Hurler syndrome is a lysosomal storage condition that occurs due to mutations in the IDUA gene on chromosome 4, leading to a deficiency or absence of the enzyme alpha-L-iduronidase. This enzyme is responsible for breaking down glycosaminoglycans (GAGs) such as heparan sulfate and dermatan sulfate. Without it, these substances accumulate in tissues, leading to progressive damage to multiple organ systems, including the heart, bones, and brain.

What is Hurler Syndrome?

Hurler syndrome, also termed mucopolysaccharidosis type I, is an autosomal recessive disorder caused by alpha-L-iduronidase deficiency. Alpha-L-iduronidase is a lysosomal enzyme that breaks down glucosaminoglycans (GAGs) like heparin sulfate and dermatan sulfate; the absence of this enzyme results in a build-up of these substances in tissues. Deposition of these mucopolysaccharides leads to thickening and enlargement of various organs, which causes severe functional disability.¹

Types Of Mucopolysaccharidoses (MPSs)

Mucopolysaccharidosis type I is a spectrum of rare hereditary disorders that present as one of the following three forms. These syndromes are placed on the spectrum according to their severity. This syndrome is the most severe form and is present on one extreme of the spectrum. Scheie syndrome, being the least severe, falls on the other extreme. Hurler-Scheie syndrome is the intermediate form of the disease.

Hurler Syndrome (MPS IH)

Hurler syndrome, also called MPS IH, is the most severe form of the disease. Common symptoms of MPH IH are coarse facial characteristics, developmental delay, contractures, and cognitive impairment. These symptoms appear soon after birth and advance rapidly; patients usually do not live past one year.²

Hurler-Scheie Syndrome (MPS IH-S)

Hurler-Scheie syndrome is an intermediate form of MPSI that appears between 2 to six years of age. Children with Hurler-Scheie syndrome present with less coarse facial characteristics and usually live into their late teens or twenties. Death primarily occurs due to respiratory failure. Other clinical manifestations of children with MPS IH-S are:

Hepatosplenomegaly causes respiratory insufficiency.
Thickening of the meninges puts pressure on the cervical spinal cord and results in paralysis and sickness.³
Tendon contractures lead to toe-walking
Mild cognitive dysfunction

Scheie Syndrome (MPS IS)

Scheie syndrome is a rare and mild type of mucopolysaccharidosis. The symptoms of MPS IS are similar to those of Hurler syndrome and Hurler–Scheie syndrome, but cognitive function is preserved. The life expectancy of individuals with Scheie syndrome is 25 to 30 years.

Hurler Syndrome Symptoms

Symptoms vary from person to person and also differ in severity. Symptoms might appear in infancy and persist through adolescence. Delayed development during childhood and gradual reduction in a child’s ability to grasp information are the predominant symptoms of this syndrome. Other symptoms include:

Accumulation of cerebrospinal fluid around the brain, i.e., hydrocephalus
Abnormally enlarged organs like heart, connective tissues, liver, muscles, and spleen.
Hernias
Vision issues like glaucoma
Cardiac valve problems, i.e., cardiomyopathy
Difficulty breathing, respiratory infections, sleep apnea
Joint disorders (joint disease, spasticity, carpel tunnel)

Following are some physical features that indicate mucopolysaccharidosis type I in children. These symptoms become visible within a year after birth.

Short height
Extreme hair growth
Dysostosis Multiplex (Abnormal None Growth)
An excess curve in the upper spine that forms a rounded shape, i.e., kyphosis.

How Does Hurler Syndrome Affect A Child’s Body?

Hurler syndrome, previously known as gargoylism, is a congenital disorder of energy metabolism that affects the body’s growth and development. Symptoms are not present at birth but become visible during the first year of life. It can affect various systems of the body in the following ways:

General Appearance

Children who develop this syndrome have an enlarged head, coarse facial characteristics, broadly spaced eye sockets, and protruding frontal bones. Also, they have wide open eyes, flat nasal bridges, short and rigid necks, and enlarged lips.

Cardiac Manifestations

Deposition of mucopolysaccharides in coronary arteries leads to their narrowing, and the result is cardiomyopathy, valvular regurgitation, and heart failure. Children diagnosed with Hurler syndrome usually have a heart attack before 10 years of age. Regular evaluation of cardiac function is required to avoid complications.

