Value of systematic genetic screening of patients with amyotrophic lateral sclerosis

Shepheard, Stephanie; Parker, Matthew; Cooper‐Knock, Johnathan; Verber, Nick; Tuddenham, Lee; Heath, Paul R.; Beauchamp, Nick; Place, Elsie S.; Sollars, Elizabeth; Turner, Martin R; Malaspina, Andrea; Fratta, Pietro; Hewamadduma, Channa; Jenkins, Thomas M.; McDermott, Christopher J.; Wang, Dennis; Kirby, Janine; Shaw, Pamela J.

doi:10.1136/jnnp-2020-325014

Cited by 78 publications

(73 citation statements)

References 41 publications

(68 reference statements)

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“…Recently, the analysis of two different cohorts, with a majority of apparently sporadic cases, showed an oligogenic basis of ALS associated with earlier age of disease [ 63 , 64 ]. Differences in genotype-phenotype correlations would have considerable therapeutic implications.…”

Section: Discussionmentioning

confidence: 99%

Individual Oligogenic Background in p.D91A-SOD1 Amyotrophic Lateral Sclerosis Patients

Gentile

Perrone

Morello

et al. 2021

Genes

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The p.D91A is one of the most common ALS-causing SOD1 mutations and is known to be either recessive or dominant. The homozygous phenotype is characterized by prolonged survival and slow progression of disease, whereas the affected heterozygous phenotypes can vary. To date, no genetic protective factors located close to SOD1 have been associated with the mild progressive homozygous phenotype. Using Next Generation Sequencing (NGS), we characterized a small cohort of sporadic and familial p.D91A-SOD1 heterozygous (n = 2) or homozygous (n = 5) ALS patients, to reveal any additional contributing variant in 39 ALS-related genes. We detected unique sets of non-synonymous variants, four of which were of uncertain significance and several in untranslated regions of ALS-related genes. Our results supported an individual oligogenic background underlying both sporadic and familial p.D91A cases irrespective of their p.D91A mutant alleles. We suggest that a comprehensive genomic view of p.D91A-SOD1 ALS patients may be useful in identifying emerging variants and improving disease diagnosis as well as guiding precision medicine.

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Section: Discussionmentioning

confidence: 99%

Individual Oligogenic Background in p.D91A-SOD1 Amyotrophic Lateral Sclerosis Patients

Gentile

Perrone

Morello

et al. 2021

Genes

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“…Moreover, a significant fraction (about 20%) of sporadic cases carried a confirmed or likely pathogenic mutation, and almost all had no family history of ALS. This occurrence establishes the importance of routinely performing the genetic sequencing on ALS patients to improve disease subclassification, patient stratification, and clinical care [43].…”

Section: Introductionmentioning

confidence: 93%

“…Mutations related the TARDBP gene, encoding the TAR DNA binding protein 43 (TDP- 43), have been also identified in ALS [46]. Mutated TDP43 is indeed the main protein found in protein aggregates in the cytoplasm of MNs [47][48][49], contributing to the alteration of several cellular processes in ALS [50].…”

Section: Genes Involved In Alsmentioning

confidence: 99%

Nearly 30 Years of Animal Models to Study Amyotrophic Lateral Sclerosis: A Historical Overview and Future Perspectives

Bonifacino

Zerbo

Balbi

et al. 2021

IJMS

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Amyotrophic lateral sclerosis (ALS) is a fatal, multigenic, multifactorial, and non-cell autonomous neurodegenerative disease characterized by upper and lower motor neuron loss. Several genetic mutations lead to ALS development and many emerging gene mutations have been discovered in recent years. Over the decades since 1990, several animal models have been generated to study ALS pathology including both vertebrates and invertebrates such as yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs, and non-human primates. Although these models show different peculiarities, they are all useful and complementary to dissect the pathological mechanisms at the basis of motor neuron degeneration and ALS progression, thus contributing to the development of new promising therapeutics. In this review, we describe the up to date and available ALS genetic animal models, classified by the different genetic mutations and divided per species, pointing out their features in modeling, the onset and progression of the pathology, as well as their specific pathological hallmarks. Moreover, we highlight similarities, differences, advantages, and limitations, aimed at helping the researcher to select the most appropriate experimental animal model, when designing a preclinical ALS study.

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“…There is an emerging appreciation for more widespread access to genetic testing in facilitating access to genetically-targeted therapies (9,10).…”

Section: Introductionmentioning

confidence: 99%

Genetic testing for amyotrophic lateral sclerosis in Canada – an assessment of current practices

Salmon

Anoja

Breiner

et al. 2021

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

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Objective: To understand current genetic testing practices at Canadian ALS clinics. Methods: An online survey and phone interviews, with clinicians practicing in 27 ALS clinics in Canada, were employed to collect data. Quantitative and qualitative analyses were conducted. Results: Ninety-three percent (25/27) of ALS clinics in Canada are routinely ordering genetic testing for familial ALS, while 33% (9/27) of clinics are routinely ordering genetic testing for sporadic ALS. Barriers to genetic testing include a perceived lack of an impact on treatment plan, difficulty in obtaining approvals, primarily from provincial Ministries of Health, and limited access to genetic counseling. Predictive testing practices were found to be the most variable across the country. The average wait time for a symptomatic patient living with ALS to see a genetic counselor in Canada is 10 months (range 0-36 months). Conclusions: Access to genetic testing, and testing practices, vary greatly across Canadian ALS clinics. There may be patients with a monogenetic etiology to their ALS who are not being identified given that genetic testing for patients diagnosed with ALS is not routinely performed at all clinics. This study highlights potential inequities for patients with ALS that can arise from variability in health care delivery across jurisdictions, in a federally-funded, but provincially-regulated, health care system. Clinical trials for both symptomatic ALS patients and pre-symptomatic ALS gene carriers are ongoing, and ALS clinicians in Canada are motivated to improve access to genetic testing for ALS.

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Value of systematic genetic screening of patients with amyotrophic lateral sclerosis

Cited by 78 publications

References 41 publications

Individual Oligogenic Background in p.D91A-SOD1 Amyotrophic Lateral Sclerosis Patients

Individual Oligogenic Background in p.D91A-SOD1 Amyotrophic Lateral Sclerosis Patients

Nearly 30 Years of Animal Models to Study Amyotrophic Lateral Sclerosis: A Historical Overview and Future Perspectives

Genetic testing for amyotrophic lateral sclerosis in Canada – an assessment of current practices

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