What is hurler syndrome?

Hurler syndrome is the most severe form of an illness called mucopolysaccharidosis type I (MPS I).¹

MPS I has three forms:¹ 

• Hurler (MPS IH, the most severe)
• Hurler-Scheie (MPS IH/S, the middle ground)
• Scheie (MPS IS, the mildest)

All forms of MPS I occur due to genetic mutations present from birth that cause the buildup of a natural compound in the body’s cells. This triggers complex cellular processes that impair the function of these cells and thereby the structures and organs of which these cells are part. In the case of Hurler syndrome (MPS IH), it leads to the early appearance of serious conditions that continuously get worse. If left untreated, one or several body organs will eventually stop functioning and result in death before the age of ten.^1,2

It is estimated that Hurler syndrome is found in approximately one newborn child for every 100.000 births in the UK. Hurler syndrome also appears to be the most frequent form of MPS I.³

Cause of hurler syndrome

The genetic origin of hurler syndrome

The specific genetic mutations causing Hurler syndrome are passed on from both parents to their children. The parents are not affected by it and most likely do not even know they possess these genetic mutations. These genetic mutations are found in the IDUA gene.^1,3 

Each of the parents of a child with Hurler syndrome has a ‘damaged’ IDUA gene with a certain mutation that causes Hurler syndrome and a fully functional IDUA gene that makes up for it. This fully functional IDUA gene is the reason the parents do not have Hurler syndrome. However, since they both carry the ‘damaged’ versions of the IDUA gene, they can pass them on to their offspring. If a child is lucky, it will receive at least one fully functional IDUA gene from its parents which means that it does not develop Hurler syndrome, just like the parents. If a child is unlucky, it will only receive the ‘damaged’ versions of the IDUA gene from the parents, resulting in Hurler syndrome.

This mode of inheriting a genetic illness is referred to as autosomal recessive inheritance, making Hurler syndrome an autosomal recessive disorder.^1,3,4

Consequence of IDUA gene mutation 

The IDUA gene allows the assembly of an enzyme called alpha-L-iduronidase. The mutations in the IDUA gene associated with Hurler syndrome result in the construction of a changed and thereby flawed alpha-L-iduronidase, completely unable to perform its function.¹ 

What is the function of alpha-L-iduronidase?

Under normal circumstances, the alpha-L-iduronidase enzyme breaks down natural compounds called glycosaminoglycans (GAGs) in a part of the cell called the lysosome.²  As it turns out, breaking down these GAGs is vital. A lack of functional alpha-L-iduronidase will result in the accumulation of GAGs in the cells. This GAG accumulation activates certain cellular processes which disrupt the function of these cells. Eventually, this will start impairing the function of the organs and structures these cells are part of, causing a variety of serious symptoms.^1,2

Consequences of hurler syndrome

Hurler syndrome is likely to have a negative impact on a multitude of different organs and structures.^5,6 It can affect:

• Facial features
• Bones including the spine
• Joints
• Eyes
• Ears
• Upper airway
• Heart
• Intestine
• Liver
• Spleen
• Brain 

Conditions and symptoms of hurler syndrome

Hurler syndrome can give rise to numerous conditions and symptoms, some of which are progressive (they become worse over time).^5,6

Coarse facial features

Coarse facial features mean that the lack of a sharp appearance of the nose, mouth, lips, brows and chin makes the face look round and heavy. This is due to a combination of the accumulation of GAGs in the soft tissue (muscle, fat and other tissues) and abnormalities of the facial bones.^5,7

Dysostosis multiplex

This describes a series of bone abnormalities characteristic of Hurler syndrome. Examples of bones which are affected are the rib and hip bones and the vertebrae of the spine.^5,8

Gibbus deformity

The Gibbus deformity is often seen in patients with Hurler syndrome. It describes an excessive forward curvature of the spine (kyphosis) which starts at a very specific place on the spine typical for Hurler syndrome The Gibbus deformity is attributed to growth defects of the vertebrae of the spine.^5,8

Short stature

Children with Hurler syndrome often exhibit a short stature.²

Heart problems

Hurler syndrome can alter the heart in several ways, causing a variety of heart-related conditions such as hypertrophic cardiomyopathy or dilated cardiomyopathy. The heart muscle (myocardium), the heart valves and the arteries providing nutrients and oxygen to the heart (coronary arteries) can be affected.^1,5,9

