Overview

Hurler syndrome is a rare genetic condition caused by an enzyme deficiency in the body, with a major impact on overall development, and possesses life-threatening consequences. It is a lysosomal storage disease, and it represents a severe form of mucopolysaccharidosis type I (MPS I). This article focuses on the main aspects of Hurler syndrome, and enzyme replacement therapy (ERT), an incredible cutting-edge treatment that provides the missing enzyme for the body, attenuates the symptoms, slows down the disease progression, improves the quality of life, and prolongs the life expectancy. Challenges arise during the fight against this disease, but help and support are available for these patients and their families. 

Understanding Hurler syndrome

What is Hurler syndrome?

Let’s start by understanding lysosomal storage disorders, particularly, mucopolysaccharidosis type I (MPS I). The lysosomal storage disorders affect the cell components, called lysosomes, responsible for toxic waste management, a kind of “cell maintenance factory”. A problem with this vital cell system will cause toxic waste products to build up inside lysosomes, and create a “cascade” of consequences over the cells, organs, and the entire body. 

Hurler syndrome is a mucopolysaccharidosis, meaning it’s a type of lysosomal storage disease in which the toxic built-up materials are mucopolysaccharides (glycosaminoglycans – GAGs), complex sugar molecules. The specific sugar molecules involved in the disorder are dermatan sulfate and heparan sulfate.^2,3

Genetics and inheritance

Type I mucopolysaccharidosis is a rare, genetically inherited disorder. It is transmitted in an autosomal recessive manner with the child inheriting a defective gene copy from both parents. Consequently, the child’s pair of genes from a specific region on chromosome 4, responsible for protein production, lacks function and is unable to produce an important enzyme, called alpha-L-iduronidase (IDUA). In such case, both parents are called “carriers” of the mutation, they don’t have the disease, but they have the risk that 25% of their children will be affected, and 50% of their children will also be carriers of the genetic defect.^3,4

Symptoms 

Based on severity, type I mucopolysaccharidosis is divided into three syndromes:

• Hurler syndrome - the most severe one 
• Hurler-Scheie and Scheie  - attenuated (less severe) forms 

The progression of the disease is faster in Hurler syndrome and the affected children have:

• Serious symptoms early after birth
• Developmental and cognitive delay
• Develop life-threatening complications that can lead to death around the age of 1

The median survival for all MPS I patients is 11.6 years. The attenuated forms have higher life expectancy, symptoms are milder, and become visible between the ages of 2 to 6. Symptoms are given by the accumulation of glycosaminoglycans (GAGs) inside the cells and tissues. The physical appearance of these children is characteristic, their facial features show:

• Large head
• Big forehead
• Flat nasal bridge
• Large distance between the eyes
• Protruding eyes
• Full cheeks and lips
• Short neck

Further, they present:

• Skeletal abnormalities
• Short stature
• Spine and hip deformities
• Joint stiffness
• Limited mobility 

Neurologically, they present developmental delay and cognitive impairment according to disease severity. Individuals with Scheie syndrome have normal intelligence.

Other symptoms include problems with: 

• Heart 
• Respiration
• Hearing
• Vision
• Hernias
• Digestion
• Liver and spleen enlargement (hepatosplenomegaly)^3,4

What is enzyme replacement therapy (ERT)?

Enzyme replacement therapy (ERT) is an innovative medical intervention approved by the FDA in 2003, aiming to replace the missing enzyme from the body and therefore modify the genetic deficiency's root cause.⁵

The approved ERT for type I mucopolysaccharidosis is laronidase, intended for patients with Hurler and Hurler-Scheie syndromes, and moderate to severe forms of the Scheie syndrome.. Mild cases of Scheie syndrome and cases with important cognitive impairment might not benefit from the therapy. The enzyme is unable to reach into the brain (what is called the Blood-Brain-Barrier), or in poorly vascularised (blood-supplied) tissues, and will NOT improve:

• Cognitive function 
• Hearing
• Bone deformities
• Joint mobility
• Visual acuity (because of corneal opacification)^2,5

Although ERT has been used for many years to improve symptoms in Hurler syndrome, currently, ERT along with another intervention, called haemopoietic stem cell transplant (HSCT), is approved to treat, improve symptoms, and prevent disease progression. Sometimes the therapies are recommended to be administered together. Unfortunately, these therapies can not reverse development regressions or already damaged tissues. At present, HSCT is the treatment of choice for a child under the age of 2 years and a half, diagnosed with Hurler syndrome.^2,5,6

Mechanism of action

ERT modifies the root cause of the deficiency of alpha-L-iduronidase (IDUA), preventing the natural progression of MPS I. By using advanced genetics techniques (recombinant DNA technology), scientists created the missing enzyme in a Chinese hamster ovary cell line. This exogenous (outside of the body) enzyme is administered into the patient’s bloodstream, reaches inside the cells, and prevents complex sugar molecules (GAGs – dermatan and heparan sulfate) from building up and damaging tissues and organs.^5,6

Benefits of enzyme replacement therapy

Improving quality of life and daily functioning

ERT replaces the missing enzyme and “repairs” the metabolism of the cells, showing successful results in the:

