Mucopolysaccharidosis Type I

Mucopolysaccharidosis type I is a rare inherited condition that affects many parts of the body, causing progressive damage to organs, bones, and tissues due to the buildup of complex sugar molecules inside cells.

Table of contents

• What is Mucopolysaccharidosis Type I?
• Types and Severity
• What Causes This Disease?
• How is the Disease Inherited?
• How Common is MPS I?
• Signs and Symptoms
• Diagnosis
• Treatment Options

What is Mucopolysaccharidosis Type I?

Alpha-L-Iduronidase Deficiency, IDUA Deficiency, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome

Mucopolysaccharidosis type I (MPS I) is a rare genetic disorder where the body cannot properly break down certain complex sugar molecules called glycosaminoglycans (GAGs), also known as mucopolysaccharides^[1]. These are large sugar molecules that help build connective tissue throughout the body, which supports and holds together other body parts and organs^[5].

MPS I is a lysosomal storage disorder, meaning that molecules build up inside special compartments within cells called lysosomes. Lysosomes normally digest and recycle different types of molecules, acting like the cell’s waste management system^[1]. When GAGs accumulate inside these lysosomes, the cells become enlarged and cannot function properly, causing progressive damage throughout the body^[2].

Types and Severity

MPS I was once divided into three separate conditions based on severity: Hurler syndrome (the most severe), Hurler-Scheie syndrome (intermediate), and Scheie syndrome (the mildest form). However, because there is significant overlap between these forms, doctors now typically classify MPS I into two main categories: severe MPS I and attenuated (less severe) MPS I^[1].

Children with severe MPS I generally begin to show symptoms within the first year of life and experience rapid disease progression. The condition causes profound intellectual disability that becomes apparent after age one or two years. Without treatment, children with severe MPS I typically do not survive beyond the first decade of life^[1].

People with attenuated MPS I typically develop milder symptoms that appear later in childhood, usually between ages three and ten years. The severity and rate of disease progression vary widely. Some individuals have normal intelligence and may only experience learning disabilities, while others face more serious complications. People with attenuated MPS I can have a normal lifespan, though many experience significant disability from progressive joint problems and heart and lung disease^[4].

The main difference between severe and attenuated MPS I is that the severe form causes major developmental delays during early childhood and significantly affects intelligence, with cognitive abilities declining over time. Attenuated MPS I may affect intelligence but not at the same severe rate^[3].

What Causes This Disease?

MPS I is caused by changes (mutations) in the IDUA gene. This gene provides instructions for the body to produce an enzyme called alpha-L-iduronidase, which is responsible for breaking down two specific types of GAGs: dermatan sulfate and heparan sulfate^[1].

When the IDUA gene is mutated, the body either produces no alpha-L-iduronidase enzyme or produces an enzyme that does not work properly. Without sufficient enzyme activity, dermatan sulfate and heparan sulfate cannot be broken down and instead accumulate within cells^[2].

The buildup of these substances increases the size of lysosomes, which is why many tissues and organs become enlarged in this disorder. Researchers believe that the accumulated GAGs may also interfere with other proteins inside the lysosomes and disrupt the normal movement of molecules within cells^[1].

How is the Disease Inherited?

MPS I is inherited in an autosomal recessive manner. This means that to have the condition, a child must inherit two copies of the mutated IDUA gene—one from each parent^[2].

Parents who each carry one copy of the mutated gene are called carriers. Carriers typically do not show signs or symptoms of MPS I. When both parents are carriers, there is a one in four (25%) chance with each pregnancy that their child will inherit both mutated genes and have MPS I^[11].

MPS I can affect any child since it results from genetic mutations that can occur randomly. However, if there is a family history of MPS I, the risk of having a child with the condition is increased^[3].

How Common is MPS I?

Severe MPS I occurs in approximately 1 in every 100,000 newborns. Attenuated MPS I is less common and occurs in about 1 in every 500,000 newborns^[1]. The condition affects males and females equally^[3].

Signs and Symptoms

Children with MPS I often have no signs or symptoms at birth, although some may have a soft bulge around the belly button (umbilical hernia) or in the lower abdomen (inguinal hernia)^[1]. As molecules continue to accumulate in cells, symptoms gradually appear. Babies may initially show little sign of the disease, but as cells sustain damage, symptoms become more apparent^[11].

