Spectrum of neuro-developmental disorders in children with congenital hyperinsulinism due to activating mutations in GLUD1

BACKGROUND: Hyperinsulinism/hyperammonemia (HI/HA) syndrome is the second most common type of congenital hyperinsulinism caused by an activating GLUD1 mutation. OBJECTIVE: The aim of this study was to determine the clinical profile and long-term neurological outcomes in children with HI/HA syndrome. METHOD: Retrospective review of patients with GLUD1 mutation, treated at two centers in the UK and Russia, over a 15-year period. Different risk factors for neuro-developmental disorders were analyzed by Mann-Whitney U test and Fisher exact p. RESULTS: We identified 25 cases with GLUD1 mutations (12 males). Median age of presentation was 7 months (12 hours-18 months). Hypoglycaemic seizures were the presenting feature in 24 (96%) cases. 24 cases responded to diazoxide and protein restriction whilst one patient underwent partial pancreatectomy. In total, 13 cases (52%) developed neurodevelopmental manifestations. Epilepsy (n=9/25, 36%), learning difficulties (n=8/25, 32%) and speech delay (n=8/25, 32%) were the most common neurological manifestation. Median age of presentation for epilepsy was 12 months with generalized tonic-clonic seizures being the most common (n=4/9, 44.4%) followed by absence seizures (n=3/9, 33.3%). Early age of presentation (p=0.02), diazoxide dose (p=0.04), and a mutation in exon 11 or 12 (p=0.01) was associated with neurological disorder. CONCLUSION: HI/HA syndrome is associated with wide spectrum of neurological disorders. These neurological manifestations were more frequent in cases with mutations affecting the GTP-binding site of GLUD1 in our cohort.The article is available via Open Access. Click on the 'Additional link' above to access the full-text.Published version, accepted versio

Clinical and genetic heterogeneity of HNF4A/HNF1A mutations in a multicentre paediatric cohort with hyperinsulinaemic hypoglycaemia

OBJECTIVE: The phenotype mediated by HNF4A/HNF1A mutations is variable and includes diazoxide-responsive hyperinsulinaemic hypoglycaemia (HH) and maturity-onset diabetes of the young (MODY). DESIGN: We characterised an international multicentre paediatric cohort of patients with HNF4Aor HNF1Amutations presenting with HH over a 25-year period (1995-2020). METHODS: Clinical and genetic analysis data from five centres were obtained. Diazoxide responsiveness was defined as the ability to maintain normoglycaemia without intravenous glucose. Macrosomia was defined as a birth weight ≥90th centile. SPSS v.27.1 was used for data analysis. RESULTS: A total of 34 patients (70.6% female, n = 24) with a mean age of 7.1 years (s.d. 6.4) were included. A total of 21 different heterozygous HNF4Amutations were identified in 29 patients (four novels). Four different previously described heterozygous HNF1A mutations were detected in five patients. Most (97.1%, n = 33) developed hypoglycaemia by day 2 of life. The mean birth weight was 3.8 kg (s.d. 0.8), with most infants macrosomic (n = 21, 61.8%). Diazoxide was commenced in 28 patients (82.3%); all responded. HH resolved in 20 patients (58.8%) following a median of 0.9 years (interquartile range (IQR): 0.2-6.8). Nine patients (n = 9, 26.5%) had developmental delay. Two patients developed Fanconi syndrome (p.Arg63Trp, HNF4A) and four had other renal or hepatic findings. Five (14.7%) developed MODY at a median of 11.0 years (IQR: 9.0-13.9). Of patients with inherited mutations (n = 25, 73.5%), a family history of diabetes was present in 22 (88.0%). CONCLUSIONS: We build on the knowledge of the natural history and pancreatic and extra-pancreatic phenotypes of HNF4A/HNF1Amutations and illustrate the heterogeneity of this condition.This article is freely available online. Click on the 'Additional Link' above to access the full-text via the publisher's site.Accepted version, submitted versio

Potential use of polymeric particles for the regulation of plant growth

Plant growth regulators (PGRs) are molecules widely applied in the agriculture, leading to increased crop yield and improved quality of agricultural products. These compounds act as plant hormones, affecting the plant hormonal homeostasis, and thus control plant growth and development. Recently, the development of polymer-based modified release systems for PGRs has emerged as a promising alternative for increasing the efficacy of these compounds. This review will focus on polymeric particles that are used as carrier systems for PGRs, allowing their controlled release and protecting them from degradation. Successful examples include the phytohormone gibberellic acid(GA3)-loaded nanoparticles, which showed higher efficacy than the non-nano active ingredient in promoting seed germination and seedling growth, and salicylic acid (SA) and nitric oxide (NO)-releasing nanoparticles as effective plant protection agents against stresses. Polymeric nanomaterials per se such as chitosan (Cs) can also alter plant signaling pathways and promote plant growth and development. Despite their great potential in improving the plant production with less damage to the environment, relatively few studies have focused on the use of these nanomaterials for the development of modified release systems for PGRs. In this scenario, this review discusses on the major advances and obstacles in the area.Fil: Pereira, Anderson E. S.. Universidade Estadual Paulista Julio de Mesquita Filho. Faculdade de Engenharia; BrasilFil: Sousa, Bruno T.. Universidade Estadual de Londrina; BrasilFil: Iglesias, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Biológicas. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Biológicas; ArgentinaFil: Alvarez, Vera Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; ArgentinaFil: Casalongue, Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Biológicas. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Biológicas; ArgentinaFil: Oliveira, Halley C.. Universidade Estadual de Londrina; BrasilFil: Fraceto, Leonardo F.. Universidade Estadual Paulista Julio de Mesquita Filho. Faculdade de Engenharia; Brasi