Une hypoplasie ponto-cérébelleuse causée par l’accumulation d’un inositol phosphate = A disruption of inositol phosphates metabolism causes pontocerebellar hypoplasia

Les hypoplasies ponto-cérébelleuses forment un groupe de maladies neurodégénératives périnatales très rares, caractérisées par une hypoplasie ou une atrophie précoce du cervelet et du tronc cérébral, une structure cérébrale impliquée dans des fonctions vitales, notamment la respiration. La dégénérescence débute au cours du développement cérébral, souvent avant la naissance. Elle est responsable d’une microcéphalie, parfois congénitale, mais plus souvent d’apparition progressive. Les développements moteur et cognitif sont altérés dès les premiers mois de vie, et la maladie est le plus souvent mortelle dans l’enfance. Ces maladies sont principalement génétiques et transmises selon un mode autosomique récessif. Près de 20 gènes responsables ont été identifiés à ce jour [1, 2]. La plupart sont impliqués dans l’épissage et la maturation d’ARN codants ou non codants, alors que les autres gènes jouent des rôles différents. Les mécanismes cellulaires et moléculaires responsables de la dégénérescence sont mal compris

MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

Inositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the multiple inositol-polyphosphate phosphatase 1 gene (MINPP1). Patients are found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We find that patient-derived and genome edited MINPP1−/− induced stem cells exhibit an inefficient neuronal differentiation combined with an increased cell death. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis

Oral and Dental Health in Children with Chronic Liver Disease in the Turkey Northeast

Background: It is important to be aware of oral and dental problems in the early period in children with chronic liver disease (CLD) to prevent late complications. Therefore, we aimed to analyze the oral and dental health status in children with CLD. Methods: The three groups of children (3–18 years old); Group 1 (disease group, n = 31) patients with CLD, Group 2 (disease control group, n = 17) patients with chronic renal failure, and Group 3 healthy children (control group, n = 35). Examination of oral and dental structures were made, and then salivary parameters were analyzed. Antegonial index were calculated from panoramic X‑rays. Results: Enamel hypoplasia was found in 54.8%, 41.1%, and 31.4% of the children in the Groups 1, 2, and 3, respectively (P1‑3 < 0.05). High salivary buffer capacity was found in 45.2% and 70.6% of the patients in Groups 1 and 2, respectively, and 45.7% of the children in healthy group, (P1‑2 and P2‑3 < 0.05). Factors associated with enamel hypoplasia in patients with CLD were male gender (64.7% vs. 21.4%, P < 0.05) and the presence of malnutrition (41.1% vs. 7.1%, P < 0.05). Conclusion: Pediatric hepatologists must be aware of the dental problems in children with CLD. Enamel hypoplasia is common in children with CLD, and it may predispose to dental caries.Keywords: Chronic liver disease, dental health, enamel hypoplasi

THE EFFECTS OF BAY K-8644 ON AGONIST-INDUCED CONTRACTIONS IN GUINEA-PIG URINARY-BLADDER

In this study the effects of Bay K 8644 a new Ca2+ channel activator, on agonist-induced contractions in guinea-pig urinary bladders were investigated. Histamine and serotonin (10(-9) - 10(-4) M) produced a dose-dependent contraction. Maximum contraction was obtained by 10(-5) M serotonin. Its value was 990.00 mg