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Mucopolysaccharidosis Type I (MPS 1)

Overview

Portrait of a Young Girl with signs of MPS smiling at the camera
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder resulting from deficiency of the enzyme α-L-iduronidase. Deficiency of this enzyme causes an accumulation of dermatan sulfate and heparan sulfate, which are known as glycosaminoglycans (GAGs). The accumulation of GAGs in the lysosomes, cellular cytosol, and extracellular matrix leads to progressive, multisystem organ damage.
Clinical variability among the mucopolysaccharidoses is broad. Historically, the most severe form of MPS I was classified as Hurler syndrome, whereas the intermediate form was called Hurler-Scheie syndrome, and the least severe form was called Scheie syndrome. More recently, the terms "severe" MPS I for Hurler syndrome and "attenuated" MPS for Hurler-Scheie or Scheie syndromes are preferred.
All individuals with MPS I require an extensive multidisciplinary team approach to care given the significant multi-organ system involvement associated with this condition.

Other Names & Coding

Hurler-Scheie syndrome Hurler syndrome Scheie syndrome
ICD-10 coding

E76.0, Mucopolysaccharidosis, type I

E76.01, Hurler's syndrome

E76.02, Hurler-Scheie syndrome

E76.03, Scheie syndrome

For further coding details, see ICD-10 for Disorders of the Glycosaminoglycan Metabolism (icd10data.com).

Prevalence

MPS I is a rare condition that is seen in all populations; there are no known ethnic predilections. The incidence of severe MPS I is estimated to be approximately 1:100,000, and the attenuated MPS I is even rarer. [Moore: 2008]

Genetics

MPS I is an autosomal recessive condition caused by inactivating mutations in the IDUA gene. This gene encodes the enzyme α-L-iduronidase. Mutation analysis is clinically available and will detect mutations in ~95% of individuals with MPS I. A genotype-phenotype correlation may identify those at risk for the more severe clinical manifestations. Parents of children with MPS I are obligate carriers of the condition and have a 25% chance of having other children with MPS I with a similar phenotype. Carriers do not have any known symptoms of MPS I. For further details about heterozygous carriers and genotype/phenotype correlations, see Missing link with id: 88d3be56.xml.

Prognosis

If untreated, individuals with a severe form of MPS I will experience progressive manifestations that begin early in life and often result in death by age 10. Individuals with attenuated MPS I usually experience onset of symptoms in childhood or adolescence and survival to adulthood is common. Individuals with an attenuated form still require stringent clinical management, particularly related to their cardio-pulmonary and skeletal manifestations.

Practice Guidelines

The following presents a consensus on the management and treatment of individuals with MPS I.

Muenzer J, Wraith JE, Clarke LA.
Mucopolysaccharidosis I: management and treatment guidelines.
Pediatrics. 2009;123(1):19-29. PubMed abstract / Full Text

Roles of the Medical Home

The medical home clinician may be the first to suspect this disorder and to approach the family about testing to confirm the diagnosis and the level of severity. The clinician can discuss potential therapeutic and treatment options for MPS I in a time-sensitive manner and help families weigh the benefits and risks related to enzyme replacement therapy (ERT), hematopoietic stem cell transplants (HSCT), and the many surgical interventions that may be recommended. Eventually, gene therapy may become available, which would require more extended consultation.
Once a diagnosis is established, coordination of selected MPS I therapies should be initiated by the medical home. In those with severe MPS I, establishing a collaboration with the transplant team is imperative for long-term care. For those with attenuated MPS I who elect to have ERT, initial infusions should be carried out in a hospital-based unit familiar with potential adverse events of enzyme replacement therapy. After at least 8 infusions and the placement of an indwelling catheter, the medical home can establish a relationship with the pharmaceutical company that supplies the recombinant enzyme and develop a plan with the metabolic genetics team and home health nursing to provide infusions in the home.
Given the rapid progression of the disease, assessments several times a year are indicated for children with severe MPS I. Those with the attenuated forms may also benefit from frequent visits, though the need will depend upon their clinical status. Because of the extensive and widespread organ system involvement, every child with MPS I should receive multidisciplinary and subspecialty care from a center with expertise in lysosomal storage disorders.

Clinical Assessment

Overview

Children with MPS I have progressive multisystem organ involvement, as well as growth and developmental delays, making initial diagnosis somewhat complicated and necessitating a thorough approach with consideration of age-dependent onset of symptoms and signs. See Table 1 (page 3 of the pdf) in Mucopolysaccharidosis I: Management and Treatment Guidelines (AAP) (PDF Document 344 KB) for a recommended schedule of assessments.

Pearls & Alerts for Assessment

Elevation of urinary glycosaminoglycans (GAGs) is not specific to MPS I

Definitive diagnosis of MPS I requires demonstration of deficient activity of the lysosomal enzyme α-L-iduronidase in peripheral blood leukocytes or cultured fibroblasts.

Anesthesia in individuals with MPS I is very risky

Airway management during anesthesia in individuals with MPS I is difficult and should be performed by anesthesiologists aware of the significant risks associated with sedation, such as airway compromise and cervical joint limitation secondary to GAG accumulation. In treated patients, these high risks abate somewhat with decreased accumulation of airway GAGs.

