Deficiency Diseases

PURPOSE OF REVIEW: Hypomagnesemia, defined as low serum/plasma magnesium concentration, is a highly prevalent yet underrecognized electrolyte disorder with extensive clinical, metabolic, and nutritional implications. This review provides an updated synthesis of magnesium physiology, dietary determinants, homeostatic regulation, diagnostic challenges, and therapeutic strategies, with particular emphasis on recent meta-analyses and large-scale epidemiological evidence linking hypomagnesemia to multisystem disease. RECENT FINDINGS: Accumulating evidence has shown consistent associations between low serum or dietary magnesium and increased risk of cardiometabolic disorders (hypertension, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular disease), neuropsychiatric conditions (migraine, depression, cognitive impairment, and dementia), osteoporosis, immune dysregulation, and adverse outcomes in hospitalized, critically ill, and chronic kidney disease patients. Mechanistic studies have clarified the roles of TRPM6/7 channels, tight junction claudins, and basolateral magnesium transporters in intestinal and renal magnesium handling, elucidating pathways underlying both inherited and acquired deficiencies. Research has also highlighted the contribution of modern dietary patterns, food processing, mineral-depleted drinking water, medication use (notably proton pump inhibitors, diuretics and chemotherapeutic agents), and gut microbiome alterations to widespread subclinical deficiency. Meta-analyses of RCTs indicate that magnesium supplementation confers modest but clinically relevant improvements in blood pressure, glycemic control, inflammatory markers, endothelial function, migraine frequency, and depressive symptoms, particularly in individuals with baseline hypomagnesemia. However, serum magnesium remains an insensitive biomarker of total body magnesium status, and consensus on optimal diagnostic thresholds and replacement strategies is lacking. Magnesium deficiency contributes to a wide spectrum of multisystem disorders, and is driven by dietary insufficiency, gastrointestinal and renal losses, medication use, chronic disease, and altered microbiome function. Meta-analytic evidence supports its role as a modifiable risk factor across cardiovascular, metabolic, neurological, skeletal, and immune disorders. Dietary modification, optimized supplementation, and correction of underlying causes of deficiency remain central to management. Future research should focus on improved diagnostic tools, personalized dosing approaches and long-term outcomes of magnesium repletion. Enhancing clinical awareness and integrating magnesium evaluation into routine care may reduce the growing burden of hypomagnesemia.

Background/objectivesAn Endocrine Society Clinical Practice Guideline on vitamin D was published in 2024. Its main objective was the use of vitamin D to lower the risk of disease in individuals without established indications for vitamin D treatment or 25-hydroxavitamin D (25(OH)D) testing. The methodology followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) and the Evidence-to-Decision (EtD) framework. Evidence from randomized controlled trials (RCTs) retrieved by a systematic review was prioritized to inform this guideline. It was concluded that vitamin D supplementation reduces rickets and respiratory tract infections in children, mortality in individuals aged 75 years or older, pregnancy complications (outcomes), and progression of prediabetes to diabetes mellitus. Consequently, empiric vitamin D supplementation was recommended for individuals aged 1 to 18 years and ≥75 years, pregnant women, and individuals with prediabetes. Empiric vitamin D supplementation is defined as a vitamin D intake that exceeds the Dietary Reference Intakes (DRIs) and is implemented without 25(OH)D testing.MethodsThis article provides a comprehensive guideline summary and critical appraisal based on a narrative review on scientific publications regarding that guideline.ResultsSeveral publications discussed the 2024 Endocrine Society Clinical Practice Guideline on vitamin D. The main criticisms and discussion relate to unclear vitamin D dosages, guideline applicability to certain populations including controversy with previous vitamin D guidelines, and the implications of 25(OH)D testing.ConclusionsThe 2024 Endocrine Society Clinical Practice Guideline on vitamin D followed a rigorous methodological approach with high quality standards but it leaves many open questions and uncertainties warranting clarification.

BackgroundMitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an extremely rare autosomal recessive disease caused by variants in the thymidine phosphorylase gene (TYMP), primarily characterized by severe gastrointestinal and neurological symptoms. The complete phenotype of MNGIE has not been linked to any gene other than TYMP.MethodsWe describe two identical twins who exhibited delayed psychomotor development, infantile bilateral cataract, congenital demyelinating polyneuropathy, and severe progressive gastrointestinal dysmotility with recurrent pseudo-obstruction episodes, along with diffuse supratentorial leukoencephalopathy that mainly overlaps with classic TYMP-related MNGIE. During the course of the disease, one patient developed Wernicke encephalopathy, triggered by chronic malnutrition related to recurrent gastrointestinal pseudo-obstruction. This patient later suffered from a catastrophic stroke-like episode, resulting in massive cerebral edema and brain death at the age of 38.ResultsNext-generation sequencing (NGS) using a custom-targeted mitochondrial gene panel identified two compound heterozygous variants in the POLG gene: the paternal variants p.Thr251Ile and p.Pro587Leu, occurring in cis, and the novel maternal variant p.Arg853Gly. Quantification of mtDNA by real-time PCR on skeletal muscle DNA detected significant depletion, but no multiple deletions were detected with mtDNA analysis by long-range PCR and Nanopore sequencing.ConclusionsThese cases showed a very distinctive POLG phenotype, with some MNGIE-like features, expanding the clinical and genetic spectrum of the POLG-related diseases. Additionally, they highlighted the importance of monitoring for thiamine deficiency in mitochondrial patients with severe gastrointestinal dysmotility who experience sudden clinical deterioration.