What Is Hurler Syndrome

Hurler syndrome, also known as mucopolysaccharidosis I (MPS IH), stands as a rare and challenging genetic disorder characterized by its autosomal recessive inheritance pattern. This disorder belongs to the group of lysosomal storage disorders and currently lacks a cure. The condition arises from a deficiency in the lysosomal enzyme alpha-L-iduronidase, which is responsible for breaking down glycosaminoglycans (GAGs), complex sugar molecules. As a result of this deficiency, GAGs accumulate within various tissues and organs.

Delve deeper into the world of Hurler syndrome: explore its distinct subtypes, comprehend its array of signs and symptoms, explore potential risk factors, gain insights into its underlying causes, discover diagnostic approaches, and delve into the available treatment options. Your journey to understanding this complex syndrome awaits.

Overview

Once referred to as 'gargoylism,' Hurler syndrome, also designated as 'mucopolysaccharidosis type I' (MPS IH), falls within the category of lysosomal storage disorders. This disorder triggers the accumulation of glycosaminoglycans (GAGs), previously termed mucopolysaccharides, within lysosomes. Lysosomes function as cellular recycling units, responsible for disposing of cellular waste. However, the absence of the lysosomal enzyme alpha-L-iduronidase hinders GAG breakdown, accumulating these sugar molecules.

This accumulation subsequently gives rise to the accumulation of harmful substances in diverse cells and tissues throughout the body, culminating in the manifestation of Hurler syndrome and, ultimately, fatality.

The origins of Hurler syndrome trace back to its initial description by German paediatrician Gertrud Hurler in 1919, which accounts for its name.¹

Causes of hurler syndrome

As previously outlined, the fundamental cause of Hurler syndrome stems from a deficiency in the enzyme alpha-L-iduronidase. This enzyme deficiency arises due to genetic mutations or alterations in the DNA sequence of the IDUA gene, specifically located on chromosome 4. The inheritance pattern of Hurler syndrome adheres to an autosomal recessive mode, necessitating two mutated IDUA gene copies – one from each parent – for the condition to manifest.¹

Alpha-L-iduronidase's primary role is to dismantle glycosaminoglycans (GAGs), sugar molecules within the body.1 Yet, the scarcity of alpha-L-iduronidase activity results in the accumulation of GAGs, including dermatan sulfate and heparan sulfate, within cells, primarily lysosomes, reaching toxic levels. Consequently, lysosomes expand in size, prompting the enlargement and thickening of diverse tissues and organs, such as the heart, spleen, liver, muscles, connective tissues, joints, and the central nervous system. This disruptive process impedes optimal cell function, culminating in the subsequent symptoms characteristic of Hurler syndrome and, ultimately, death.

Signs and symptoms of hurler syndrome

The signs and symptoms of Hurler syndrome vary depending on severity level and the specific subtype of MPS I. ¹

MPS I has 3 different subtypes including:¹

Hurler syndrome (MPS IH): Among the eleven MPS disorders, this is the most prevalent and severe form. out of all the eleven available MPS disorders, this is the most common and severe form. 

The main symptoms include: 

Developmental Delays in Children Child developmental delays 

Cognitive decline 

Corneal clouding leading to vision impairment Corneal clouding and vision loss 

Recurrent ear infections leading to hearing loss: due to GAG accumulation of GAGs in the middle ear  

Pronounced Coarse facial features 

Enlargement of the liver and spleen (hepatosplenomegaly) Hepatosplenomegaly (enlarged liver and spleen) 

Cardiac and liver disease 

Protrusion of internal tissue or organ (hernia) Hernias (bulging of an internal organ or tissue)

Frequent respiratory infections and breathing challenges Respiratory infections, and breathing difficulties 

Skeletal irregularities (dysostosis multiplex), including short stature, joint stiffness, abnormal bone growth, and deformities in the spine and hips Skeletal abnormalities (referred to as ‘’dysostosis multiplex’’) e.g. short stature, joint stiffness, abnormal bone development, and/or spine and hip deformities 

Abnormal curvature rounding of the lower spine (referred to as ‘’Gibbus deformity) ’’)

Excessive hair growth 

Individuals affected by this variant of MPS I Patients with this form of MPS I often die within the first year of life.

It is important to note that Hurler syndrome shares similar symptoms with other MPS disorders, including Hunter syndrome (MPS II) and Sly syndrome (MPS VII)1.1 However, Hunter syndrome has a slower progression rate compared to Hurler syndrome and does not result in corneal irregularities abnormalities. On the other hand, Sly syndrome, on the other hand, mainly differs from Hurler syndrome as it in that it often leads to hydrops fetalis (accumulation of excess fluid in a newborn) and cognitive impairment. Results in hydrops fetalis (oedema oedema or excess fluid accumulation in a newborn baby) and mental retardation. 

Hurler-Scheie syndrome (MPS I H-S): An intermediate form of MPS I, typically diagnosed in children aged 2 to 6 years. Which is usually diagnosed in children aged 2 to 6 years old.

Main symptoms include: 

Facial features that are less coarse than MPS IH

Mild cognitive impairment 

Hepatosplenomegaly

Spondylolisthesis (displacement of one vertebra)(spondylolisthesis)

Kyphoscoliosis (an Abnormal curving or rounding of the spine)(Kyphoscoliosis)

Patients with this form of MPS I usually die in their late teens or early twenties due to respiratory failure stemming from hepatosplenomegaly. from respiratory failure due to hepatosplenomegaly. 