Signs of hydrocephalus/intracranial pressure may be subtle

A rapid increase in head circumference, acute behavioral changes, or headaches could be signs of hydrocephalus. If they are present, an ophthalmologic assessment of the optic nerve, brain MRI, and lumbar puncture with measurement of opening pressure of cerebrospinal fluid (CSF) are helpful in assessing the degree of pressure elevation. On MRI, the ventricles can be resistant to volume changes with increased pressure due to GAG accumulation in the intracranial arachnoid and meningeal membranes.

Carpal tunnel syndrome

Finger tingling and pain with children chewing on fingertips could represent carpal tunnel syndrome with median nerve entrapment.

Risk for spinal cord compression

Because of the risk for ligamentous laxity and vertebral hypoplasia leading to spinal cord compression, parents/patients should be instructed to avoid "high-risk" activities, such as contact sports, and should be cautioned about manipulation of the cervical spine.

Screening

For the Condition

The clinical manifestations of MPS I may not become evident until the child is a few months to a few years of age; therefore, screening in early childhood is not indicated unless a family member is affected. When there is suspicion of MPS I, measurement of urinary excretion of glycosaminoglycans (GAGs) is a non-invasive way to evaluate the condition. An elevation of urinary GAGs is a strong indication of an underlying mucopolysaccharide disorder. The pattern of GAG excretion should be compared to the patterns seen in each of the MPS disorders. If consistent with an MPS, confirmatory enzyme testing should be performed. Genotype confirmation after enzyme analysis is preferred.
Newborn screening has been implemented in a number of states, including Utah in 2019, and is under consideration in other states where it will likely be added to the Newborn Screen Panel.

Of Family Members

Any sibling of an individual with confirmed MPS I should have an enzyme screening and/or genetic testing (if the mutations in the family have already been identified) at birth so that treatment may be discussed and initiated as early as possible. Those with severe MPS I should be offered hematopoietic stem cell transplant, whereas those with the attenuated form should begin enzyme replacement therapy (ERT) as soon as possible.
Carrier screening of parents and other family members via enzyme analysis is not recommended since there can be significant overlap in enzyme levels between carriers and non-carriers. Carrier screening via molecular genetic testing is indicated in family members if the mutations within the family are known.

Presentations

Infants with severe MPS I (Hurler syndrome) frequently appear normal at birth, though they may have inguinal or umbilical hernias. Coarsening of facial features with increased body hair, thoracolumbar gibbus, and enlargement of the liver and spleen occur over the first few months leading to diagnosis usually by 18 months. Within the first year, skeletal deformities, joint stiffness, and developmental delay may become apparent. Chronic otitis media is common, and if anesthesia is required for surgical intervention for ear tubes or hernia repair, an alert anesthesiologist can identify those with increased GAG accumulation of the airway. Individuals with the attenuated forms of MPS I are typically diagnosed in early childhood or adolescence and have a slower progression of disease. Often, joint contractures of the hands are initially noted. If a combination of these features is suspected, measurement of urinary excretion of glycosaminoglycans (GAGs) is a noninvasive way to rule out the condition.
Manifestations observed include:
  • Frequent upper airway infections with otitis media
  • Hepatosplenomegaly
  • Corneal clouding
  • Cardiac involvement, valve disease
  • Skeletal dysplasia (dysostosis multiplex)
  • Growth delay
  • Profound neurological involvement (in the severe form only)
  • Macrocephaly

Diagnostic Criteria

Diagnosis of MPS I is established by:
  • Confirming deficiency of α-L-iduronidase in peripheral blood leukocytes or cultured fibroblasts
  • Molecular genetic testing for mutations in IDUA, the gene that encodes α-L-iduronidase

Clinical Classification

Traditional classifications of MPS I, Hurler, Hurler-Scheie, and Scheie syndromes do not reflect the wide variation in clinical findings. Manifestations often overlap between categories. The disease is best characterized as either severe or attenuated MPS I.
Severe MPS I (formerly Hurler syndrome): Infants may appear normal at birth. Coarsening of facial features and enlargement of the liver and spleen occurs over the first few months. If untreated, death occurs in the first decade. The following features are usually present at an early age:
  • Skeletal deformities including gibbus and distinctive radiographic findings
  • Obstructive airway disease
  • Progressive and severe physical problems
  • Communicating hydrocephalus
  • Limited language ability and progressive mental deterioration
  • Hepatosplenomegaly
  • Recurrent ear/nose infections
  • Multiple hernias; umbilical and inguinal
  • Coarse facial features with increased body hair for family background
Attenuated (formerly Hurler-Scheie syndrome): If development is normal at 24 months of age and moderate somatic involvement is evident (mild coarsening, little skeletal involvement), individuals are classified as having intermediate severity. The onset of symptoms tends to occur between 3–8 years of age. Cognitive impairment may be present to a lesser extent; however, rapid and progressive cognitive decline is not characteristic of the attenuated forms. If intellectual decline is present, it tends to follow a more gradual course occurring at a later age and over a longer period of time. Cardiac involvement and upper respiratory tract obstruction contribute to mortality (often in teens or early twenties). Individuals with attenuated MPS I have progressive somatic involvement, including:
  • Dysostosis multiplex
  • Arthropathy
  • Corneal clouding
  • Joint stiffness
  • Hearing loss
  • Cardiac involvement, including valvular heart disease
  • Spinal cord compression
  • Obstructive airway disease
Attenuated (formerly Scheie syndrome): Often diagnosed in adolescence or young adulthood, individuals generally have normal intellect and a longer lifespan. Major clinical manifestations are:
  • Corneal clouding
  • Sleep apnea
  • Arthropathy and joint stiffness
  • Carpal tunnel syndrome and other nerve entrapment (such as cervical cord compression)
  • Valvular heart disease
  • Visual impairment
  • Mild facial coarseness
  • Spinal cord compression
The overlap of attenuated forms of MPS I makes it difficult to separate Scheie syndrome from Hurler-Scheie syndrome. It may be easier to reflect the continuum and simply state either more- or less-attenuated, primarily based on age of clinical presentation.

