Overview of hurler syndrome

Hurler syndrome is a rare genetic disorder and the most severe form of mucopolysaccharidosis type I (MPS1), of which there are eleven types, followed by the milder forms of Hurler-Scheie syndrome and Scheie syndrome.¹ MPS disorders are a collection of inherited metabolic diseases typically caused by the absence of certain enzymes our body needs to break down molecules called glycosaminoglycans – carbohydrates in cells that help with the formation of bone, skin, and cartilage, amongst others.² Individuals with MPS disorders have abnormalities in the production of one of the eleven enzymes needed to break down glycosaminoglycans.² The mucopolysaccharidoses are classified within a larger group of disorders called lysosomal storage diseases, which are conditions where molecules or unwanted cellular debris – that are normally broken down or degraded in intracellular compartments called lysosomes–are not cleared properly, and consequently accumulate around the body, leading to the onset of symptoms associated with the disease.²

In Hurler syndrome, there is an absence of alpha-L-iduronidase, an enzyme responsible for the degradation of glycosaminoglycans (GAGs or mucopolysaccharides).¹ This leads to the accumulation of certain GAGs, particularly dermatan sulphate (DS) and heparan sulphate (HS), in various tissues and organs throughout the body, leading to a wide range of symptoms that affect several body systems (i.e., multisystem disorder).³

Clinical presentation of hurler syndrome

The symptoms of Hurler syndrome commonly become apparent in the newborn or in infancy, and may include the following:

General appearance

• Coarse facial features¹
• Short neck¹
• Flat appearance of nasal bridge¹
• Short stature⁴
• Hirsutism (i.e., increased hair growth over most areas of the body)⁴

Body system-level abnormalities

• Intellectual disability⁴
• Hepatomegaly (i.e., enlarged liver)⁴
• Dysostosis multiplex (i.e., abnormal bone development)⁴
• Frequent ear, sinus and pulmonary infections¹
• Tissue thickening in the nose and tonsils¹
• Cardiomyopathy (i.e., abnormal structure and function of the heart muscle)⁴
• Structural defects of heart valve⁴

Diagnostic methods for Hurler syndrome

Hurler syndrome can be diagnosed through clinical examination and urine tests which involve measuring the levels of GAGs in urine, and if the test is positive, it is suggestive of MPS.¹ 

However, there is a risk of false-negative results (i.e., the test may indicate that the patient does not have the condition when they actually do). The gold standard tests for Hurler syndrome are enzyme activity assays which can identify enzyme deficiencies and help to distinguish Hurler syndrome from other types of MPS1.¹ Studies show that certain enzymes excreted in urine are characteristic of certain types of MPS disorders, and may form the foundation of further enzymatic analysis.⁷ Additionally, prenatal screening tests can identify genetic abnormalities in the unborn baby before birth. Tests like amniocentesis or chorionic villus sampling can diagnose Hurler syndrome in the child during pregnancy.¹ 

Amniocentesis

Amniocentesis is a procedure that can identify genetic defects in the baby, and it typically involves collecting a small sample of cells from amniotic fluid, which is the fluid that surrounds the baby in the womb.⁵ This procedure is usually carried out in the second trimester of pregnancy but can be done later if necessary. It involves inserting a long, thin needle into the abdominal wall, guided by an ultrasound image to visualise the process.⁵ The needle enters the amniotic sac surrounding the growing baby and a small sample of amniotic fluid is extracted for analysis. The test takes around 10 minutes to complete and some women may feel discomfort akin to period pain.

However, in some medical procedures, complications can occur. This is especially true for amniocentesis if it is carried out before 15 weeks of pregnancy.⁵

An alternative to amniocentesis is a test called chorionic villus sampling (CVS), which can also check for genetic defects in the baby. CVS is carried out a little earlier than amniocentesis and the risk of complications is still prevalent.

