Gargoylism

Signs and symptoms

Hurler syndrome is not apparent at birth; its signs emerge during early childhood, and the severity varies from one child to another. A first noticeable change, often appearing between three and six months of age, is a coarsening of the facial features. The head may become large with a prominent forehead, the skull elongated, and the nose flattened with a constant runny discharge. The eyes can be widely spaced and may bulge, while the lips grow large and the jaw may hang open.

Skeletal issues begin around six months but may not be obvious until ten to fourteen months, leading to painful spine and hip deformities, carpal tunnel syndrome, and stiff joints. Children grow normally at first but stop growing by age two, rarely exceeding four feet in height. Inguinal and umbilical hernias may be present at birth or develop soon after. Within the first year, clouding of the cornea and retinal degeneration can cause blindness.

The liver and spleen enlarge significantly due to GAG buildup, though they still function normally. Diarrhea and aortic valve disease are possible. Airway obstruction, often from abnormal neck vertebrae, and frequent respiratory infections are common.

Developmental delays become clear by age one or two, with a peak functional level of two to four years, followed by steady decline. Most children gain only limited speech. Death typically occurs before age ten.

Diagnosis

Diagnosis often can be made through clinical examination and urine tests, as excess mucopolysaccharides are excreted in the urine. Enzyme assays testing cells or body fluids in culture for enzyme deficiency provide definitive diagnosis. Prenatal diagnosis using amniocentesis and chorionic villus sampling can verify if a fetus carries a copy of the defective gene or is affected.

Genetic counseling can help parents with a family history determine if they carry the mutated gene. Mucopolysaccharidosis type I (MPS I) is divided into three subtypes based on severity: MPS-IH (Hurler syndrome) is the most severe, while MPS-IS (Scheie syndrome) and MPS-IHS (Hurler–Scheie syndrome) are milder. Because of substantial overlap, some sources consider these terms outdated and instead divide MPS I into severe and attenuated forms.

Treatment

While a complete cure for Hurler syndrome does not yet exist, several treatments can help manage the condition. Infusions of the enzyme iduronidase, sold as Aldurazyme, may boost lung function and movement while cutting down on the abnormal buildup of carbohydrates in the body. Surgery might be needed to correct misshapen hands and feet, and operations on the cornea can improve eyesight. Transplanting bone marrow or stem cells from umbilical cord blood are also options.

When marrow comes from a sibling or relative with matching HLA genes, it can greatly boost survival, thinking ability, and physical symptoms. A 1998 study found that children with a matched sibling donor had a 75% chance of living five years, compared to 53% with a non-sibling donor. However, graft versus host disease is a risk, especially with unrelated donors. For those without a suitable marrow donor, cord blood transplants from unrelated donors can also improve survival, reduce physical signs, and enhance cognition, though graft versus host disease remains a possible complication.

Research

Gene therapy for MPS I is being actively researched. In animal studies, the iduronidase gene has been delivered using retrovirus, adenovirus, adeno-associated virus, and plasmid vectors. Both mice and dogs with the condition have shown successful treatment. Most vectors correct the disorder in the liver and spleen, and high doses can also address brain effects.

This approach has improved survival, neurological function, and physical symptoms, though some treated animals developed unexplained liver tumors. If these safety concerns are resolved, gene therapy could become a future treatment option for humans. Sangamo Therapeutics, based in Richmond, California, is currently running a clinical trial for MPS I using zinc finger nuclease gene editing.

Did You Know?

• The IDUA gene has been mapped to the 4p16.3 site on chromosome 4.
• As of 2018, more than 201 different mutations in the IDUA gene have been shown to cause MPS I.
• In 1919, Gertrud Hurler described a syndrome involving corneal clouding, skeletal abnormalities, and intellectual disability; a similar disease had been described in 1917 by Charles A. Hunter.