Differential Diagnosis

Individuals with other lysosomal storage disorders, such as Hunter syndrome, multiple sulfatase deficiency, and I-cell disease, can have features similar to those found in individuals with MPS I. Clinical and biochemical enzyme assays distinguish these conditions. Beckwith-Wiedemann syndrome presents with macroglossia and umbilical hernia, which can be in the differential diagnosis.

History & Examination

See Table 1 (page 3 of the pdf) in Mucopolysaccharidosis I: Management and Treatment Guidelines (AAP) (PDF Document 344 KB) for a recommended schedule of assessments.

Current & Past Medical History

In the patient’s history, it is important to note the age and presentation of the first symptoms. Typical clinical findings at various ages include:
  • 0 - 6 months
    • Chronic rhinitis
    • Recurrent otitis media or "glue ear" with thick cerumen
    • Umbilical or inguinal hernia
    • Above normal growth and head size
    • Gibbus of the thoracolumbar spine
  • 6 months -12 years
    • Distinctive facial gestalt, with coarsening over time
    • Hepatosplenomegaly
    • Skeletal deformities
    • Joint stiffness - especially distal interphalangeal and elbow joints
    • Developmental delay
    • Corneal clouding
    • Chronic rhinitis
    • Recurrent otitis media or "glue ear"
  • 12+ years
    • Corneal clouding
    • Joint stiffness
    • Valvular heart disease
    • Cardiopulmonary disease with easy fatigue
Assess caloric intake, feeding problems, and time required for feeding.

Family History

A detailed family history should be obtained. Questions that may help elucidate the presence of other affected individuals include:
  • Are there any individuals with developmental delays, regression, or learning problems?
  • Any children who died at a young age?
  • Any individuals with joint problems? Pain, tingling, or numbness in the hands or difficulty with fine motor skills? (It may signify carpal tunnel syndrome.)
  • Any individuals with heart problems? Recurrent ear infections or chronic rhinitis?
  • Which ethnicities exist in the family?
  • Are the parents related to each other (consanguinity)?

Developmental & Educational Progress

Monitor developmental milestones closely, especially in children with severe MPS I, as this will help determine a recommended treatment option. Individuals with the attenuated forms of MPS I may have normal to mildly delayed development. Intelligence in individuals with attenuated MPS I can range from normal cognition to mild learning disabilities. Baseline cognition and mental status should be carefully assessed; acute changes in cognition or mental status should be promptly evaluated because this may represent increased intracranial pressure due to hydrocephalus that is not easily determined by imaging because GAG accumulation in the intracranial membranes attenuates ventriculomegaly.

Social & Family Functioning

Ask about the child's social abilities, interactions with other children, and about family functioning (including the availability of resources and supports from community groups and extended family).

Physical Exam

A physical exam is recommended every 6 months. See Table 1 (page 3) in Mucopolysaccharidosis I: Management and Treatment Guidelines (AAP) (PDF Document 344 KB) for a recommended schedule of assessments.

General

Look for coarsening of facial features resulting in a remarkably consistent appearance that involves a short nose, flat face, thick lips and gums and large head (relatively elongated front to back with a prominent forehead). The eye sockets are shallow, the eyes protrude slightly, and the tongue is large. Body hair is coarse and abundant. Patients have protruding bellies and joint contractures, which cause them to stand and walk with a bent-over stance. Patients with milder forms of MPS I have normal facial features but a stocky build, a trunk that is shorter than the limbs, and a shortened, stiff neck.

Vital Signs

Pursue any respiratory distress with concern about aspiration, cardiac failure, or respiratory muscle compromise.

Growth Parameters

Children with severe MPS I may have above-normal growth and head circumference in the first 6 months of life; however, look for growth to plateau and diminution of linear growth by 3 years. Assess weight and length/height.

Skin

Tough, thickened skin in individuals with MPS I often makes needle sticks difficult. Examine optic nerve for compression and atrophy.

HEENT/Oral

Close-up of a child's face showing Corneal clouding
Chronic and recurrent ear infections are common. Assess basic auditory skills. Look for upper airway obstruction, since the trachea becomes narrowed and may be floppy or softer than usual, due to abnormal cartilage rings. Assess swallowing. Examine the mouth for signs of infection and tooth decay. Gum cysts can lead to dental crowding.
Corneal clouding (image, left) occurs in all individuals with MPS I, and its presence should be documented.