Chorionic villus sampling (CVS)

CVS involves removing a small sample of cells from the placenta, – an organ that connects the mother’s blood supply to the unborn baby’s. There are two common methods in CVS: transabdominal CVS and transcervical CVS (more common).⁶ Transabdominal CVS involves inserting a needle into the stomach while transcervical CVS involves inserting a tube or small forceps through the cervix.⁶

There are currently no reliable biomarkers for MPS disorders (i.e., molecules present in bodily fluid that can be used to confirm the presence of a disease). Urinary GAG levels are known to fall with treatment.⁷ An ideal biomarker would be specific to a type of MPS, and even more so, capable of differentiating severe forms from milder forms of the condition. However, certain biomarkers are currently being investigated as potential indicators of MPS disorders, including heparin cofactor II-thrombin complex (measured in serum).⁷

Management of hurler syndrome

Hurler syndrome management techniques focus on dealing with symptoms.

Enzyme replacement therapy (ERT)

Enzyme replacement therapy involves replacing missing or malfunctioning enzymes and can help prevent the worsening of the symptoms. Healthcare providers prescribe a synthesised version of alpha-L-iduronidase to replace this deficient enzyme in individuals with Hurler syndrome.¹ Patient outcomes are better if enzyme replacement therapy is carried out before symptoms get severe. This therapy is recommended for patients with Hurler syndrome as well as the other milder forms of MPS1. ERT is usually prescribed alone for patients with the milder forms of Hurler syndrome.⁸

Haematopoietic stem cell transplantation (HSCT)

Patients with Hurler syndrome, the severe form of MPS1, are often recommended for HSCT.⁸ Transferring donor-derived enzymes (that are normally deficient in patients with Hurler syndrome) from the healthy bone marrow of a compatible donor to the affected individual is considered a progressive form of replacing enzyme-deficient haematopoietic cells.¹ This is recommended for patients under 2 years of age as it can prolong life expectancy, preserve cognitive function and reduce symptom severity.¹ Haematopoietic stem cells are found in the bone marrow and can differentiate into cells that produce enzymes which the body needs to carry out many vital functions. A donor may donate healthy stem cells to a Hurler syndrome patient (recipient), allowing the patient’s body access to alpha-L-iduronidase (Aldurazyme), needed to improve skeletal function and other bodily processes.¹

Additional management options

Patients with Hurler syndrome may also undergo surgical procedures to alleviate symptoms, like replacing damaged or faulty heart valves and removing tonsils (i.e., tonsillectomy). They may also receive respiratory support such as continuous ventilation with oxygen, or cornea transplants to correct vision problems.¹

FAQs

How common is hurler syndrome?

Hurler syndrome is known to affect an estimated 1 in every 100,000 newborns. People assigned male at birth (AMAB) and people assigned female at birth (AFAB) are affected equally.

What is the life expectancy for hurler syndrome?

The average life expectancy for a person with Hurler syndrome is 11.6 years.

What are the long-term effects of hurler syndrome?

The treatment for Hurler syndrome plays a crucial role in symptom management. Without proper treatment, the severity of the symptoms will increase, leading to multisystem defects, such as intellectual disability, skeletal deterioration, visual and hearing impairments, and even death. 

What builds up in hurler syndrome?

In Hurler syndrome, unprocessed sugar molecules accumulate in the body, gradually affecting the brain, heart and other organs.

Summary

Hurler syndrome is a rare genetic disorder characterised by the absence or malfunctioning of alpha-L-iduronidase, an enzyme required to break down complex molecules called glycosaminoglycans (GAGs) in the body. If GAGs are not properly broken down, they can accumulate and cause damage to cells and tissues throughout the body, subsequently leading to the symptoms associated with this condition. Hurler syndrome is the most severe form of mucopolysaccharidoses (MPS), a group of rare inherited disorders characterised by deficient or absent enzymes needed to break down GAGs. Diagnosis of Hurler syndrome may occur during pregnancy through prenatal screening tests such as amniocentesis or chorionic villus sampling, or after birth in the newborn, like urine tests to measure levels of GAGs. There is no cure for Hurler syndrome, but management options exist to control its symptoms. Enzyme replacement therapy involves administering a synthetic version of the deficient enzyme alpha-L-iduronidase, which can reduce the severity of symptoms. Alternatively, Hurler syndrome patients may receive healthy cells from donors that produce alpha-L-iduronidase.