’s disease/Dementia

Wightman

Savage

Leeuw

et al. 2021

Preprint

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We generated a proxy Alzheimer's disease phenotype for 148,508 individuals in the UK biobank in order to perform exome-wide rare variant aggregation analyses to identify genes associated with proxy Alzheimer's disease. We identified four genes significantly associated with the proxy phenotype, three of which have been previously associated with clinically diagnosed Alzheimer's disease (SORL1, TREM2, and TOMM40). We identified one gene (HEXA) which has not been previously associated with Alzheimer's disease but is known to contribute to neurodegenerative disease. Here we show that proxy Alzheimer's disease can capture some of the rare variant association signal for Alzheimer's disease and can be used to highlight genes and variants of interest. The proxy phenotype allows for the utilisation of large genetic databases without clinically diagnosed Alzheimer's disease patients to uncover variants and genes that contribute to Alzheimer's disease.

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“…These conditions usually present as global developmental delay and regression associated with distinct features such as macrocephaly, cherry-red spots, muscular hypotonia, ataxia, as well as exaggerated startle responses to sounds, light flashes and tactile stimuli. 1-5 Patients with attenuated phenotypes may not show all classical manifestations which lowers the degree of the clinician’s clinical suspicion. These individuals may be more difficult to diagnose which may mean that the time to diagnosis is delayed.…”

Section: Introductionmentioning

confidence: 99%

Quantitative longitudinal natural history of eight gangliosidoses – conceptual framework and baseline data of the German 8-in-1 disease registry. A cross-sectional analysis

Ries

Arash-Kaps²,

Amraoui³

et al. 2022

Preprint

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Purpose: Gangliosidoses are a group of inherited neurogenetic autosomal recessive lysosomal storage disorders usually presenting with progressive macrocephaly, developmental delay and regression, leading to significant morbidity, and premature death. A quantitative definition of the natural history would support and enable clinical development of specific therapies. Methods: Single disease registry of eight gangliosidoses (NCT04624789). Cross-sectional analysis of baseline data in N= 26 patients. Primary endpoint: disease severity assessed by the 8-in-1 score. Secondary endpoints: first neurological sign or symptom observed a. by parents and b. by physicians, diagnostic delay, as well as phenotypical characterization. Tertiary endpoints: Neurological outcomes (development, ataxia, dexterity) and disability. Results: The 8-in-1 score quantitatively captured severity of disease. Parents recognized initial manifestations (startle reactions) earlier than physicians (motor developmental delay and hypotonia). Median diagnostic delay was 3.16 [IQR 0.69...6.25] years. Eight patients presented with late-infantile phenotypes. Conclusion: Data in this registry raise awareness of these rare and fatal conditions in order to accelerate diagnosis, inform counselling of afflicted families, define quantitative endpoints for clinical trials, and can serve as historical controls for future therapeutic studies. The characterization of a late-infantile phenotype is novel. Longitudinal follow-up is planned.

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The GM2 gangliosidoses: Unlocking the mysteries of pathogenesis and treatment

Cited by 29 publications

References 157 publications

Rare variant aggregation in 148,508 exomes identifies genes associated with proxy dementia

Rare variant aggregation in 148,508 exomes identifies genes associated with proxy dementia

Rare Variant Aggregation in 148,508 Exomes Identifies Genes Associated with Proxy Alzheimer’s disease/Dementia

Quantitative longitudinal natural history of eight gangliosidoses – conceptual framework and baseline data of the German 8-in-1 disease registry. A cross-sectional analysis

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