Understanding Mucopolysaccharidosis Type I: The Role of IDUA Gene Mutations

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Last Updated: July 26, 2025

Introduction

Inside nearly every cell in our body are tiny “recycling centers” called lysosomes, which break down waste materials to keep the cell healthy. But what happens when these centers malfunction? This is the reality for individuals with Mucopolysaccharidosis Type I (MPS I), a rare and progressive genetic condition classified as a lysosomal storage disorder. The disease arises from a defect in a single gene—the IDUA gene—which prevents the body from breaking down complex sugar molecules called glycosaminoglycans (GAGs). This post explores the genetic and molecular foundations of MPS I, from its severe and attenuated forms to the latest treatment strategies, all through the lens of Sadaqat Ijaz’s in-depth thesis research.

Thesis Excerpt & Analysis

What is Mucopolysaccharidosis Type I and the IDUA Gene?

Mucopolysaccharidosis Type I is a rare, autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme alpha-L-iduronidase. This crucial enzyme is encoded by the IDUA gene. The alpha-L-iduronidase enzyme is responsible for the stepwise degradation of glycosaminoglycans (GAGs), specifically heparan sulfate and dermatan sulfate.

When an IDUA gene mutation leads to an absence or malfunction of this enzyme, these GAGs are not broken down. Instead, they progressively accumulate within the lysosomes of cells throughout the body. This buildup leads to widespread cellular damage, multi-organ dysfunction, and the chronic, progressive symptoms characteristic of MPS I. Symptoms typically begin to appear between 6 to 8 months of age in severe cases.

(Source: Ijaz, S. (2018). MOLECULAR CHARACTERIZATION AND COMPARATIVE GENOMIC STUDIES OF RECESSIVE METABOLIC DISORDERS RELATED GENES FAH, FBP1 AND IDUA. University of Veterinary and Animal Sciences, Lahore, Pakistan. Supervised by Dr. Muhammad Yasir Zahoor. p. 46.)

The Spectrum of Disease: Hurler vs. Scheie Syndromes in MPS I

Mucopolysaccharidosis Type I is not a single, uniform condition; it presents as a spectrum of severity. The disorder is sub-classified into three distinct phenotypes based on the severity of symptoms and the presence of central nervous system involvement.

Hurler Syndrome (Severe MPS I)

This is the most severe form of Mucopolysaccharidosis Type I.

• Onset: Symptoms appear within the first year of life and progress rapidly.
• Prognosis: Without treatment, survival beyond the first decade is rare due to cardiorespiratory complications and brain damage.
• Key Manifestations:
  • Hepatosplenomegaly (enlarged liver and spleen)
  • Coarsening of facial features
  • Corneal clouding
  • Severe skeletal deformities (dysostosis multiplex)
  • Developmental delay and cognitive decline

Scheie Syndrome (Attenuated MPS I)

This is the mildest form on the MPS I spectrum.

• Onset: Symptoms typically appear after the age of 5 and progress much more slowly.
• Prognosis: Individuals often have a normal life span, albeit with significant medical challenges.
• Key Manifestations:
  • Stiff joints and contractures (carpal tunnel syndrome is common)
  • Corneal clouding
  • Heart valve abnormalities
  • Normal cognitive function

An intermediate form, known as Hurler-Scheie syndrome, also exists, with symptoms appearing between 1 and 6 years of age and variable levels of cognitive impairment.

(Source: Ijaz, S., 2018, p. 48.)

The Genetic Basis of MPS I: The Impact of an IDUA Gene Mutation

The root cause of all forms of Mucopolysaccharidosis Type I is a faulty IDUA gene. Located on chromosome 4p16.3, this gene contains 14 exons that provide the blueprint for the 653-amino-acid alpha-L-iduronidase enzyme.

To date, over 200 different disease-causing mutations have been identified in the IDUA gene, including missense/nonsense mutations, deletions, insertions, and splicing variants. The type and location of the specific IDUA gene mutation often correlate with the severity of the disease. Mutations that result in a complete absence of enzyme activity typically cause Hurler syndrome, whereas mutations that allow for some residual enzyme function lead to the more attenuated Scheie or Hurler-Scheie phenotypes.

(Source: Ijaz, S., 2018, p. 50.)

Novel IDUA Gene Mutations in Mucopolysaccharidosis Type I

Sadaqat Ijaz’s research on Pakistani families identified three mutations, including a novel one not previously documented in scientific literature. A novel c.908T>C transition (p.L303P) was identified in two siblings with an attenuated form of MPS I without neurological complications.

• Pathogenicity: This mutation was predicted by multiple bioinformatics tools (Mutation-Taster, SIFT, PolyPhen-2) to be disease-causing and damaging.
• Structural Impact: The mutation replaces the amino acid leucine with proline at position 303. Proline is smaller and more rigid than leucine, creating an “empty space” in the core of the protein. This likely disrupts proper protein folding and function.
• Significance: Identifying novel mutations like this one is critical for expanding the global database of genetic variants, improving the accuracy of genetic diagnosis, and providing families with precise information for genetic counseling.

(Source: Ijaz, S., 2018, pp. 80, 123-124.)

Modern Treatment for Mucopolysaccharidosis Type I

While there is no cure for Mucopolysaccharidosis Type I, several treatments can manage symptoms and improve quality of life. The two primary therapeutic approaches are enzyme replacement therapy and hematopoietic stem cell transplantation.

Enzyme Replacement Therapy (ERT)

ERT involves the intravenous infusion of a recombinant form of the missing alpha-L-iduronidase enzyme (laronidase).

• Mechanism: The infused enzyme is taken up by cells, where it can help break down the accumulated GAGs.
• Effectiveness: ERT is most effective for the somatic (non-neurological) symptoms of MPS I and is the primary treatment for Scheie and Hurler-Scheie syndromes.
• Limitation: The enzyme cannot cross the blood-brain barrier, making it ineffective for treating the central nervous system damage seen in Hurler syndrome.

Hematopoietic Stem Cell Transplantation (HSCT)

HSCT is a more invasive but potentially superior treatment for severe Mucopolysaccharidosis Type I (Hurler syndrome).

• Mechanism: The patient receives stem cells from a healthy donor, which differentiate into cells that produce the functional IDUA enzyme. These enzyme-producing cells can migrate into the brain, addressing neurological decline.
• Effectiveness: To be effective, HSCT must be performed before the age of two, before significant irreversible cognitive damage has occurred.

(Source: Ijaz, S., 2018, pp. 52-53.)

Conclusion

Mucopolysaccharidosis Type I is a devastating lysosomal storage disorder, but one where molecular research has paved the way for meaningful intervention. The identification of a specific IDUA gene mutation is the key to an accurate diagnosis, predicting disease severity, and guiding treatment decisions. With therapies like enzyme replacement therapy and HSCT, the focus has shifted from palliative care to actively managing the disease, offering hope and improved outcomes for affected families.

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Disclaimer: Some sentences have been lightly edited for SEO and readability. For the full, original research, please refer to the complete thesis PDF provided in the initial prompt.

Author Bio: This analysis is based on the doctoral research of Sadaqat Ijaz, a specialist in Molecular Biology and Biotechnology from the University of Veterinary and Animal Sciences, Lahore, Pakistan. Her work provides critical insights into the genetic landscape of rare metabolic disorders.

How can we improve early diagnosis and access to advanced treatments for rare genetic conditions like MPS I, especially in developing countries? Share your thoughts in the comments below, and pass this article on to spread awareness.