6 research outputs found
Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis
IMPORTANCE Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.OBJECTIVE To identify the genetic variants associated with juvenile ALS.DESIGN, SETTING, AND PARTICIPANTS In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.MAIN OUTCOMES AND MEASURES De novo variants present only in the index case and not in unaffected family members.RESULTS Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p. Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.CONCLUSIONS AND RELEVANCE These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.Genetics of disease, diagnosis and treatmen
Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.
BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362
Measuring aging rates of mice subjected to caloric restriction and genetic disruption of growth hormone signaling
Pathophysiology, epidemiology and therapy of agein
Régulation de l'IGF-I par la nutrition: mécanismes et implications
LâIGF-I (Insulin-like Growth Factor I) est un facteur de croissance indispensable Ă la croissance staturopondĂ©rale. LâIGF-I prĂ©sent dans la circulation est essentiellement dâorigine hĂ©patique. Sa production est stimulĂ©e par lâhormone de croissance et rĂ©gulĂ©e par la nutrition. En effet, la rĂ©duction de lâapport alimentaire diminue les taux circulants dâIGF-I. Les mĂ©canismes responsables de la rĂ©gulation de la production dâIGF-I par lâapport alimentaire, notamment en protĂ©ines, ont Ă©tĂ© largement caractĂ©risĂ©s. Le contrĂŽle de la production dâIGF-I par lâapport nutritionnel a permis dâimaginer un mĂ©canisme par lequel la nutrition est capable de rĂ©guler les grandes fonctions physiologiques et peut contribuer au dĂ©veloppement de certaines pathologies. Ainsi, le retard de croissance causĂ© par la malnutrition protĂ©inocalorique est en partie secondaire Ă une rĂ©duction des taux circulants dâIGF-I. Outre le retard de croissance, la rĂ©duction de lâapport nutritionnel induit Ă©galement un allongement de la durĂ©e de vie dans de nombreuses espĂšces. De façon surprenante, lâinhibition de lâactivitĂ© dâIGF-I obtenue par des manipulations gĂ©nĂ©tiques sâaccompagne elle aussi dâun allongement de la durĂ©e de vie. Il est dĂšs lors possible que la rĂ©duction des taux dâIGF-I induite par la diminution de lâapport alimentaire contribue Ă lâallongement de la durĂ©e de vie observĂ©. Contrairement Ă la malnutrition, un apport alimentaire excessif est susceptible dâaugmenter, bien que modestement, les taux circulants dâIGF-I. Sur cette base, il a Ă©tĂ© suggĂ©rĂ© que les taux dâIGF-I Ă©levĂ©s observĂ©s dans lâobĂ©sitĂ© pourraient contribuer au risque accru de cancer observĂ© dans cette population. En conclusion, les variations dâIGF-I circulante induites par des changements de lâapport nutritionnel pourraient affecter la croissance staturopondĂ©rale, la longĂ©vitĂ© et le risque de cancer