What is Hurler syndrome? |

Risk Factors

The US National Library of Medicine's Genetic Home Reference reported in 2014 that severe MPS I occurs in about 1 per 100,000 newborns; the incidence of attenuated MPS I is less frequent, occurring in approximately 1 in 500,000 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. Genetics Home Reference reports that, as of 2014, that more than one hundred distinct mutations of the IDUA gene (iduronidase, alpha-L-) have been identified. 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 age 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 amniotic fluid 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. Based on reports published up to 2011, 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.

Korf, Bruce R., and Mira B. Irons. Human Genetics and Genomics. 4th ed. Chichester: Wiley, 2013.

Lewis, Ricki. Human Genetics. 11th ed. [S.I.]: McGraw, 2014. Print.

Scriver, Charles. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. McGraw, 2007. Print.