• Liver
• Spleen
• Heart
• Respiratory function
• Growth and weight gain
• Joint mobility
• Urine health (lowered GAG levels) 

The reduction in hepatosplenomegaly, which improves breathing due to less upper airway restriction, and increased joint mobility change everyday life for the patients. They become more active, engage in more activities, and gain more independence in their daily routines, which significantly improves their quality of life.^2,5,7,8 

Slowing down disease progression

In the present, MPS I syndromes (Hurler, Hurler-Scheie, and Scheie) benefit from both, enzyme replacement therapy (ERT) and haemopoietic stem cell transplant (HSCT). They are administered separately or in combination, depending on the case particularities, and severity. These therapies are “disease-modifiers”, improving the symptoms, slowing down the disease progression, and prolonging life expectancy. A key factor in slowing down the disease progression is:

• Early detection
• Precise diagnosis
• Immediate treatment initiation

Replacing the missing enzyme prevents the accumulation of GAGs inside the cells, and further tissue damage, successfully impacting growth, motor development, and even cognitive status (when HSCT is administered early).^2,9

Administering Enzyme Replacement Therapy

Treatment schedule

Enzyme replacement therapy (ERT) is a lifelong treatment. It is administered intravenously, once or twice a week, depending on the patient’s particularities, needs, and case severity. Once initiated, the therapy must be administered continuously, strictly following the treatment schedule. ERT is not a cure, but respecting the treatment schedule maintains the replacement enzyme present in the body and prevents disease progression.⁵

Intravenous infusion     

ERT is commonly administered by intravenous infusions. At the beginning of the treatment, the therapy needs to be given in the hospital, because doctors need to closely monitor the patient's adverse reactions to the drug, and be able to intervene if necessary. Therefore, the patient and their families need to go to the hospital usually once a week and the administration takes 3 to 5 hours. Because most of the time patients tolerate the treatment well, doctors can approve home infusions and improve the overall experience regarding the weekly burden of taking the therapy.⁵

Challenges

Suffering from Hurler syndrome carries many difficulties for the patient, but also for their families (or caregivers). Challenges arise at every step of the way such as:

• Access to early detection
• Newborn screening
• Fast and precise diagnosis
• Immediate treatment initiation
• Treatment options
• Treatment response
• Adverse reactions
• Emotional burden

Everything varies from case to case, but society, health institutions, and support societies offer their help and support in various ways to improve patients’ outcomes. 

Financial implications        

Even though enzyme replacement therapy (ERT) and haemopoietic stem cell transplant (HSCT) are life-changer treatments and bring hope to Hurler patients, the costs of these therapies are overwhelming and families often need financial support. National health insurance, financial assistance programs, non-profit organizations, government programs, The National Organization for Rare Disorders (NORD), and community-based fundraising, can help patients access their treatment. 

• National MPS Society
• NIH. GARD. Genetic And Rare Disease Information Center

Adverse reactions     

ERT is considered a safe treatment and is well tolerated by the patients. Common reactions associated with the intravenous infusion are not severe and include: 

• Rash
• Hives
• Angioedema
• Nausea
• Vomiting
• Fever
• Chills
• Increased blood pressure
• Increased heart rate
• Runny nose
• Sneezing
• Difficulty breathing

These reactions usually resolve by stopping or slowing down the infusion. Doctors closely monitor the treatment and can administer antihistamines (allergy medication), antipyretics (medication to reduce fever), or corticosteroids (powerful anti-inflammatory drugs). Very serious adverse reactions, such as life-threatening anaphylaxis can also happen, so the doctor overseeing the ERT administration should be prepared to respond.^2,7

ERT anti-drug antibodies (ADAs)

ERT provides the missing enzyme in Hurler syndrome, however, this molecule is a stranger to the body, and, in most cases (up to 90%), the immune system will produce anti-drug antibodies (ADAs) against the enzyme. This immune response (ADA levels in the blood) is monitored by the doctors during the treatment, and studies show that they can interfere with the enzyme activity and influence, in a certain manner, the progression of the disease. As for now, the antibody levels decrease as the treatment continues, showing a certain tolerance from the immune system towards the therapy, but further studies are needed to understand their role better.^2,7 

Future directions and research

Current research aims to optimise ERT shortcomings, such as insufficient reach into the central nervous system, and its insufficient effect on cognitive impairment, heart, eyes, and bones. Studies also explore new delivery methods and assess the long-term effectiveness and safety of ERT.² 

Summary

Hurler syndrome is a severe type of mucopolysaccharidosis type I, caused by the deficiency of the enzyme called alpha-L-iduronidase (IDUA). This causes a major impact on the overall development of the affected child and possesses life-threatening consequences. Enzyme replacement therapy (ERT), is currently recommended, along with haemopoietic stem cell transplant (HSCT) to treat Hurler syndrome. By providing the missing enzyme for the body, the treatment attenuates the symptoms, slows down the disease progression, improves the quality of life, and prolongs the life expectancy. Clinical studies bring hope for a brighter future, addressing the present shortcomings of the available therapies, and exploring new treatment options using advanced technologies. Challenges arise continuously for the patients and their families, but connecting with support groups and organisations dedicated to Hurler Syndrome can provide valuable resources, information, and emotional support.