Heart

Stenotic or regurgitant murmurs are common, secondary to GAG accumulation in cardiac valves (primarily aortic and mitral valves). Check for tachycardia, which may be present due to aberrant conduction pathways. Absence of a murmur on physical exam does not exclude cardiac involvement. Echocardiograms are needed to assess valve stenosis, regurgitation, and ventricular function.

Abdomen

Protruding abdomen and inguinal or umbilical hernias may be present. Hepatosplenomegaly is common in children and adolescents.

Extremities/Musculoskeletal

Contractures of small and large joints and gibbus deformity of the spine are very common in the early stages of MPS I. Assess for joint stiffness (elbows with lack of supination/pronation range of motion, shoulders with inability to fully extend arms over the head, hand limitations, and contractures (initially present in the fingers resulting in the characteristic "claw-hand"); limited hip abduction and genu valgum. Assess grip strength and thenar muscle atrophy, related to carpal tunnel syndrome. (See Missing issue with id: 479f4eb8.xml.)

Neurologic Exam

Progressive compression of the spinal cord with resulting cervical myelopathy is relatively common in older individuals. Communicating hydrocephalus may occur without ventriculomegaly, due to the thickened arachnoid membrane. Presence of acute behavioral changes, headaches, and vomiting should trigger an evaluation of hydrocephalus.

Testing

Sensory Testing

Assess on a regular basis:
  • Hearing and speech discrimination
  • Visual acuity, including peripheral vision
  • Fingertip touch

Laboratory Testing

Baseline and serial measurement of urinary GAGs are useful for assessing response to ERT and/or HSCT.

Imaging

Brain and spine imaging with MRI provides a baseline for ongoing evaluation that is performed every 2-3 years to evaluate hydrocephalus and spine stability. Nerve conduction studies may be helpful to assess carpal tunnel syndrome. Skeletal survey should be performed at diagnosis to assess for signs of dysostosis multiplex, a combination of skeletal abnormalities on X-ray imaging, which is highly concerning for MPS 1.

Genetic Testing

Molecular genetic testing for mutations in IDUA, the gene that encodes α-L-iduronidase, can be used for confirmatory diagnostic testing, carrier testing, prenatal diagnosis, and genotype-phenotype correlations with certain types of mutations. Mutation detection rate in affected individuals is approximately 95%. Mucopolysaccharidosis Type I (MPS 1) Genetics has information about obtaining tests. Testing can be done by your preferred genetics subspecialists or see Testing Laboratories for MPS I (Genetic Testing Registry).

Other Testing

  • Annual ophthalmology assessments should include measurement of visual acuity and intraocular pressure, slit lamp examination of the cornea, and electroretinography. Assessment of optic nerve for signs of intracranial pressure
  • Regular sleep assessments, with sleep studies as needed, to identify the presence of sleep apnea, both obstructive and central
  • Pulmonary function tests when of age with regular assessments
  • Dental exam every 6-12 months
  • Annual audiology exam to determine the degree and cause of hearing impairment

Specialty Collaborations & Other Services

Medical Genetics (see UT providers [7])

Referral is indicated when the diagnosis of MPS I is suspected or confirmed. Continue annual visits to assess status and initiate appropriate interventions. A geneticist will help coordinate referral to other subspecialists. Geneticists generally have the most clinical experience with MPS I.

Genetic Testing and Counseling (see UT providers [9])

Referral can be helpful to families in understanding the condition, its inheritance patterns, the need for testing and impact on other family members, and plans for having future children. Genetic counselors are often very knowledgeable about community resources and family support.

Early Intervention for Children with Disabilities/Delays (see UT providers [52])

Refer at the time of diagnosis for services that incorporate physical, occupational, and speech therapy is important to maximize developmental outcome, especially for children with severe MPS I.

Pediatric Ophthalmology (see UT providers [4])

Refer at time of diagnosis and if there are changes in behavior. Assessment at diagnosis and annual assessments would include measurement of visual acuity and intraocular pressure, slit lamp examination of the cornea, electroretinography, and assessment of optic nerve for intracranial pressure.

Pediatric Orthopedics (see UT providers [10])

Refer every year for assessment of spine, hips, knees, carpal tunnel syndrome, and gait.

Pediatric Cardiology (see UT providers [4])

Referral is indicated at diagnosis and every 1-2 years for regular follow-up by cardiac ultrasound, electrocardiogram, and possible Holter monitoring with a cardiologist familiar with the complications of MPS I.

Audiology (see UT providers [23])

Refer at the time of diagnosis and for annual visits to determine the degree, cause, and progression of hearing impairment.

Pediatric Neurology (see UT providers [7])

Biennial visits may include an MRI of the brain and the spine; an assessment of hydrocephalus and spine stability; ventriculoperitoneal shunting, which if indicated, generally improves quality of life; and nerve conduction studies to assess possible carpal tunnel syndrome.

Pediatric Otolaryngology (ENT) (see UT providers [9])

Refer at diagnosis to assess asymptomatic otitis media with thick cerumen and sinusitis and as clinically indicated for evaluation or for tonsillectomy and adenoidectomy to decrease upper airway obstruction.