The range of symptoms in MPS I is broad and can affect multiple body systems:

• Facial features: Individuals often develop distinctive facial characteristics described as “coarse,” including widely spaced eyes, a flattened nose bridge, thick lips, and a large tongue (macroglossia)^[1].
• Head and brain: Many people have an enlarged head (macrocephaly) and some develop a buildup of fluid in the brain (hydrocephalus)^[1].
• Vision and hearing: Clouding of the clear covering of the eye (cornea) is common and can cause significant vision loss. Hearing loss and recurrent ear infections are also frequent^[1].
• Respiratory system: The vocal cords can enlarge, resulting in a deep, hoarse voice. The airway may become narrow, causing frequent upper respiratory infections and brief pauses in breathing during sleep (sleep apnea)^[1].
• Heart: Heart valve abnormalities are common and represent a major cause of serious complications^[1].
• Abdomen: Many individuals have an enlarged liver and spleen (hepatosplenomegaly)^[1].
• Bones and joints: Short stature and joint stiffness (contractures) that affect movement are common. Most people with severe MPS I also have dysostosis multiplex, which refers to multiple bone abnormalities visible on X-rays. A curved lower spine (gibbus deformity) often appears within the first year^[4].
• Hands: Carpal tunnel syndrome develops in many children, causing numbness, tingling, and weakness in the hands and fingers^[1].
• Spine: Narrowing of the spinal canal (spinal stenosis) in the neck can compress and damage the spinal cord^[1].
• Development: In severe MPS I, developmental delay is usually present by age one year, and children eventually lose basic functional skills. People with attenuated MPS I may have normal psychomotor development in early childhood, though learning disabilities and psychiatric problems can appear later in life^[4].

Heart disease and airway obstruction are major causes of death in people with both severe and attenuated forms of MPS I^[1].

Diagnosis

The diagnosis of MPS I is established through a combination of clinical examination, laboratory testing, and genetic analysis^[4].

When MPS I is suspected based on symptoms, doctors will order tests to measure the activity of the alpha-L-iduronidase enzyme and check for elevated levels of glycosaminoglycans. The diagnosis is confirmed by detecting deficient activity of the enzyme in combination with elevated GAG levels^[4].

Genetic testing to identify mutations in the IDUA gene can also confirm the diagnosis and plays an important role in determining whether a person has severe or attenuated MPS I^[4].

In some places, newborn screening programs test babies shortly after birth for low levels of alpha-L-iduronidase. When the newborn screen flags for MPS I, follow-up testing is essential as soon as possible. Not all babies with an abnormal screening result will be diagnosed with MPS I, but early detection and treatment can help prevent or delay some symptoms^[5].

Treatment Options

While there is no cure for MPS I, several treatment approaches can help manage symptoms and slow disease progression. An essential first step is determining whether a person has severe or attenuated MPS I, as this influences treatment decisions^[4].

Enzyme Replacement Therapy (ERT): Laronidase (marketed as Aldurazyme) is an enzyme replacement therapy approved for treating MPS I. This treatment replaces the missing alpha-L-iduronidase enzyme to help break down accumulated GAGs. ERT has been shown to improve walking capacity and lung function^[9]. However, the therapy cannot reverse damage that has already occurred, making early treatment essential^[12].

Hematopoietic Stem Cell Transplantation (HSCT): Also known as bone marrow transplantation, HSCT is considered the standard of care for children with severe MPS I. This procedure has been successful in extending lifespan compared to untreated children, who typically die of heart and respiratory complications in the first decade of life. The outcome of HSCT is significantly influenced by how much disease damage has already occurred, emphasizing the importance of early diagnosis and treatment^[4]. However, bone abnormalities typically do not improve with HSCT^[9].

Supportive Care: Management of MPS I requires care from multiple medical specialists and includes:

• Physical therapy and range-of-motion exercises to limit progressive loss of joint movement^[9]
• Regular hearing assessments and management, as severe hearing loss affects about 70% of patients^[9]
• Surgical procedures as needed to address complications such as hernias, heart valve problems, or spinal cord compression^[9]
• Management of airway obstruction and breathing difficulties
• Treatment of recurrent infections

Children with MPS I often require multiple surgical procedures and need careful monitoring because of underlying respiratory and heart problems^[9].

Emerging treatments including gene therapy approaches are currently being studied in clinical trials, offering hope for improved future treatment options^[12].