Abstract
Mucopolysaccharidosis type I (MPS I) is caused by the deficiency of α-l-iduronidase, leading to the storage of dermatan and heparan sulfate. There is a broad phenotypical spectrum with the presence or absence of neurological impairment. The classical form is known as Hurler syndrome, the intermediate form as Hurler–Scheie, and the most attenuated form is known as Scheie syndrome. Phenotype seems to be largely influenced by genotype. Patients usually develop several somatic symptoms such as abdominal hernias, extensive dermal melanocytosis, thoracolumbar kyphosis odontoid dysplasia, arthropathy, coxa valga and genu valgum, coarse facial features, respiratory and cardiac impairment. The diagnosis is based on the quantification of α-l-iduronidase coupled with glycosaminoglycan analysis and gene sequencing. Guidelines for treatment recommend hematopoietic stem cell transplantation for young Hurler patients (usually at less than 30 months of age). Intravenous enzyme replacement is approved and is the standard of care for attenuated—Hurler–Scheie and Scheie—forms (without cognitive impairment) and for the late-diagnosed severe—Hurler—cases. Intrathecal enzyme replacement therapy is under evaluation, but it seems to be safe and effective. Other therapeutic approaches such as gene therapy, gene editing, stop codon read through, and therapy with small molecules are under development. Newborn screening is now allowing the early identification of MPS I patients, who can then be treated within their first days of life, potentially leading to a dramatic change in the disease’s progression. Supportive care is very important to improve quality of life and might include several surgeries throughout the life course.
Highlights
The dual-receptor targeting of the HIRMAb–IDUA fusion protein provided the rationale for reversal of lysosomal inclusions in both somatic and central nervous system (CNS) tissues following chronic IV treatment of Mucopolysaccharidosis type I (MPS I) subjects with valanafusp alpha
Newborn screening (NBS) programs might vary the algorithms used for first-tier testing (DMF or MS/MS) and second-tier testing (GAG analysis and/or IDUA sequencing), but it is clear that regardless of the chosen methodology, affected infants will benefit from early intervention
The first successful therapeutic intervention was reported in 1980, and in 2003, intravenous replacement therapy with a recombinant enzyme became available. These therapeutic approaches transform the natural history of the disease, several problems remain, with unmet needs related to the CNS manifestations of the disease, the skeletal abnormalities, the heart valve problems, and the corneal clouding, among others
Summary
Despite being described by Dr Gertrud Hurler in 1919, two years after the description of the first cases of mucopolysaccharidosis (MPS) by Dr Charles Hunter, Hurler syndrome was classified as MPS. As some patients cannot be identified as having the severe Hurler phenotype (MPS IH) or as presenting the attenuated Scheie phenotype (MPS IS), an intermediate form called Hurler–Scheie syndrome (MPS IH-S) was proposed [3,4]. It is recognized that there is a severe phenotype that is relatively homogeneous and includes the patients with Hurler syndrome, and an attenuated phenotype that is quite variable and ranges from severe Hurler–Scheie cases to quite mild Scheie patients [5,6,7]. The current status of newborn screening and the genotype–phenotype correlations for this disease are discussed
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