Pediatric Pulmonology (see UT providers [3])

Refer and maintain visits every 6-24 months for pulmonary function assessment and testing.

Pediatric Physical Medicine & Rehabilitation (see UT providers [11])

Refer for range of motion issues - exercises appear to offer some benefits in preserving joint function and should be started early. Also, refer for evaluation and treatment of carpal tunnel syndrome. If possible, find someone who specializes in hand therapy.

Developmental - Behavioral Pediatrics (see UT providers [9])

Refer at the time of diagnosis and at least every 2 years to establish baseline parameters and to begin early intervention.

Pediatric Gastroenterology (see UT providers [2])

Refer if constipation or loose stools interfere with daily activities, including school.

Pediatric General Surgery (see UT providers [2])

Refer to a general surgeon for routine repair of umbilical and inguinal hernias and potential placement of indwelling catheter prior to HSCT and after ERT has been established to decrease GAG accumulation in the airway prior to initial anesthesia.

Wish Foundations (see UT providers [18])

Consider organizations dedicated to helping seriously ill children and their families. Programs include entertainment while hospitalized, getaways for families, patient education, and online chat rooms where kids can communicate with other seriously ill children.

Treatment & Management

Overview

Early treatment is critical to better long-term clinical outcomes. Treatment options become more limited with increasing age and clinical severity:
  • Hematopoietic stem cell transplantation (HSCT) for severe MPS I increases survival, reduces facial coarseness and hepatosplenomegaly, improves hearing, and preserves normal heart function. If HSCT is accomplished before significant developmental delay (usually before 2 years old), the degree and rate of cognitive decline will likely be reduced; however, individuals may still have mild intellectual disability. Cardiac valvular disease, skeletal manifestations, and corneal clouding may continue to progress. [Kunin-Batson: 2016]
  • Enzyme replacement therapy (ERT) can significantly reduce liver size, improve the distance traveled in a 6-minute walk test, decrease joint restriction, lessen sleep apnea, and improve breathing in individuals with attenuated MPS I. The benefit of ERT in those with severe disease has not been assessed; 1 patient with severe MPS who had been treated for 3 years with ERT continued to experience a decline in respiratory status, musculoskeletal and spinal involvement, and developmental skills. [Thomas: 2006] Because the recombinant enzyme is not thought to cross the blood-brain barrier, the best option to reduce the risk of cognitive impairment remains early HSCT.
  • Combined HSCT and ERT is another option for individuals with severe MPS I. Providing ERT before and into the peri-HSCT period may improve the child's existing respiratory and cardiac manifestations to an extent that may reduce the risk of transplant-related complications. [Tolar: 2008] See Mucopolysaccharidosis Type I (MPS 1) Hematopoietic Stem Cell Transplantation & Enzyme Replacement Therapy for details about therapy and dosing regimen.
  • Under investigation for the treatment of cognitive decline in severe MPS I is intrathecal ERT (injecting the enzyme into the spinal fluid). Some long-term benefits to the heart from successful bone marrow transplantation have been documented. [Braunlin: 2003]
The benefits, limitations, and risks of each therapeutic option should be thoroughly discussed with the family and other health care providers as soon as possible after diagnosis. Management of the multiple organ system involvement in MPS I requires a multispecialty and multidisciplinary approach, ideally guided in part by the medical home.

Pearls & Alerts for Treatment & Management

Spine instability

Dysostosis multiplex can lead to instability of the spine, including the atlantoaxial joint. Careful positioning and avoidance of hyperextension of the neck are necessary.

Narrow trachea

Induction of anesthesia can be difficult; smaller than anticipated endotracheal tubes are usually required for intubation because the trachea may be narrowed and the vocal cords thickened.

Postoperative recovery issues

Recovery from anesthesia may be slow and postoperative airway obstruction is a common problem. Overnight stays for typical outpatient procedures are prudent.

How should common problems be managed differently in children with Mucopolysaccharidosis Type I (MPS 1)?

Growth or Weight Gain

There are no growth curves specific to MPS I, so growth and weight should be followed on standardized growth curves based on age and gender. Children with severe MPS I may have above-normal growth and head circumference in the first 6 months of life, but their growth usually slows down between 6 and 18 months of age and may plateau between 3-6 years of age.

Bacterial Infections

Chronic ear infections are common. Physicians should have a low threshold for placing pressure equalization (PE) tubes since most individuals will have recurrent and frequent ear infections. Heavy-duty grommets are preferred due to recurrent infections and buildup of cerumen.

Over the Counter Medications

Instruct parents to avoid over-the-counter drugs commonly used to treat colds and congestion (antihistamines that make mucus thicker and harder, decongestants that contain stimulants that raise blood pressure and narrow blood vessels, cough suppressants that may contribute to sleep apnea).