Scheie syndrome (MPS IS): A mild and rare form of MPS I, the Scheie syndrome gives rise to symptoms that are similar to Hurler syndrome and Hurler-Scheie syndrome. However, individuals afflicted with this form often retain normal cognitive function. ., but patients often have normal intelligence.

Patients with this form of MPS I die between the ages of 25 to 30 years old.¹

Management and treatment for Hurler syndrome

The primary approaches for managing and treating  Hurler syndrome include:

• Enzyme replacement therapy (ERT): This involves substituting the damaged alpha-L-iduronidase enzyme with a recombinant human form (Aldurazyme) via intravenous injections). The injection frequency depends upon symptom severity. 
• Hematopoietic stem cell transplant (HSCT): This technique involves replacing the alpha-L-iduronidase enzyme-deficient hematopoietic stem cells of patients with healthy hematopoietic stem cells from donors containing functioning alpha-L-iduronidase enzymes. HSCT proves particularly advantageous for children aged 2 years with Hurler syndrome, diminishing disease advancement, elongating life expectancy, and protecting cognitive function. 
• Surgery: These interventions include heart valve replacements, corneal transplantation, hernia repairs, and correction of bone growth anomalies, among others. 
• Physical, occupational, and speech therapies: These therapeutic modalities aid in enhancing physical abilities, promoting occupational skills, and refining speech and communication. 
• Hearing aids
• Continuous positive pressure ventilation with oxygen supplementation (CPAP): This is employed to provide respiratory support, including oxygen supplementation, to counteract respiratory infections and breathing challenges. 
• Medications: Utilized to alleviate pain and address gastrointestinal concerns.  

Innovative treatment avenues for Hurler syndrome encompass gene therapy.¹ This approach involves introducing a functional IDUA gene into the cells of individuals with Hurler syndrome using "viral vectors" or genetically engineered viruses for safe and targeted gene delivery.¹

Diagnosis

A diagnosis of Hurler syndrome is established by a healthcare provider through a series of sequential tests: 

1. Physical examination and medical history: The initial stage involves assessing the presence of Hurler syndrome symptoms and identifying potential occurrences of MPS I within the patient's family due to its genetic nature.
2. Enzyme activity assays (considered the gold standard): This entails quantifying GAG levels in the patient's urine utilizing specific enzyme assays to gauge alpha-L-iduronidase levels and definitively confirm the diagnosis. Enzyme assays play a crucial role in distinguishing Hurler syndrome from both Hurler-Scheie syndrome and Scheie syndrome. 

In addition to enzyme assays, diagnosis verification may involve blood and urine analyses, bone X-rays, and a cardiac echocardiogram (ultrasound assessment of heart function).

Diagnosis for Hurler syndrome can be improved significantly by utilising prenatal or newborn screening tests during pregnancy. These screening evaluations are designed to assess the baby's vulnerability to genetic anomalies. Notable prenatal screening methods for Hurler syndrome include: 

• Amniocentesis: This procedure involves analysing a small quantity of amniotic fluid, the protective fluid enveloping the fetus, obtained via a fine needle.
• Chorionic villus sampling (CVS testing): This technique involves testing a small cell portion from the placenta known as chorionic villi, which share the same genetic material (DNA) as the fetus.

FAQs

How can I prevent hurler syndrome?

Unfortunately, Hurler syndrome cannot be prevented as it is an inherited genetic condition. 

How common is hurler syndrome?

Hurler syndrome is a rare disorder, with research studies indicating an estimated prevalence of around 1 in 100,000 births being impacted by this condition.¹ The less severe variants of MPS I, namely Hurler-Scheie syndrome and Scheie syndrome, are thought to have an even more infrequent occurrence, with an incidence of approximately 1 in 500,000. 

Who is at risk of hurler syndrome?

Hurler syndrome can affect any child with a mutation in the IDUA gene without distinction based on gender, race, or ethnicity.¹ Consequently, individuals with a familial history of MPS I bear a heightened risk of being affected by the syndrome. 

What can I expect if I have Hurler syndrome?

Anticipate an unfavourable prognosis characterised by the gradual deterioration of symptoms and an average life expectancy of approximately 10 years. Nevertheless, the implementation of Enzyme Replacement Therapy (ERT) and/or Hematopoietic Stem Cell Transplant (HSCT) has the potential to substantially enhance life expectancy, enabling certain individuals to survive into their early 20s to 30s ². 

When should I see a doctor?

See a doctor immediately if you or your child experience:

• Indications suggestive of Hurler syndrome
• Hearing or vision impairments

If you or your child encounter the following situations, Dial  911 immediately or rush to the emergency room (ER):

• Breathing difficulties
• Irregular heartbeat 
• Manifestations of cardiomyopathy, such as heart thickening, enlargement, and rigidity, including instances of fainting.²

Summary

Hurler syndrome, a rare and incurable lysosomal storage disorder caused by IDUA gene mutations, disrupts enzyme function, leading to GAG accumulation and organ enlargement. It presents in three subtypes with varying severity. Hurler syndrome sufferers face cognitive impairments, while other subtypes maintain normal intelligence. Diagnosis involves prenatal screening or post-birth tests. Current treatments, including Enzyme Replacement Therapy and Hematopoietic Stem Cell Transplant, extend life expectancy. Seek medical help for symptoms or vision/hearing problems. Call 911 for fainting, heart, or breathing issues.