Hurler syndrome
Hurler syndrome, also known as Hurler's disease or mucopolysaccharidosis type I (MPS I), is a rare autosomal recessive genetic disorder characterized by the deficiency of the enzyme alpha-L-iduronidase. This deficiency leads to the accumulation of glycosaminoglycans (GAGs) in the body, resulting in progressive organ and tissue damage. Symptoms typically do not present at birth, but developmental delays become noticeable by the age of one, with progressive mental and physical decline occurring shortly thereafter. Common physical features include a large head, thickened lips, and skeletal deformities, while additional complications can involve hearing loss, heart issues, and respiratory diseases.
Diagnosis can be made through prenatal testing or enzymatic analysis of blood samples in infants. Although there is currently no cure, treatment options include allogeneic stem cell transplantation and enzyme replacement therapy, which can improve certain symptoms. Early diagnosis is critical for managing the condition and may help mitigate severe effects. Genetic counseling is recommended for families affected by Hurler syndrome, as both parents must be carriers of the mutated gene for a child to be affected.
Hurler syndrome
ALSO KNOWN AS: Hurler’s disease; mucopolysaccharidosis type I (MPS I); MPS I H; alpha-L-iduronidase deficiency; IDUA deficiency
DEFINITION: Hurler syndrome is an autosomal recessive genetic disorder that belongs to a group of diseases called mucopolysaccharidosis (MPS) and is the most severe of three overlapping syndromes known as MPS I. The syndrome is often classified as a lysosomal storage disease. Individuals with Hurler syndrome lack the enzyme alpha-L-iduronidase.
Risk Factors
The US National Library of Medicine Genetic Home Reference reported in 2023 that MPS I occurs in about 1 per 100,000 newborns. Both parents of an affected individual are carriers of a mutated IDUA gene (the gene that produces the alpha-L-iduronidase enzyme). Carriers produce less alpha-L-iduronidase enzyme than a normal individual; however, the enzyme level is sufficient for normal function.
Etiology and Genetics
Hurler syndrome is caused by a mutated autosomal recessive gene, which is located on the 4p16.3 site on chromosome 4. As of 2022, more than three hundred distinct mutations of the IDUA gene (iduronidase, alpha-L-) were identified in the Human Genetic Mutation Database (HGMD). The syndrome is characterized by the lack of the enzyme alpha-L-iduronidase, which is responsible for the degradation of complex sugar molecules known as glycosaminoglycans (GAGs), formerly known as mucopolysaccharides. GAGs are present in cells throughout the body and are constantly being produced. In normal individuals, GAGs are also constantly being broken down; however, in individuals without this enzyme, the GAG level increases, resulting in organ and tissue damage.
Affected children appear normal at birth; however, developmental delay is obvious by the age of one year. Mental development ceases between the ages of two and four. Progressive mental and physical decline follows, accompanied by dwarfism. Physical features are widespread and striking (typical patients bear a strong resemblance to one another). The head is large with a prominent ridge along the sagittal suture. The lips are thickened, the tongue is enlarged, and the teeth are peg-like. Many patients exhibit a gibbus (deformed spine) as well as other skeletal deformities. The hair and skin are thickened. The corneas are often clouded.
Symptoms
Widespread symptoms are present with this syndrome. Umbilical and inguinal hernias are common (many patients undergo a herniorrhaphy before the syndrome is diagnosed). Deafness is both frequent and variable in severity. Heart damage is common (valvular disease, coronary artery disease, and angina pectoris). Respiratory diseases are common. Severe intellectual disability is common; however, neurologic symptoms are highly variable.
Screening and Diagnosis
Prenatal diagnosis can be made before twelve weeks of gestation with chorionic villus sampling and measurement of alpha-L-iduronidase in the villi. At around sixteen weeks of gestation, the diagnosis can be made by amniocentesis. A direct assay of glycosaminoglycans in the can be made. A more reliable diagnosis can be made by analysis of fetal tissues and/or cultured skin fibroblasts; this step can be completed within eighteen days of the amniocentesis.
The diagnosis can be made in a newborn or young child via an enzymatic analysis of a blood sample. Carriers for Hurler syndrome can be identified by assay of alpha-L-iduronidase in leukocytes (white blood cells). Leukocytes of carriers have half the normal level.
Treatment and Therapy
Ongoing research and clinical trials are being conducted for Hurler syndrome. Allogeneic stem cell transplantation has been reported to be effective in preventing disease progression in Hurler syndrome patients. Success has also been reported using unrelated umbilical cord blood, bone marrow, or peripheral blood stem cells. In all cases, the success rate is highest when the transplantation is conducted at an early age.
Another treatment modality is hematopoietic stem cell transplantation (HSCT); however, transplanted children usually experience progressive growth failure after this procedure. A modest improvement in growth has been reported with growth hormone administration. In eighteen consecutive patients, enzyme replacement therapy was employed in conjunction with hematopoietic stem cell transplantation. Overall, the survival and engraftment rate was 89 percent; the rate was 93 percent for fifteen patients who received full-intensity conditioning.
Lorne A. Clarke and Jonathan Heppner reported for the online version of GeneReviews in 2011 that laronidase is licensed for use in the United States, Europe, and Canada as enzyme replacement therapy (ERT) for non-central nervous system manifestations of MPS I. ERT is well tolerated and capable of improving certain effects of the disease. Studies are ongoing of laronidase's effect on the progression of symptoms and its efficacy when started early in patients with attenuated forms of MPS I.
In animal models (mouse, dog, and cat), retroviral, lentiviral, adeno-associated virus (AAV), and even nonviral vectors have been used to successfully deliver the iduronidase gene. Human trials may be conducted in the near future.
Prevention and Outcomes
Prevention of Hurler syndrome can only occur with prenatal diagnosis (chorionic villus sampling or amniocentesis) and pregnancy termination if an affected fetus is found. Siblings of an affected child should be screened for carrier status. When these children reach maturity, a potential marital partner should be screened for carrier status. If the partner is not a carrier, there is no risk. If he or she is a carrier, then genetic counseling should be conducted. For children born with the syndrome, an early diagnosis is essential for reducing the severe impact of this syndrome.
Bibliography
Clarke, Lorne A., and Jonathan Heppner. "Mucopolysaccharidosis Type I." GeneReviews. Ed. Roberta A. Pagon, et al. Seattle: U of Washington, Seattle, 1993–2014. NCBI Bookshelf. Natl. Center for Biotechnology Information, 21 July 2011. Web. 25 July 2014.
Cummings, Michael. Human Heredity: Principles and Issues. 10th ed. Belmont: Brooks, 2014. Print.
Genetics Home Reference. "Mucopolysaccharidosis Type I." Genetics Home Reference. US NLM, 21 July 2014. Web. 25 July 2014.
Haldeman-Englert, Chad. "Hurler Syndrome." MedlinePlus. US NLM/NIH, 7 May 2013. Web. 25 July 2014.
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Voskoboeva, E. Yu, et al. "Mucopolysaccharidosis Type I in the Russian Federation and Other Republics of the Former Soviet Union: Molecular Genetic Analysis and Epidemiology." Frontiers Molecular Bioscience, 23 Jan. 2022, doi.org/10.3389/fmolb.2021.783644. Accessed 4 Sept. 2024.