Systems

Cardiology

Cardiac involvement includes cardiomyopathy, endocardiofibroelastosis, progressive valvular disease, and coronary artery disease. Aortic valvular disease and occasional poly-valvular disease is common in the attenuated forms of MPS I. Echocardiograms and ECGs are necessary to monitor valvular involvement and cardiac function. Cardiac valve replacement may be required. Sudden death from arrhythmia and cardiovascular collapse may occur. It is very difficult to assess coronary artery disease because it is a generalized phenomenon instead of focal occlusion. Other cardiac problems include:
  • Thickening of the mitral and aortic valves leading to regurgitation and/or stenosis
  • Myocardial thickening that contributes to heart failure
  • Cardiac arrhythmias that lead to heart block, resulting in the need for a permanent pacemaker
  • Narrowing of the coronary arteries, often within the first year of life - complete occlusions of the coronary arteries have been reported within the first 5 years of life, with sudden death occurring during illness or with blood pressure changes associated with anesthesia
  • Narrowing of the thoracic aorta, possibly resulting in elevated blood pressure in the head and neck with normal blood pressure in the legs
  • Congenital cardiac abnormalities, including atrial septal defect or patent ductus arteriosus
  • Cor pulmonale
Tachycardia is usually treatable by conventional means. Coronary artery involvement is difficult to assess because of the diffuse involvement (as opposed to the focal narrowing more commonly encountered). Assume coronary involvement if there is evidence of substantial deposition of glycosaminoglycan in other parts of the heart, such as the valves or walls. The cardiac effects of enzyme replacement therapy have yet to be described in any MPS Syndrome.

Specialty Collaborations & Other Services

Pediatric Cardiology (see UT providers [4])

Involvement is essential for evaluation and ongoing management of cardiac complications.

Musculoskeletal

Orthopedic problems will exist in varying degrees for all individuals with MPS I. Because of the risk for spinal cord compression, parents/patients should be instructed to avoid "high-risk" activities, such as contact sports, and should be cautioned about manipulation of the cervical spine. Range of motion exercises appear to offer some benefits in preserving joint function and should be started early. Hip replacement, knee surgery, and Achilles tendon release are a few of the more common surgical procedures that may improve function and quality of life. For more information, see Mucopolysaccharidosis Type I (MPS 1) Orthopedic Manifestations & Treatments.

Specialty Collaborations & Other Services

Pediatric Orthopedics (see UT providers [10])

Collaborate for management of orthopedic problems. A subspecialist comfortable with the management of MPS I is very important.

Respiratory

Restrictive lung disease is common in MPS I, and pulmonary function testing usually demonstrates diminished lung volumes. Respiratory infections often lead to secondary bacterial infections of the sinuses or ears that require antibiotic treatment. Some patients will need chronic antibiotic therapy, but many become allergic to antibiotics and some acquire resistant infections. Instruct parents to avoid over-the-counter drugs commonly used to treat colds and congestion (antihistamines that make mucus thicker and harder, decongestants that contain stimulants which raise blood pressure and narrow blood vessels, cough suppressants that may contribute to sleep apnea).
Airway obstruction and sleep apnea are common. Enlarged tonsils and adenoids may need to be removed. Supplemental oxygen and/or a tracheostomy is sometimes necessary for patients with chronic dyspnea. For sleep apnea, CPAP & BIPAP Therapy for Children are non-invasive options if the patient can adjust to wearing the mask and mouthpiece at night. Complications include the buildup of mucus in the nasal passages or discomfort if the pressure is inappropriately high. Pulmonary function testing with lung vital capacity measurements are helpful in monitoring cardio-respiratory status and response to therapies.

Specialty Collaborations & Other Services

Pediatric Pulmonology (see UT providers [3])

Consultation and a sleep study are recommended before placing the patient on a positive airway pressure device.

Neurology

Those with significant neurologic impairment are at greater risk for developing hydrocephalus. Communicating hydrocephalus can be present without overt ventriculomegaly; it is often under-diagnosed and may be associated with cortical atrophy. Brain imaging (CT or MRI) may allow pre-symptomatic identification. In infants and toddlers, if there is a rapid increase in head circumference, the preferred method for assessing the degree of pressure elevation is a lumbar puncture with measurement of opening pressure of cerebrospinal fluid.
Prior to surgery, the cervical region should be evaluated for evidence of narrowing at the foramen magnum, which places the spinal cord at risk. A laminectomy may need to be performed at the time of surgery. Consider a high-pressure shunt (10-15 mm Hg) to prevent rapid decompression.

Specialty Collaborations & Other Services

Pediatric Neurology (see UT providers [7])

Referral may be helpful in evaluating, monitoring, and managing neurologic complications, such as hydrocephalus and carpal tunnel syndrome.

Pediatric Neurosurgery (see UT providers [2])

Refer for initial and ongoing evaluation of children with hydrocephalus, as well as to place a shunt and manage potential complications.

Ears/Hearing

Hearing loss, both conductive (early) and sensorineural (later), is common and is correlated with the severity of somatic manifestations of disease. Important contributing factors are frequent middle ear infections caused by storage of glycosaminoglycans within the oro-pharynx, dysostosis of the ossicles of the middle ear, scarring of the tympanic membrane, GAG accumulation in the hair cells, and cranial nerve damage. [Kakkis: 2001] In most cases, hearing loss is sensorineural and can be managed by use of a hearing aid. Management information for hearing loss can be found in the Portal's Hearing Loss and Deafness.
Otitis media is a persistent problem in children with MPS I. Pseudomonas aeruginosa and Staphylococcus aureus are more common as children age. Pneumococcal vaccine and corticosteroids may be helpful. Some children may benefit from eliminating common food allergens (soy, citrus, peanuts, wheat, fish, eggs, corn, and tomatoes) from their diet. With draining ears, fungal infection should be considered. Tympanostomy tubes with heavy-duty grommets are recommended; removal of the adenoids and tonsils are often necessary to prevent recurrent and persistent infections.

