A Boy with Mucopolysaccharidosis Type II and Novel Variation

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A Boy with Mucopolysaccharidosis Type II and a Novel Heparan-N-Sulfatase Variation

Introduction

Mucopolysaccharidosis (MPS) disorders are rare, inherited lysosomal storage disorders. One of the types, MPS II (Hunter Syndrome), is caused by a deficiency of iduronate-2-sulfatase (IDS). In this study, we present a case of a Tibetan boy with MPS II who also has a novel variation in heparan-N-sulfatase (SGSH).

Patient Profile

The proband is a 10-year-old boy from a Tibetan family. He was born at home after 35 weeks of gestation with unclear birth weight and body length. He rarely cried or spoke. At 3 years old, his short stature was noticed. He had unusual facial features like a receding forehead, wide inter – eye distance, flat nose, full lips, and thick auricles. He also had contractures of distal inter – phalangeal joints (claw hands), a short neck, abnormal gait, umbilical hernia, and hearing loss. His speech was normal but he was not talkative. At 10 years old, he was severely growth – retarded (height: 113.1 cm, weight: 23.5 kg, head circumference: 55 cm). X – rays of the left wrist joints showed Madelung deformity and delayed bone age. Abdominal color Doppler ultrasound showed no hepatosplenomegaly despite obvious abdominal distension. He had no impaired mental or psychomotor development, and his parents were symptom – free.

Biochemical and Genetic Analyses

Biochemical analysis showed that the IDS enzyme activity in the proband was 2.10 nmol·mg⁻¹·4h⁻¹ (reference range >30 nmol·mg⁻¹·4h⁻¹), and the urinary polysaccharide toluene blue staining test was positive.

Genomic DNA was sent for analysis. Genes associated with MPS (I – VII) were screened. Two mutations were identified: a non – sense mutation c.1327C>T (p.R443X) in exon 9 of IDS and a novel variation c.616C>T (p.R206C) in exon 5 of SGSH.

Protein Structure and Function Analysis

Homology modeling was used to explore the impact of mutations. IDS is a monomer with a compact spherical a/b sandwich fold, divided into SD1 (N – terminal) and SD2 (C – terminal) domains. The mutation in IDS (c.1327C>T) led to the loss of residues after 443, resulting in a deficient SD2 domain. This significantly affected IDS enzyme activity. For SGSH, the variation (c.616C>T) replaced arginine residue 206 with cysteine. However, since the SGSH variation was heterozygous and unverified, its pathogenicity is unclear.

Discussion on Disease Severity and Mutation Impact

Developmental delay is a key feature of MPS II. This boy had significant growth retardation with a bone age of approximately 6.5 years. The severity of MPS II is mainly determined by the mutation type and cognitive impairment. Non – sense mutations like c.1327C>T (p.R443X) in IDS are associated with more severe phenotypes. This mutation causes a premature stop codon and loss of 107 amino acids from the C – terminus of IDS. The truncated protein retains the SD1 domain (catalytic core) but lacks important structural elements (twisted four – stranded anti – parallel b – sheet, short C – terminal a – helix, five helical turns, and two putative N – linked glycosylation sites). This destabilizes the protein structure and makes it susceptible to proteolytic cleavage. As a result, the patient may have a very low level of enzyme activity, causing an attenuated type of MPS II as reported in previous studies.

Conclusion

MPS II is the predominant form of mucopolysaccharidoses in China, and the IDS gene is its only pathogenic gene. Identifying IDS mutations is crucial for genetic counseling, prenatal diagnosis, and treatment. This study not only presents the clinical and genetic features of a MPS II patient but also explores the effect of the non – sense mutation in IDS on enzyme activity. The novel variation in SGSH (c.616C>T) requires further investigation to determine its pathogenicity.

References

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  2. Kosuga M, Mashima R, Hirakiyama A, Fuji N, Kumagai T, Seo JH, et al. Molecular diagnosis of 65 families with mucopolysaccharidosis type II (Hunter syndrome) characterized by 16 novel mutations in the IDS gene: genetic, pathological, and structural studies on iduronate – 2 – sulfatase. Mol Genet Metab 2016;118:190–197. doi: 10.1016/j.ymgme.2016.05.003.
  3. Tuschl K, Gal A, Paschke E, Kircher S, Bodamer OA. Mucopolysaccharidosis type II in females: case report and review of literature. Pediatr Neurol 2005;32:270–272. doi: 10.1016/j.pediatrneurol.2004.10.009.
  4. Demydchuk M, Hill CH, Zhou A, Bunkoczi G, Stein PE, Marchesan D, et al. Insights into Hunter syndrome from the structure of iduronate – 2 – sulfatase. Nat Commun 2017;8:15786. doi: 10.1038/ncomms15786.
  5. Zhang W, Xie T, Sheng H, Shao Y, Lin Y, Jiang M, et al. Genetic analysis of 63 Chinese patients with mucopolysaccharidosis type II: functional characterization of seven novel IDS variants. Clin Chim Acta 2019;491:114–120. doi: 10.1016/j.cca.2019.01.009.

DOI

10.1097/CM9.0000000000000426 (doi.org/10.1097/CM9.0000000000000426)

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