The diagnosis of neurogenetic disorders is often prolonged due to clinical variability and significant genetic heterogeneity, making molecular diagnosis challenging. This study aimed to investigate the molecular basis of rare inherited neurological conditions in three consanguineous Moroccan families. We performed Whole exome sequencing (WES) on probands from three unrelated consanguineous Moroccan families (NP 69, NP 84, NP 89). Candidate variants were validated by Sanger sequencing and segregated within the families. Pathogenicity was assessed through in silico prediction tools. Molecular modeling and molecular dynamics simulations were applied to assess the structural impact of selected variants. Whole exome sequencing revealed likely disease-causing variants in all three families. In Family NP 69, we found compound heterozygous missense variants in RYR3 gene (p.Gly2168Arg and p.Val854Ile) in a proband presenting with developmental delay and hippocampal sclerosis. In Family NP 84, a homozygous missense variant (p.Trp671Arg) in POLR3A gene, was associated with classic hypomyelinating leukodystrophy and ataxia, but with atypical features including preserved cognition, myoclonus, and oligodontia, consistent with recurrence of a previously reported variant in North Africa and suggestive of a possible founder effect. In Family NP 89, a homozygous splice-site mutation in LAMA2 gene (c.8244 + 1G > A) was confirmed in a proband with severe congenital muscular dystrophy. This study reports a novel compound heterozygous configuration in RYR3, confirms a previously reported bi-allelic variant in POLR3A, and validates a recurrent LAMA2 variant. Together, these findings add new insights into the genotype–phenotype spectrum of neurogenetic disorders in consanguineous North African populations, all consistent with a shared autosomal recessive inheritance pattern.
Essential oils (EOs) extracted from leaves (JTEOL) and cones (JTEOC) of Juniperus turbinata leaves were analysed to determine their chemical composition and studied in vitro their antioxidant, antidiabetic, dermatoprotective, and neuroprotective effects. The results of GC-MS-MS characterization revealed significant qualitative and quantitative differences in volatile profiles between the two parts of the plant. JTEOC was dominated by alpha-pinene (81 %), followed by limonene (2.38 %), trans-verbenol (2.37 %), and alpha-terpinyl acetate (1.8 %), while JTEOL contained alpha-pinene (20.71 %), alpha-terpinyl acetate (19.87 %), and beta-phellandrene (15.56 %) as major components. The antioxidant assays showed varying activities, with JTEOL showing superior radical scavenging capacity in DPPH and ABTS assays with 9.33 f 0.55 mg TE/g and 41.16 f 0.97 mg TE/g, respectively, while JTEOC exhibited higher reducing power in CUPRAC and FRAP assays as 85.69 f 1.35 mg TE/g 47.78 f 0.27 mg TE/g, respectively. In enzyme inhibition assays, both EOs showed significant alpha-amylase inhibition (JTEOC: 1.380 f 0.019 mmol ACAE/g; JTEOL: 1.084 f 0.055 mmol ACAE/g) but no alpha-glucosidase activity. JTEOL demonstrated superior tyrosinase inhibition (68.07 f 3.74 mg KAE/g) compared to cone EO (17.14 f 4.27 mg KAE/g). In cholinesterase inhibition assays, JTEOC specifically inhibited acetylcholinesterase (7.25 f 0.16 mg GALAE/g), while both EOs showed butyrylcholinesterase inhibition, with JTEOL being more potent (2.85 f 0.64 mg GALAE/g versus 1.52 f 0.32 mg GALAE/g). Our current study suggests that J. turbinata EOs, particularly from leaves, possess a promising potential for applications in antioxidant, dermatoprotective, and neuroprotective treatments.
Leishmania tropica causes cutaneous leishmaniasis (CL) from North Africa and Ethiopia to India, and is reported to be transmitted from human to human through sand fly bites. While this species is characterized by a high genomic diversity in all the area of endemicity, there is very little information on diversity at a microepidemiological scale. Here, we concentrated on an epidemic Moroccan focus of CL and studied transmission patterns by comparative genomics of parasites in human patients. We used a culture-independent method of genome sequencing, applied directly on dermal scrapings. We identified 7 groups of nearly identical genotypes, as well as parasites with mixed ancestry. Our results reveal a microfocal transmission among humans, underlain by (pseudo)clonal and sexual reproductive modes. This study demonstrates the power of direct genome sequencing for evolutionary genetics at a microepidemiological scale.
Sirtuin 2 (SIRT2), a NAD+-dependent histone deacetylase implicated in α-synuclein aggregation, is an emerging target for disease-modifying therapies in Parkinson’s disease (PD). Here, we employed an integrated computational drug-repurposing strategy to identify potent SIRT2 inhibitors from the DrugBank database. A curated set of 949 inhibitors was used to construct quantitative structure–activity relationship (QSAR) models with four gradient-boosting algorithms, yielding CatBoost as the optimal predictor ( R_val^2 = 0.74, Q_tenfold^2 = 0.72). The model screened 4947 drug-like compounds, from which 97 candidates with predicted pIC50 ≥ 6 were prioritized. Molecular docking against the SIRT2 crystal structure (PDB: 4RMG) revealed high-affinity binding modes for multiple hits, notably DB14822, DB03571, and DB06506, engaging conserved residues (Phe119, Tyr139, Phe190, Ile232) through hydrophobic and π-stacking interactions. ADMET profiling indicated favorable drug-likeness and acceptable pharmacokinetic/toxicity properties for most candidates. All-atom molecular dynamics simulations (250 ns) demonstrated that top ligands maintained compact, stable complexes with low RMSD, restricted radius of gyration, and minimal solvent exposure. Principal component and free energy landscape analyses confirmed constrained global motions, while MM/GBSA calculations yielded favorable binding free energies (− 32.6 to − 35.7 kcal/mol) for lead compounds. Given SIRT2’s established role in α-synuclein aggregation and neurodegeneration, these compounds represent potential therapeutic starting points for Parkinson’s disease and merit experimental validation.
Tuberculosis (TB) is a major health burden, the leading cause of death among people living with HIV, and one of the main causes of death linked to antimicrobial resistance. The World Health Organization (WHO) launched in 2015 the End TB Initiative that aims to reduce TB cases and deaths by 2035. However, despite some progress, significant gaps persist in TB detection, treatment, prevention, and funding. Diagnosis is most often by sputum smear and culture and, when available, by nucleic acid amplification tests (NAATs), which revolutionizes TB diagnosis and monitoring, improving early detection, resistance surveillance, and treatment response evaluation. In this review, we report on the implication of various Real-Time PCR (RT-PCR) laboratory diagnostic tests and compare their performance in detecting MTB. We show that the Xpert MTB/RIF test is currently the most effective and widely validated molecular tool for diagnosing pulmonary TB, though its accuracy in extrapulmonary TB remains inconsistent. These findings suggest that combining molecular tests with other methods—such as radiology, microbiology, biomarkers, and immunological approaches—could provide a more reliable diagnostic strategy. Scaling up molecular tools worldwide, especially in high-burden regions, is essential to achieving the WHO End TB Strategy and ultimately eliminating TB.