Specialty Collaborations & Other Services

Audiology (see UT providers [23])

Refer patients for routine testing and consider early intervention with hearing aids, which are generally underutilized in MPS patients.

Pediatric Otolaryngology (ENT) (see UT providers [9])

Co-management of children with recurrent/persistent otitis media and/or hearing loss with an ENT specialist is recommended.

Speech and Hearing Services (see UT providers [29])

Services include providers and programs for hearing aids and loaner programs.

Eyes/Vision

Visual deficits occur, especially in dim light, if corneal clouding is severe. Some patients cannot tolerate bright lights (sunglasses and visors can help). Night blindness can increase fear of walking anywhere when it is dark. Patients may suffer from glaucoma, severe visual impairment with retinal degeneration, optic nerve compression and atrophy, and the loss of peripheral vision. Corneal transplantation is not routinely offered in individuals with severe MPS I, but may prove beneficial in those with the attenuated forms, although there is the risk that the donor cornea would accumulate GAG material that cannot be cleared by ERT.

Specialty Collaborations & Other Services

Pediatric Ophthalmology (see UT providers [4])

Refer for initial evaluation and periodic management of visual acuity, corneal opacity, optic nerve abnormalities, and peripheral vision.

Gastro-Intestinal & Bowel Function

Inability to maintain adequate nutrition may call for supplementation, but the decision to change to enteral nutrition is a difficult one. In assessing the need for enteral nutrition, monitor the child's weight, caloric intake, choking/gagging problems, episodes of pneumonia, and time required for feeding.
Diarrhea, possibly due to a defect in the autonomic nervous system, is common in younger patients. Try decreasing roughage in the diet and, if taking antibiotics, taking a live-culture yogurt or probiotics. Constipation can be a problem in older patients, requiring laxatives or enemas. Information for management of constipation can be found in the Portal's Constipation.

Specialty Collaborations & Other Services

Pediatric Gastroenterology (see UT providers [2])

Consider for assessments and management of constipation, hernias, and difficult nutritional challenges.

Dental

Dental caries and abscessed teeth occur because teeth in MPS I tend to be poorly formed and have fragile enamel, which causes susceptibility to infection and decay. Instruct parents to clean the teeth gently and to avoid foods that contribute to dental decay. If the water is not treated with fluoride, prescribe daily fluoride tablets or drops. Prophylactic antibiotics are advised before and after dental treatment if the child has any cardiac involvement. Gum cysts are common and can be treated by simple excision. Virtually all MPS I patients require subacute bacterial endocarditis prophylaxis at dental visits.

Specialty Collaborations & Other Services

General Dentistry (see UT providers [98])

Referral for regular dental care is essential. Even with excellent care, abscesses can develop due to abnormal formation of the teeth. A dentist familiar with treating children who have challenging medical problems can make a huge difference in oral health.

Development (general)

Formal developmental assessment at diagnosis and close monitoring of developmental milestones will help determine the level of cognitive impairment and progression of the condition. Early development in children with severe MPS I may be normal; however, developmental delays and varying degrees of progressive intellectual disability ensue secondary to build-up of glycosaminoglycans within the brain. Developmental delay may plateau, but then the child’s developmental skills may regress. Monitoring developmental milestones closely, especially in children with severe MPS I, will help determine recommendation for treatment options.
Individuals with the attenuated forms of MPS I may have normal to mildly delayed development, and intelligence can range from normal cognition to mild learning disabilities. Baseline cognition and mental status should be carefully assessed; acute changes in cognition or mental status should be promptly evaluated as this may represent increased intracranial pressure due to hydrocephalus. Families may need assistance in developing plans for school (IEP and 504). Information can be found at School Accommodations: IEPs & 504s.

Specialty Collaborations & Other Services

Developmental - Behavioral Pediatrics (see UT providers [9])

Refer for testing and early intervention. Refer as needed to help families cope with obstinate and immature behavior patterns and to establish appropriate expectations for cognitive level.

No Related Issues were found for this diagnosis.

Ask the Specialist

What are the first clinical indications that a child could have MPS I?

For severe MPS I, children may have recurrent ear infections, umbilical or inguinal hernias, gibbus, above-average growth and large head circumference, and coarsening of facial features with excess body hair. Slowing of growth, increased joint stiffness, hepatosplenomegaly, and developmental delays may be noted shortly thereafter.

What treatments are available for MPS I?

Currently, there are 2 FDA-approved treatment options for MPS I. 1) Hematopoietic stem cell transplantation (HSCT) and 2) Enzyme replacement therapy (ERT). See Mucopolysaccharidosis Type I (MPS 1) for details.