Respiratory Manifestations

Upper and lower respiratory tract infections occur more frequently. Moreover, the thickening of the soft tissue of the airways causes obstruction and sleep apnea. Also, there are complications like cor pulmonale and pulmonary hypertension due to hypoxemia.⁴

Musculoskeletal Manifestations

Musculoskeletal abnormalities are evident in children with Hurler syndrome. Growth usually stops by the age of 2 years, leading to a short stature. Also, bone deformities, contractures, and stiffness limit mobility and cause pain.

Neurological Manifestations

Children with this syndrome have a developmental delay that affects their cognitive skills. Abnormal accumulation of GAGs in the spinal cord and meninges obstruct the CSF and results in convulsions.

Ocular Manifestations

This syndrome can cause structural abnormalities in collagen filaments and corneal stroma, resulting in corneal clouding and, ultimately, blindness. Compression of the optic nerve and retinal degeneration are also very common.

Gastrointestinal Manifestations

Deposition of GAGs in tongue muscles causes macroglossia, which causes problems with speech and swallowing.

What Causes Hurler Syndrome?

Hurler syndrome is a disorder that is inherited in an autosomal recessive pattern. This syndrome is caused by a mutation in the gene on chromosome 4 that contains instructions for the enzyme alpha-L-iduronidase.⁵ IDUA enzyme is present in lysosomes, where it participates in the breakdown of complex carbohydrates. Variations in IDUA genes result in deficiency or complete absence of this enzyme, which causes an abnormal build-up of GAGs in the body.

How Hurler Syndrome Is Diagnosed?

Your healthcare provider will recommend various tests during pregnancy and after the baby’s birth to diagnose this syndrome.

Prenatal Screening:

Antenatal diagnosis is based on prenatal screening, including chorionic villus sampling and amniocentesis. These tests detect any genetic abnormalities in the fetus and help suggest possible solutions before the baby’s birth. Prenatal screening is usually recommended for women with a family history of MPS.

Chorionic Villus Sampling

Chorionic villus sampling (CVS) is a prenatal screening test involving a placental tissue biopsy for early detection of genetic disorders. Your healthcare provider might recommend a CVS between the 10th and 12th week of gestation. The placenta is a tissue that provides nutrition and oxygen to the fetus. The chorionic villi are finger-like projections in the placenta that contain genetic material identical to that of the fetus.
Examination of chorionic villi helps detect chromosomal defects and other genetic abnormalities, particularly MPS-I. However, CVS does not provide details about neural tube defects. For this reason, women who go through CVS screening also need blood screening for neural tube defects.

Amniocentesis

Amniocentesis uses a small portion of amniotic fluid for screening genetic abnormalities.⁶ Amniotic fluid is a pale yellow fluid that surrounds the fetus and provides additional protection from infections and mechanical injuries. Your healthcare practitioner might suggest an amniocentesis between the 15th and 20th week of gestation if there is a greater risk of genetic defects. It will help identify any neural tube and inherited defects, including MPS I.

Physical Examination:

After birth, diagnosis is established on physical examination and enzyme activity assays. Babies born with Hurler syndrome have distinct physical features that indicate MPS I. Your medical practitioner might inquire about the family history, as this disease is congenital. Moreover, blood and urine analysis, an X-ray exam, and echocardiography are sometimes required to confirm diagnosis.

Hurler Syndrome Treatment

The treatment of Hurler syndrome is mainly symptomatic and focuses on preventing the symptoms from worsening. Treatment can extend the lifespan of mild forms of mucopolysaccharidosis. The following options are widely recognized for the treatment of Hurler syndrome.

Enzyme Replacement Therapy

Enzyme replacement therapy (ERT) helps restore impaired enzymes to avoid complications. Shortly after diagnosis, your healthcare provider will give your child a regular dose of the enzyme alpha-iduronidase. However, the dose frequency depends on the severity of the symptoms and is required for a lifetime.

Hematopoietic Stem Cell Transplant (HSCT)

Your healthcare provider will recommend an HSCT if your child has severe symptoms of Hurler syndrome. They will use chemotherapy to replace the disrupted cells with hematopoietic stem cells from a donor with functional enzymes. HSCT is recommended in children younger than two years. This therapy can increase lifespan, minimize somatic symptoms, prevent disease advancement, and restore cognitive function.⁷
Some other treatment options include:

Occupational, physical, and speech therapy
Employing hearing aids
Take medications to relieve pain
Surgery is needed to repair damaged body parts, like the replacement of cornea, bones, and heart valves, as well as the repair of hernias, etc.

