Hurler Syndrome - A Rare Genetic Disorder

Introduction:

Hurler syndrome, otherwise mucopolysaccharidosis type I (MPH I), is a severe, rare, and genetically inherited condition. It was earlier named gargoylism. Gertrud Hurler first described hurler syndrome in the year 1919. Hurler syndrome is one of the 11 mucopolysaccharidoses (MPS) disorders. This genetic lysosomal disorder occurs due to the absence of the enzyme alpha-L-iduronidase, which is responsible for the metabolism of glycosaminoglycans (GAG). The inability to degrade glycosaminoglycans may cause several organ system damages causing various symptoms like skeletal abnormalities, heart disease, characteristic facies, cognitive impairment, respiratory problems, and reduced life expectancy.

What Is Mucopolysaccharidosis?

Mucopolysaccharidosis consists of a group of metabolic disorders that occur due to the absence or abnormal functioning of lysosomal enzymes necessary for the breakdown of glycosaminoglycans (GAGs). Thus the collection of glycosaminoglycans (GAGs) in the cells, connective tissue, and blood vessels results in permanent cellular damage that affects physical abilities, appearance, and organ system functions.

What Is Hurler Syndrome?

Hurler syndrome is an autosomal recessive type I mucopolysaccharidosis (MPS) disorder. The underlying etiology behind this condition is the absence of an alpha -L iduronidase (IUDA) enzyme that degrades glycosaminoglycans (GAG). This results in the building up of heparan sulfate and dermatan sulfate in multiple tissues, leading to multisystem complications and, eventually, death. In addition, deposition of glycosaminoglycans (GAG) in the cells causes thickening and enlargement of various organs like the spleen, heart, muscles, liver, joints, connective tissue, and the central nervous system resulting in severe functional impairments. The signs and symptoms related to Hurler syndrome may vary depending on the mutations involving the alpha -L iduronidase (IUDA) enzyme and the consequent defect in enzyme activity. Based on that, mucopolysaccharidosis (MPS) type I is divided into three subtypes. It includes:

1. Hurler Syndrome (MPS I H) is a common and severe form of Hurler syndrome. Patients usually develop symptoms after birth and progress rapidly, leading to death within the first year of life.

2. Hurler - Scheie Syndrome (MPS I H-S) is usually diagnosed around two to six years of age. The affected individuals have mild cognitive impairment with life expectancy up to the late teens or early twenties.

3. Sheie Syndrome (MPS IS) - This is a mild and rare type of Hurler syndrome. The patients have normal intelligence and usually die before 25 to 39 years of age.

What Are the Causes of Hurler Syndrome?

Hurler syndrome is a recessive genetic condition (autosomal recessive). Mutations involving the IDUA gene are the main cause of Hurler syndrome. The IDUA gene provides instructions for the production of enzymes involved in the breakdown of glycosaminoglycans (GAGs). The lack of these enzymes leads to the accumulation of glycosaminoglycans inside the lysosomes and causes tissue damage.

What Are the Symptoms of Hurler Syndrome?

Babies with Hurler syndrome are unusually not born with specific signs and symptoms. Instead, most symptoms develop during the first year of life. The most common symptoms associated with Hurler syndrome are the following.

• Large head.

• Curved spine.

• Bulging forehead.

• Thick skin.

• Elongated skull.

• Flat nasal bridge.

• Joint stiffness.

• Speech problems.

• Hip deformities.

• Rough skin.

• Large tongue.

• Thick lips.

• Spaced dentition.

• Walking on toes.

• Broad hands.

• Knock-knees.

• Curved fingers.

• Short nose.

• Cloudy eyes.

• Dental problems.

• Ear infections.

• Weak neck.

• Abnormal facial appearance.

• Nasal discharge.

• Airway infections.

• Bad breath.

• Heart diseases.

• Walking difficulties.

• Diarrhea.

• Sleep apnea.

• Tingling feet or fingers.

• Umbilical and inguinal hernias.

• Enlarged spleen and liver.

• Retinal degeneration.

• Aortic valve disease.

• Corneal clouding.

• Airway obstruction.

How Can We Diagnose Hurler Syndrome?

Hurler syndrome can be diagnosed through physical, urine, and clinical examinations. The diagnostic tests used are:

• Urine tests for excess mucopolysaccharides in the urine.

• Prenatal diagnosis using chorionic villus sampling and amniocentesis.

• Genetic counseling.

• Enzyme assays.

• Genetic testing for IDUA gene changes.

• X-ray of the spine.

• Electrocardiogram (ECG).

• Urinary glycosaminoglycans levels.

• DNA analysis.

What Are the Treatment Options for Hurler Syndrome?

There is no specific cure for Hurler syndrome. The treatment options for Hurler syndrome focus on the management of complications and abnormalities.

The most commonly used therapeutic options for Hurler syndrome are the following.

• Enzyme Replacement Therapy

Aldurazyme (recombinant human alpha L-iduronidase) is given weekly as an intravenous injection. It reduces the number of stored carbohydrates in the cells and improves pulmonary mobility and function. It is used in patients with Hurler and Hurler-Scheie forms and moderate to severe symptoms in the Scheie form of Hurler syndrome.

• Hematopoietic Stem Cell Transplant (HSCT)

A hematopoietic stem cell transplant is considered the ideal treatment for patients under the age of two years. It involves replacing defective hematopoietic cells with donor-derived enzyme cells. It helps to reduce airway obstruction, hepatosplenomegaly, and cerebrospinal fluid pressure and improves cardiac functions, joint mobility, and hearing.

• Supportive Therapy

Additional supportive therapy for Hurler syndrome involves the management of symptoms and complications.

It includes:

• Hernia repair.

• Cardiac valve replacement.

• Adenotonsillectomy.

• Ventriculoperitoneal shunt.

• Spinal decompression.

• Carpal tunnel release.

• Speech therapies.

• Occupational and physical therapies.

• Hearing aids.

• Corneal transplants.

• Respiratory support using continuous positive pressure ventilation and oxygen supplementation.

• Medications for gastrointestinal symptoms.

• Pain-relieving medications.

• Newer Therapies

Various research is developing newer therapies for managing Hurler syndrome. It involves gene therapy using viral vectors to deliver the iduronidase enzyme (IDUA). Gene therapy has improved neurological and physical symptoms in study models. There are some complications to introducing this newer therapy to humans.

Conclusion:

Hurler syndrome is a rare, inherited condition due to the lack of the enzyme alpha-L-iduronidase (IDUA) in the body resulting from a gene mutation in the IUDA gene. This condition leads to the building up of glycosaminoglycans (GAG) in the lysosomes affecting multiple organs in the body. Hurler syndrome involves respiratory, skeletal, and cardiovascular complications with retarded mental and physical development of the child. The affected babies show very few signs of the disorder at birth, but later on, within a few months, the symptoms progress.