Inherited Dyslipidemic Splenomegaly: A Genetic Macrophage Storage Disorder Caused by Disruptive Apolipoprotein E () Variants.

Elise A Ferreira, Machteld M Oud, Susan M I Goorden, Miranda Versloot, Mirjam Langeveld, Clara D M van Karnebeek, Jeffrey Kroon, Saskia N van der Crabben

Journal: Genes 2025;16(3):

PMID: 40149441

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Abstract

BACKGROUND

Persistent splenomegaly, often an incidental finding, can originate from a number of inherited metabolic disorders (IMDs). Variants of are primarily known as risk factors in terms of cardiovascular disease; however, severe dysfunction of APOE can result in a disease phenotype with considerable overlap with lysosomal storage disorders (LSDs), including splenomegaly and gross elevation of N-palmitoyl-O-phosphocholine-serine (PPCS).

METHODS

A case study (deep phenotyping, genetic and FACS analysis) and literature study was conducted.

RESULTS

The index patient, with a family history of early-onset cardiovascular disease, presented with splenic infarctions in a grossly enlarged spleen. The identified genetic cause was homozygosity for two variants (c.604C>T, p.(Arg202Cys) and c.512G>A, p.(Gly171Asp); ε1/ε1), resulting in a macrophage storage phenotype resembling an LSD that was also present in the brother of the index patient. A FACS analysis of the circulating monocytes showed increased lipid content and the expression of activation markers (CD11b, CCR2, CD36). This activated state enhances lipoprotein intake, which eventually converts these monocytes/macrophages into foam cells, accumulating in tissues (e.g., spleen and vascular wall). A literature search identified seven individuals with splenomegaly caused by variants (deletion of leucine at position 167). The combined data from all patients identified male gender, splenectomy and obesity as potential modifiers determining the severity of the phenotype (i.e., degree of triglyceride increase in plasma and/or spleen size). Symptoms are (partially) reversible by lipid-lowering medication and energy restricted diets and splenectomy is contra-indicated.

CONCLUSIONS

Inherited dyslipidemic splenomegaly caused by disruptive variants should be included in the differential diagnoses of unexplained splenomegaly with abnormal lipid profiles. A plasma lipid profile consistent with dysbetalipoproteinemia is a diagnostic biomarker for this IMD.

Address: Department of Paediatrics, Emma Children's Hospital, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.; United for Metabolic Diseases, 1105 AZ Amsterdam, The Netherlands.; United for Metabolic Diseases, 1105 AZ Amsterdam, The Netherlands.; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.; Department of Human Genetics, Amsterdam University Medical Centres, Amsterdam Reproduction & Development, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.; Department of Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.; Center for Lysosomal and Metabolic Diseases, Department of Clinical Genetics, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands.; Department of Clinical Chemistry, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands.; Department of Paediatrics, Emma Children's Hospital, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.; United for Metabolic Diseases, 1105 AZ Amsterdam, The Netherlands.; Department of Human Genetics, Amsterdam University Medical Centres, Amsterdam Reproduction & Development, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.; Department of Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.; Amsterdam Cardiovascular Sciences, Atherosclerosis & Ischemic Syndromes, 1105 AZ Amsterdam, The Netherlands.; Laboratory of Angiogenesis and Vascular Metabolism, VIB-KU Leuven Center for Cancer Biology, VIB, 3000 Leuven, Belgium.; Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), 3000 Leuven, Belgium.; Department of Endocrinology and Metabolism, Amsterdam UMC, Research Institute Gastroenterology, Endocrinology & Metabolism (AGEM), University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

DOI: 10.3390/genes16030289

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MeSH Terms: Female, Humans, Male, Apolipoproteins E, Dyslipidemias, Macrophages, Pedigree, Splenomegaly