2026-06-13 | Unwrapping the Lysosomal Dysfunction: Clinical Imaging of Hurler’s Multisystem Impact
Hurler's syndrome is a rare lysosomal storage disorder caused by deficiency of lysosomal enzyme α-iduronidase. It follows an autosomal recessive pattern of inheritance, leading to progressive accumulation of Glycosaminoglycans (GAGs) within lysosomes, resulting in cellular damage and multiorgan dysfunction [1]. Individuals with mucopolysaccharidosis type I (MPS-I Hurler syndrome) cannot degrade GAGs such as dermatan and heparan sulphate, important components of extracellular matrix and cartilaginous tissues including heart valves and joints. Estimated global prevalence of Hurler syndrome is 1 in 100,000 live births usually in early childhood [2,3]. It is characterised by progressive multisystem involvement causing skeletal deformities, dental irregularities, coarse facial features, organ enlargement, and cardiovascular complications [4,5].
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2026-05-21 | Homozygous R383H variant in IDUA gene causing pericentric retinitis pigmentosa in attenuated mucopolysaccharidosis type I.
Biallelic variants in the IDUA gene are linked to Mucopolysaccharidosis type I (MPS I), a rare type I lysosomal storage disorder characterized by systemic manifestations of coarse facies, macrocephaly, hepatosplenomegaly, dysostosis multiplex, hearing loss, cardiac issues, airway involvement, hydrocephalus, and intellectual disability. Based on the age at which symptoms appear and the degree of intellectual impairment, MPS I can be categorized into Hurler, Hurler-Scheie, and Scheie syndromes. Here, we describe a patient with congenital onset familial dyschromatopsia, adult-onset pericentric retinitis pigmentosa, and cardiac valve disease requiring surgery. Retinitis pigmentosa panel testing showed a heterozygous pathogenic variant in ABCA4 (c.6729+5_6729+19del) gene and a heterozygous variant of uncertain significance (VUS) in AHI1 (c. 2971C>T, p. Arg991Cys) gene. Later, whole exome sequencing revealed a homozygous pathogenic variant in IDUA: c.1148G>A, p. Arg383His (R383H) and a pathogenic 35kb deletion of Xq28 (153418413_153453555) encompassing OPN1LW, TEX28P2, and OPN1LM gene. Iduronidase enzyme activity in blood leukocytes was 0.06 nmol/h/mg Prot (normal ≥2.06 nmol/h/mg Prot). The urine glycosaminoglycans were 23.7 mg/mmol of creatinine (normal <3.1 mg/mmol of creatinine). The homozygous variant of R383H in IDUA gene presents with attenuated MPS I with adult-onset retinitis pigmentosa and reduced iduronidase activity. Enzyme activity helps in interpreting genetic results, especially when there are multiple variants in different genes causing a similar phenotype, guiding appropriate systemic evaluation. This case also highlights the need for broader genetic testing when small panel results are negative despite a strong clinical phenotype.
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2026-05-15 | CSF GAG non-reducing ends in MPS IH after peripheral and brain-penetrating therapies: A model comparing IV non-targeted ERT and HCT.
Mucopolysaccharidosis type IH (MPS IH) is a lysosomal disease caused by insufficient L-iduronidase (IDUA), resulting in progressive accumulation of glycosaminoglycans (GAGs) in the central nervous system (CNS). Hematopoietic cell transplantation (HCT) replaces IDUA through cellular cross-correction, stabilizing the CNS. Intravenous (i.v.) enzyme replacement therapy (ERT) is also effective at reducing GAG accumulation; however, it is thought to inefficiently cross the blood-brain barrier. To compare the effect of i.v. ERT on GAG degradation in the CNS with the effect of brain-penetrant therapy, i.e., HCT, we measured cerebrospinal fluid (CSF) GAG non-reducing ends in patients with MPS IH who were ERT-naive (n = 33), received i.v. ERT prior to HCT (n = 34), or underwent HCT (n = 26). We found that CSF GAGs (cGAGs) were 33%-65% lower in patients exposed to i.v. ERT. One year after HCT, cGAGs declined to their lowest levels. There was no difference in cGAG levels between patients treated with i.v. ERT for 52 weeks after HCT and those treated for only 8 weeks after HCT. In summary, i.v. ERT can lead to a significant decrease in cGAGs prior to HCT, indicating that i.v. ERT may affect CNS biomarkers, which reach their lowest levels with a brain-penetrant therapy.
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