Mucopolysaccharidoses in Morocco: a 19-year retrospective study reveals a founder mutation in mucopolysaccharidosis type I and delineates the clinical spectrum

INTRODUCTION: Mucopolysaccharidoses (MPS) are lysosomal storage disorders characterized by distinctive dysmorphic features and skeletal abnormalities, with marked genetic heterogeneity across populations. Limited data exist on the MPS clinical spectrum and molecular characteristics in North Africa. METHODS: We conducted a retrospective study of 24 MPS patients followed at Mohammed V Military Hospital, Rabat, Morocco (2005-2023). Clinical phenotyping utilized Human Phenotype Ontology terminology. Biochemical analyses included urinary glycosaminoglycans and enzymatic assays. Molecular analysis comprised DNA sequencing of relevant genes. RESULTS: MPS I predominated (75%, n = 18), followed by MPS IV (17%, n = 4), and MPS III and VII (4% each). The consanguinity rate was 78% (first-degree: 72%). All 16 genotyped MPS I patients carried the homozygous p.P533R (c.1598C>G) mutation (100%), confirming a founder effect. Despite genetic homogeneity, phenotypic variability was observed: Hurler-Scheie intermediate phenotype (83.3%) versus severe Hurler (16.7%). Common features included coarse facial features (HP:0000280, 89%), dysostosis multiplex (HP:0000925, 94%), joint contractures (HP:0001371, 94%), hepatosplenomegaly (78%), and corneal opacity (HP:0007957, 100%). The median age at diagnosis was 4.0 years (range 1 month-13.5 years), with a median diagnostic delay of 3.0 years. CONCLUSION: This first comprehensive Moroccan MPS series establishes p.P533R as a major founder mutation in MPS I, with implications for targeted genetic testing and counseling in consanguineous North African populations. The phenotypic variability despite complete genetic homogeneity suggests modifier genes influence disease expression.