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MPSI Manifestations and Treatment Outcome: Skeletal Focus
Giada De Ponti1, Samantha Donsante2, Marta Frigeni3
1San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
Abstract:
Mucopolysaccharidosis type I (MPSI) (OMIM #252800) is an autosomal recessive disorder caused by pathogenic variants in the IDUA gene encoding for the lysosomal alpha-L-iduronidase enzyme. The deficiency of this enzyme causes systemic accumulation of glycosaminoglycans (GAGs). Although disease manifestations are typically not apparent at birth, they can present early in life, are progressive, and include a wide spectrum of phenotypic findings. Among these, the storage of GAGs within the lysosomes disrupts cell function and metabolism in the cartilage, thus impairing normal bone development and ossification. Skeletal manifestations of MPSI are often refractory to treatment and severely affect patients' quality of life. This review discusses the pathological and molecular processes leading to impaired endochondral ossification in MPSI patients and the limitations of current therapeutic approaches. Understanding the underlying mechanisms responsible for the skeletal phenotype in MPSI patients is crucial, as it could lead to the development of new therapeutic strategies targeting the skeletal abnormalities of MPSI in the early stages of the disease.
Insights
Mucopolysaccharidosis type I (MPSI) impairs bone development due to glycosaminoglycan buildup. Understanding MPSI
Area of Science:
- Genetics and Molecular Biology
- Skeletal Biology and Disease
- Lysosomal Storage Disorders
Background:
- Mucopolysaccharidosis type I (MPSI) is an autosomal recessive disorder caused by pathogenic variants in the alpha-L-iduronidase (IDUA) gene.
- Deficiency in alpha-L-iduronidase leads to systemic accumulation of glycosaminoglycans (GAGs).
- GAG accumulation disrupts cellular function, particularly in cartilage, impairing bone development and ossification.
Purpose of the Study:
- To review the pathological and molecular processes underlying impaired endochondral ossification in MPSI.
- To discuss the limitations of current therapeutic strategies for skeletal manifestations in MPSI.
- To highlight the importance of understanding MPSI's skeletal phenotype for developing targeted therapies.
Main Methods:
- Literature review of pathological and molecular mechanisms in MPSI.
- Analysis of existing therapeutic approaches and their efficacy for skeletal abnormalities.
- Synthesis of current understanding of MPSI's impact on endochondral ossification.
Main Results:
- GAG storage in lysosomes disrupts cartilage cell function and metabolism.
- Impaired endochondral ossification leads to significant skeletal abnormalities in MPSI patients.
- Current treatments often show limited efficacy in addressing the severe skeletal phenotype.
Conclusions:
- Understanding the molecular basis of skeletal defects in MPSI is critical.
- Further research is needed to develop novel therapeutic strategies targeting early skeletal abnormalities.
- Effective treatments for skeletal MPSI could significantly improve patients' quality of life.