Risks Associated With the Treatment Of Hurler Syndrome:

Some risks associated with surgical treatment of Hurler syndrome might worsen the symptoms. For instance, anesthetics administered for a surgical treatment might aggravate symptoms in individuals with breathing difficulty. Also, children with Hurler syndrome might have contractures, which makes it difficult for the healthcare provider to secure IV lines for administering drugs and other fluids during surgery.

Hurler Syndrome Prognosis

Children who are born with Hurler syndrome have a short life expectancy of about ten years. They have a poor prognosis because the disease adversely affects the lungs and heart. However, treatment with ERT and HSTC can increase the lifespan of mild cases of MPS-I up to 20 to 30 years.⁸ Early death occurs due to respiratory failure. Children with less severe symptoms and early diagnosis can continue a normal life with treatment.

Who is at Risk?

Hurler syndrome can develop in any child, as it is a consequence of random genetic mutations. However, parents with a family history of mucopolysaccharidosis are at a greater risk of having a child with Hurler syndrome.

Is It Possible to Prevent Hurler Syndrome?

Since Hurler syndrome is a genetic disorder, it is not possible to prevent it. However, you can reduce the risk of having a child with Hurler syndrome through genetic counseling and testing.

Hunter Vs. Hurler Syndrome

Hurler and Hunter syndrome both result from gene mutations and cause similar symptoms. However, the difference lies in their cause. Hunter syndrome occurs due to a deficiency in the iduronate-2-sulfatase enzyme, leading to the deposition of complex molecules in cells. On the other hand, Hurler syndrome results from alpha-L-iduronidase deficiency. Hunter syndrome is also called mucopolysaccharidosis type II (MPS II) disorder, while Hurler syndrome is Mph I disorder. Moreover, Hunter syndrome is an X-linked recessive disorder, compared to Hurler syndrome, an autosomal disorder. Symptoms of Hunter syndrome are less severe and become visible after two years.

Final Words

Having a child with Hurler syndrome is not easy, as it comes with many painful symptoms and a short life span. However, once diagnosed, it is important to regularly consult your child’s healthcare practitioner to negotiate possible treatment options. Timely diagnosis can help prolong your child’s lifespan with ERT and HSCT. Moreover, various support groups can provide emotional support and comfort during this phase.

Refrences

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Braunlin E; Steinberger J; DeFor T; Orchard P; Kelly AS; (2018) Metabolic syndrome and cardiovascular risk factors after hematopoietic cell transplantation in severe mucopolysaccharidosis type I (hurler syndrome), Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. Retrieved 03 April 2024 https://pubmed.ncbi.nlm.nih.gov/29409846/
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Horovitz DD; Magalhães Tde S; Pena e Costa A ; Carelli LE; Souza e Silva D; de Linhares e Riello AP; Llerena JC; (2011) Spinal cord compression in young children with type VI mucopolysaccharidosis, Molecular genetics and metabolism. Retrieved 03 April 2024 https://pubmed.ncbi.nlm.nih.gov/21813307/
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Harrison R; Schaefer S; Warner L; Mercer J; Jones S; Bruce I; (2018) Transnasal adenoidectomy in Mucopolysaccharidosis, International Journal of pediatric otorhinolaryngology. Retrieved 03 April 2024https://pubmed.ncbi.nlm.nih.gov/29958599/
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Mossman, J. (1981) Counselling following a diagnosis of congenital heart disease – Allan…https://obgyn.onlinelibrary.wiley.com/doi/abs/10.1002/pd.1071, Wiley online library. Retrieved 03 April 2024 https://obgyn.onlinelibrary.wiley.com/doi/abs/10.1002/pd.1071
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Navarro, C. et al. (2015) Bone Marrow Transplant in a case of Mucopolysaccharidosis I scheie phenotype: Skin Ultrastructure before and after transplantation – Acta neuropathological, SpringerLink. Retrieved 03 April 2024 https://link.springer.com/article/10.1007/BF00310920?error=cookies_not_supported&code=1c2efb36-adca-40ca-9283-881d23082fc6
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Aldenhoven, M. et al. (2015) Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: An international Multicenter Study, American Society of Hematology. Retrieved 03 April 2024 https://ashpublications.org/blood/article/125/13/2164/33988/Long-term-outcome-of-Hurler-syndrome-patients

Hurler Syndrome: Understanding Its Causes & Treatments

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