People with Down syndrome represent a highly vulnerable population, frequently showing vitamin D deficiency together with an elevated risk of metabolic and neuromuscular dysfunction. This susceptibility derives from several factors, including muscular hypotonia, excess body weight, thyroid abnormalities, and immune dysregulation. The coexistence of these conditions compromises bone and muscle health, increases cardiometabolic risk, and reduces motor abilities and coordination, thereby predisposing individuals to falls, sarcopenia, sarcopenic obesity, and long-term disability. Vitamin D, traditionally known for its essential role in bone health, is now recognized as a pleiotropic hormone regulating immune responses, metabolic balance, and muscle performance. Its deficiency is increasingly linked to obesity, insulin resistance, diabetes mellitus, dyslipidemia, and metabolic syndrome. These adverse outcomes are mediated through mechanisms involving chronic inflammation, oxidative stress, mitochondrial impairment, and disrupted adipokine signaling. This review integrates current molecular, cellular, and clinical evidence on the multifaceted actions of vitamin D in Down syndrome. Particular emphasis is placed on its effects on insulin signaling, adipose tissue metabolism, inflammatory regulation, and muscle strength. Finally, vitamin D is discussed as a biomarker and therapeutic target to guide personalized interventions aimed at improving metabolic health, maintaining muscle function, and promoting long-term independence in this high-risk population.

A homozygous loss-of-function (LoF) variant in POC5 was previously described in an individual with retinitis pigmentosa. We identified POC5 variants in 12 probands with a syndromic phenotype. We aim to define the phenotype spectrum and molecular mechanism associated with biallelic POC5 LoF variants. We studied a cohort of 12 families with bi-allelic LoF POC5 variants and performed detailed phenotype analysis. POC5 localization studies were performed in 3 proband-derived fibroblast cell lines. Detailed phenotyping of probands with POC5 variants expands the phenotype spectrum beyond ocular manifestations. This syndrome causes not only rod-cone dystrophy but also diabetes mellitus with severe insulin resistance and partial lipodystrophy, kidney disease, and muscle cramps. The POC5 protein plays an essential role during cell cycle and cilium formation. Interestingly, POC5 localization studies in 3 proband-derived fibroblast cell lines show aberrant localization suggesting a ciliary defect. The phenotypes of the 12 families in this study fit well within the ciliopathy phenotype spectrum, except for lipodystrophy, which is not common in ciliopathies. We describe a multiorgan syndrome caused by bi-allelic LoF variants in POC5. This underscores the pleiotropic effects of POC5 variants and highlights the significance of adipose tissue and metabolic dysfunction in ciliopathies.

To evaluate the diagnostic yield of exome sequencing (ES) in isolated polyhydramnios. This retrospective study included 40 cases of isolated polyhydramnios. All patients underwent screening for gestational diabetes mellitus (GDM) and chromosomal microarray analysis (CMA). ES was performed in CMA-negative cases, along with targeted testing for spinal muscular atrophy, myotonic dystrophy type 1, and Prader-Willi syndrome. Pathogenic or likely pathogenic variants were identified in 7 cases, yielding a 17.5% diagnostic rate. Diagnostic yield was 12% (2/17) in mild cases and 22% (5/23) in moderate-severe cases. Diagnoses included Bartter syndrome (KCNJ1, BSND, MAGED2), Noonan syndrome (RIT1), Osteopathia Striata with Cranial Sclerosis (AMER1), and AUTS2-related neurodevelopmental disorder. In addition, one case was diagnosed postnatally with myotonic dystrophy 1. Two ES-positive cases had concurrent GDM. Postnatal follow-up showed normal development in 85% of live-born infants, with a few cases of global or speech delay. ES yields a substantial diagnostic benefit in isolated polyhydramnios, including mild cases and those with GDM. These findings support incorporating ES into the diagnostic approach for isolated polyhydramnios.

Diabetes-induced muscle atrophy, characterized by progressive loss of skeletal muscle mass and function, poses a major challenge in diabetes management. To address this, we developed a phyto-exosomal formulation derived from Anemarrhena asphodeloides small extracellular vesicle (AA-sEV) and evaluated its therapeutic potential against diabetic muscle atrophy. AA-sEV were isolated by ultracentrifugation and characterized for exosomal morphology. The therapeutic efficacy of AA-sEV was assessed through in vivo studies in diabetic db/db mice and in vitro assays using C2C12 myoblasts exposed to high glucose conditions. Fluorescently labeled AA-sEV efficiently accumulated in skeletal muscle tissue and myoblasts. Oral administration of AA-sEV enhanced muscle performance, as indicated by increased grip strength and hanging endurance, restoration of myofiber cross-sectional area, and upregulation of FNDC5 expression. Transcriptomic analysis revealed that mitophagy served as the central mechanism mediating AA-sEV's therapeutic effects. Specifically, AA-sEV activated the Pink1/Parkin-dependent mitophagy pathway, reducing mitochondrial reactive oxygen species accumulation. This restoration of mitochondrial quality control promoted the MyoG/MyoD1-driven anabolic program while suppressing the MuRF1/MAFbx-mediated catabolic response. Treatment with the mitophagy inhibitor 3-methyladenine abolished the anabolic and catabolic regulatory effects of AA-sEV under hyperglycemic conditions. Our findings demonstrate that AA-sEV mitigate diabetes-induced muscle atrophy by restoring protein anabolic-catabolic balance via Pink1-mediated mitophagy. These results highlight a novel extracellular vesicle-based therapeutic strategy for managing diabetic myopathy and related complications.

Women with gestational diabetes mellitus (GDM) have increased risk of insulin resistance, glucose intolerance, and low-grade systemic inflammation in the postpartum. Higher cardiorespiratory fitness (CRF) and muscular strength are associated with improved metabolic outcomes in the general population, but data in women with GDM are lacking. We investigated the longitudinal associations of CRF and muscular strength during pregnancy with glucose intolerance, insulin resistance and inflammation parameters at 1-year postpartum in women with GDM. This is a secondary analysis of the MySweetHeart trial, which included 179 women with GDM. During pregnancy, CRF was assessed using the Chester Step test, and muscular strength was measured via handgrip strength (HS) and adjusted for pre-pregnancy body mass index (BMI). At one-year postpartum, participants underwent a 75 g oral glucose tolerance test, and we calculated HOMA-IR and MATSUDA index. We calculated glucose intolerance and assessed metabolic syndrome (MetS) and c-reactive protein (CRP) at 1-year postpartum. Higher CRF during pregnancy was associated with lower risk of glucose intolerance, MetS, and insulin resistance at one-year postpartum (all p ≤ 0.047). These associations were attenuated after adjusting for classical diabetes risk factors including family history of diabetes, age, ethnicity, and pre-pregnancy BMI. Higher HS during pregnancy was associated with lower CRP, HOMA-IR, higher MATSUDA index, and reduced MetS (BMI-based) at one-year postpartum, independent of classical diabetes risk factors (all p ≤ 0.035). In this longitudinal cohort of women with GDM, higher CRF and HS during pregnancy were protective of adverse metabolic health outcomes at 1-year postpartum. The relationship between HS and metabolic health was independent of classical diabetes risk factors.