Familial hypercholesterolemia (FH) is a genetic disorder characterised by elevated plasma LDL-cholesterol, predisposing to premature atherosclerotic cardiovascular disease. Most cases follow an autosomal dominant pattern (ADH) caused by pathogenic variants in LDLR, APOB or PCSK9. In contrast, the rare autosomal recessive form (ARH) results from biallelic mutations in LDLRAP1, leading to defective LDL receptor-mediated endocytosis. Despite the high rate of consanguinity in Tunisia, LDLRAP1 variants have not yet been reported in this population. In this study, Whole Exome Sequencing of two consanguineous Tunisian families, identified distinct pathogenic variants. In the first family (FH-A), a recurrent LDLR splice-site variant (c.1845+1G>A) was detected in both heterozygous and homozygous states, consistent with an autosomal dominant inheritance pattern. In the second family (FH-B), a novel homozygous LDLRAP1 missense variant (c.161G>A; p.Gly54Asp) was identified, confirming autosomal recessive inheritance. In silico analyses using MutationTaster, DynaMut2, MUpro, DDGun, NetSurfP-2.0, ConSurf and PyMOL predicted that the p.Gly54Asp substitution destabilises the PTB domain of LDLRAP1 by disrupting key hydrogen bonds and hydrophobic interactions, thereby likely impairing LDLR internalisation. According to ACMG guidelines, this variant is classified as likely pathogenic. Clinically, ARH patients exhibited early-onset xanthomas and an unusual quadricuspid aortic valve (QAV). Targeted analysis of valvulogenesis genes (NOTCH1, GATA4, NKX2-5, TBX5, AGTR1, BMP2) revealed no co-segregating pathogenic variants, suggesting that QAV may result from embryonic LDL accumulation disrupting Notch1 signalling rather than a monogenic defect. Comparison with other ADH Tunisian families carrying the same LDLR mutation showed phenotypic variability, likely influenced by genetic modifiers, treatment response and environmental factors. These findings provide the first evidence of LDLRAP1-associated ARH in Tunisia and highlight the genetic heterogeneity of FH, emphasising the importance of integrating molecular, structural and functional analyses for accurate diagnosis, personalised management and early prevention.

Objective. Multiple endocrine neoplasia type 1 (MEN1) is a very rare genetic disorder characterized by an autosomal dominant inheritance. We aim through this case series to delineate the wide spectrum of its clinical features. Methods. In the present study, we report the clinical and genetic findings of four siblings affected by this disorder. DNA was extracted from patients' blood leukocytes using a phenol-chloroform method and assessed for purity with a NanoDrop spectrophotometer. Ten exons of the MEN1 gene were amplified by PCR, verified by gel electrophoresis, and sequenced using Big Dye Terminator chemistry followed by capillary electrophoresis. The sequences were than analyzed with CHROMAS and compared to reference sequences. As for the variant, interpretation and pathogenicity were assessed using Ensembl, ClinVar, dbSNP, gnomAD, Alamut Visual, and VARSOME. Results. We highlight the wide range of phenotypes encompassing primary hyperparathyroidism, macroprolactinoma, lipomas, papillary thyroid carcinoma, ectopic thyroid, multinodular goiter, and bilateral adrenal nodules observed in this family contrasting with the same pathogenic frameshift mutation. We also pinpoint to a second mutation detected in two of the siblings while discussing its pathogenicity. Finally, we provide an overview of the clinical manifestations of MEN1 and its genetic background. Conclusion. This research sets the stage to further investigate the molecular mechanisms underlying the novel nonsense mutation. Additionally, it incites other research to explore the frequency of this mutation in other populations and finally to conduct functional studies.

ObjectiveThis study aimed to evaluate the effect of a 50% reduction in preprandial bolus insulin (50%-B) on plasma glucose (PG) responses during postprandial exercise of continuous moderate intensity (CONT) and intermittent high intensity (INT) in individuals with type 1 diabetes (T1D).MethodsSixteen adults with T1D (31% male), treated with multiple daily insulin injections (MDI), participated in a randomized crossover study comprising four experimental conditions, separated by a washout period of at least 48 hours. Participants performed two 30-minute, preceded by a 3-minute warm-up without weights:• CONT: continuous cycling at 60% of maximal aerobic power (MAP).• INT: 2-minute intervals alternating between 40% and 80% of MAP, repeated for 7 intervals, with the last interval adjusted so that the total exercise time is exactly 30 minutes. Each exercise modality was performed under two insulin conditions: a full preprandial bolus (100%-B) and a 50% reduction (50%-B). Plasma glucose, insulin, and cortisol were measured before, during, and after exercise. Linear mixed models were used to analyze temporal changes and condition effects.ResultsBlood glucose decreased significantly over time for both exercise types (p < 0.001). During CONT, the decline in PG was similar between doses (Δ100%-B: –3.01 ± 2.96 vs. Δ50%-B: –2.82 ± 2.28 mmol/L; p = 0.18), However, the nadir PG was higher with 50%-B compared to 100%-B (8.59 ± 4.07 vs. 5.69 ± 3.06 mmol/L, respectively; β = +2.91 mmol/L; p = 0.026), and hypoglycemia was less frequent (2 vs. 18 episodes; p = 0.028). During INT, PG decreased less with 50%-B than with 100%-B (Δ: –2.03 ± 1.63 vs. –3.62 ± 2.76 mmol/L; p = 0.022), with no hypoglycemic episodes under 50%-B compared to six with 100%-B. Mean PG remained higher with 50%-B across both exercise types (p < 0.01). Plasma insulin decreased over time (p = 0.038) regardless of bolus condition, while cortisol increased more during INT with 100%-B than with 50%-B (p = 0.02).ConclusionsReducing the preprandial bolus insulin by 50% effectively attenuates exercise-induced declines in plasma glucose and substantially reduces hypoglycemia risk, particularly during intermittent high-intensity exercise. These results emphasize the clinical relevance of personalized insulin adjustments to enhance metabolic safety during exercise in individuals with T1D.

INTRODUCTION:Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women worldwide, posing a major public health concern. This multifaceted condition significantly impairs quality of life (QOL) across multiple domains. AIM:To assess QOL and eating disorders (EDs) in patients with PCOS. METHODS:A cross-sectional descriptive and comparative study was conducted on women with confirmed PCOS who were followed in the Endocrinology Department of Hedi Chaker Hospital, Sfax, Tunisia, and a targeted group of women with PCOS recruited through Google Forms. The PCOSQ-42 questionnaire for unmarried women, the PCOSQ-47 for married women, and the SCOFF questionnaire were used as assessment tools. Participants were divided into two groups: Group 1, consisting of French participants, and Group 2, consisting of Tunisian participants. RESULTS:A total of 71 French participants (Group 1) and 101 Tunisian participants (Group 2) were included in the study. All participants reported a compromised QOL. Among married women, the psychological well-being domain had the lowest score (2.86 ± 0.7), while the menstrual and fertility disorders domain was the most affected among unmarried women, with an average score of 2.84 ± 0.8. EDs were identified in 70.93% of participants, with a higher prevalence among unmarried women. A better QOL was observed among married women in Group 2 compared to their counterparts in Group 1. CONCLUSION:The findings reveal a high prevalence of impaired QOL and EDs in women with PCOS, with cultural and marital status differences warranting tailored interventions.