CASE PRESENTATION: A 33-year-old Palestinian woman born to consanguineous parents presented with a lifelong history of recurrent severe respiratory infections, growth failure (short stature and microcephaly), recurrent nephrolithiasis, chronic vomiting, generalized hirsutism, and bilateral hallux valgus. Laboratory evaluation revealed marked hypogammaglobulinemia (IgG <320 mg/dL, IgA <25 mg/dL, IgM <25 mg/dL), microcytic anemia, and severe vitamin D deficiency. Imaging confirmed chronic pulmonary small-airway changes and a chronically small right kidney with recurrent stones. Whole-exome sequencing identified a homozygous pathogenic SLC29A3 variant (c.1309G>A; p.Gly437Arg), establishing a diagnosis within the SLC29A3-related disorder spectrum. This case is unique due to its adult presentation, the exceptional severity of the humoral immunodeficiency, and the associated renal manifestations, which are infrequently reported in this spectrum.
CONCLUSION: This report underscores the importance of considering SLC29A3-related disorder spectrum in adults with multisystem disease. Recognition of this spectrum enables targeted multidisciplinary care, including immunoglobulin replacement therapy and anticipatory surveillance for endocrine and renal complications.
OBJECTIVES: To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends.
DESIGN, SETTING, AND POPULATION: This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals.
EXPOSURE: Population-level LDL-C concentrations.
MAIN OUTCOMES AND MEASURES: Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C-attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals.
RESULTS: In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C-attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings.
CONCLUSIONS AND RELEVANCE: Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.