Brain alterations

Hurler syndrome regularly results in increased perivascular spaces (i.e. the space around the blood vessels, also called PVSs).¹⁰ PVSs are found in certain locations in the brain, surrounding the nearby blood vessels. They are filled with fluid and can be enlarged due to Hurler syndrome.⁵ 

Unfortunately, Hurler syndrome can also give rise to a condition known as hydrocephalus.⁵ It is characterised by an overabundance of a fluid called cerebrospinal fluid (CSF) in the skull. This results in an increased intracranial pressure (increased pressure inside the skull) which puts excessive pressure on the brain. Increased intracranial pressure can be one of the factors that result in the quickly decreasing cognitive functions (e.g. reasoning, thinking, remembering) of patients with Hurler syndrome.⁵

Additionally, the overabundance of CSF also leads to enlarged ventricles (ventriculomegaly) which is consistently found in children with Hurler syndrome.⁵ Ventricles are cavities in the brain where a large amount of CSF can be found. If too much CSF is present, the ventricles will expand, resulting in ventriculomegaly.

Delays in psychomotor development

Due to the effects Hurler syndrome has on the brain, it can also cause delays in psychomotor development.¹¹ This means it delays the development of the child’s mental capacities and motor skills.⁵ 

Impaired vision

The three parts of the eye that are most likely to be affected by Hurler syndrome are the cornea, the retina and the optic nerve.¹² The cornea is a transparent layer covering the front of your eye. Hurler syndrome can cause the cornea to lose its transparency, which is called corneal opacity or corneal clouding.¹²    

The retina is located at the back of your eye. It converts light into electric impulses which travel via the optic nerve to the brain. There, the electric impulses will be transformed into visual information to allow us to perceive our surroundings.

Hurler syndrome frequently gives rise to retinopathy (abnormal changes to the retina resulting in decreased function) and optic neuropathy (damage to the optic nerve).^12,13  Corneal opacity/corneal clouding, retinopathy and optic neuropathy all contribute to the deterioration of the eyesight of those afflicted by Hurler syndrome.¹²

Hearing loss

The hearing loss due to Hurler syndrome can be sensorineural, conductive or a mixture of both.¹⁴ Sensorineural hearing loss is due to defects impacting the inner ear or the nerve connected to it (auditory nerve). In contrast, conductive hearing loss is caused by problems with the outer and middle ear. 

Breathing problems

Children with Hurler syndrome frequently suffer from infections of the upper respiratory tract (infections of the sinuses and the throat) and rhinitis (irritated nose that is runny or blocked). Obstructive sleep apnea (having trouble breathing while sleeping due to an obstruction of the upper airway) is also common.⁵

Gastrointestinal issues

Hurler syndrome can cause hernias, hepatomegaly and splenomegaly.⁵ A hernia is when an organ pokes through a muscle or tissue that normally holds it in place. Umbilical and inguinal hernias are the two types of hernias strongly associated with Hurler syndrome.⁵

Furthermore, an enlarged liver (hepatomegaly) and an enlarged spleen (splenomegaly) are a common occurrence in people with Hurler syndrome.⁵

Summary

Hurler syndrome is the most severe and most frequent form of mucopolysaccharidosis type I. Hurler syndrome is caused by an inherited genetic defect that accumulates a natural compound called glycosaminoglycans (GAGs) in various cells across the body. This GAG accumulation sparks a number of cellular responses which result in the functional impairment of these cells. Over time, this cellular dysfunction will also affect the corresponding organs (such as the heart, the brain and the liver) and structures (such as bones and joints). This leads to severe conditions and symptoms, many of which become progressively worse. Without treatment, children with Hurler syndrome will succumb to the disease before they reach the age of ten.

FAQs

What are the symptoms of mucopolysaccharidosis?

Common symptoms and conditions include coarse facial features, impaired hearing, short stature, hydrocephalus, bone abnormalities and heart disease. 

What is the life expectancy with Hurler syndrome?

Without treatment, patients with Hurler syndrome do not live past their first decade of life. With treatment, life expectancy is extended, often significantly so. 

Who is most likely to get Hurler syndrome?

Only people whose biological parents both carry the relevant genetic defect can get Hurler syndrome. A family history of Hurler syndrome can indicate if a person is likely to carry the genetic defect.  

What are the symptoms of mucopolysaccharidosis type 1?

The symptoms and conditions caused by mucopolysaccharidosis type I are incredibly diverse. The most common ones include coarse facial features, valvular disease (disease affecting the heart valves), corneal opacity (clouding of the cornea of the eye) and an enlarged liver (hepatomegaly).