Resources for Clinicians

On the Web

Mucopolysaccharidosis Type I (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Hurler Syndrome (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

MPS 1 - Information for Health Care Professionals (Genzyme)
Clinical information about diagnosis and genetics; Genzyme Therapeutics, manufacturer of Aldurazyme (laronidase) enzyme replacement therapy.

Helpful Articles

PubMed search for mucopolysaccharidosis type I in children, last 4 years.

Muenzer J.
The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations.
J Pediatr. 2004;144(5 Suppl):S27-34. PubMed abstract

Beck M, Arn P, Giugliani R, Muenzer J, Okuyama T, Taylor J, Fallet S.
The natural history of MPS I: global perspectives from the MPS I Registry.
Genet Med. 2014;16(10):759-65. PubMed abstract / Full Text

de Ru MH, Boelens JJ, Das AM, Jones SA, van der Lee JH, Mahlaoui N, Mengel E, Offringa M, O'Meara A, Parini R, Rovelli A, Sykora KW, Valayannopoulos V, Vellodi A, Wynn RF, Wijburg FA.
Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure.
Orphanet J Rare Dis. 2011;6:55. PubMed abstract / Full Text

Kunin-Batson AS, Shapiro EG, Rudser KD, Lavery CA, Bjoraker KJ, Jones SA, Wynn RF, Vellodi A, Tolar J, Orchard PJ, Wraith JE.
Long-Term Cognitive and Functional Outcomes in Children with Mucopolysaccharidosis (MPS)-IH (Hurler Syndrome) Treated with Hematopoietic Cell Transplantation.
JIMD Rep. 2016. PubMed abstract / Full Text

Clinical Tools

Medication Guides

Aldurazyme Information for Physicians (Genzyme) (PDF Document 247 KB)
Fourteen-page handout for physicians covering pharmacology, dosage, precautions, and contraindications; Genzyme Therapeutics (manufacturer of Aldurazyme (laronidase) enzyme replacement therapy).

Patient Education & Instructions

MPS Fact Sheets (National MPS Society)
More than 25 fact sheets about mucopolysaccharidoses and related diseases for patients, families, and providers; topics include cardiac problems, caregiver support, family coping strategies, melatonin, transplants, pamidronate, tube feedings, stem cell transplants, and more.

Understanding MPS (National MPS Society)
Booklets for each type of MPS with in-depth information about related physical and emotional issues; available in English and Spanish.

Resources for Patients & Families

Families may find the For Parents & Families section of the Medical Home Portal helpful in caring for their child with MPS 1.

Information on the Web

Mucopolysaccharidosis Type I (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

MPS I - Information for Families (Genzyme)
Information about treatment, clinical trials, support groups, and resources related to MPS 1. Discusses the use of Aldurazyme (laronidase) enzyme replacement therapy manufactured by Genzyme.

About Lysosomal Diseases (LDNZ)
Offers background information, family stories, newsletters, and research updates; Lysosomal Diseases New Zealand.

National & Local Support

National MPS Society
Provides detailed information, research, and support for families.

Studies/Registries

Children and Adolescents with MPS I (ClinicalTrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Services for Patients & Families in Utah (UT)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: February 2006; last update/revision: May 2019
Current Authors and Reviewers:
Author: Pilar L. Magoulas, MS, CGC
Reviewer: David Viskochil, MD, PhD
Authoring history
2011: update: David Viskochil, MD, PhDR
2011: update: Pilar L. Magoulas, MS, CGCA
2009: update: David Viskochil, MD, PhDSA
2006: first version: Pilar L. Magoulas, MS, CGCA
AAuthor; CAContributing Author; SASenior Author; RReviewer

Bibliography

Beck M, Arn P, Giugliani R, Muenzer J, Okuyama T, Taylor J, Fallet S.
The natural history of MPS I: global perspectives from the MPS I Registry.
Genet Med. 2014;16(10):759-65. PubMed abstract / Full Text

Braunlin EA, Stauffer NR, Peters CH, Bass JL, Berry JM, Hopwood JJ, Krivit W.
Usefulness of bone marrow transplantation in the Hurler syndrome.
Am J Cardiol. 2003;92(7):882-6. PubMed abstract

de Ru MH, Boelens JJ, Das AM, Jones SA, van der Lee JH, Mahlaoui N, Mengel E, Offringa M, O'Meara A, Parini R, Rovelli A, Sykora KW, Valayannopoulos V, Vellodi A, Wynn RF, Wijburg FA.
Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure.
Orphanet J Rare Dis. 2011;6:55. PubMed abstract / Full Text

Kunin-Batson AS, Shapiro EG, Rudser KD, Lavery CA, Bjoraker KJ, Jones SA, Wynn RF, Vellodi A, Tolar J, Orchard PJ, Wraith JE.
Long-Term Cognitive and Functional Outcomes in Children with Mucopolysaccharidosis (MPS)-IH (Hurler Syndrome) Treated with Hematopoietic Cell Transplantation.
JIMD Rep. 2016. PubMed abstract / Full Text

Moore D, Connock MJ, Wraith E, Lavery C.
The prevalence of and survival in Mucopolysaccharidosis I: Hurler, Hurler-Scheie and Scheie syndromes in the UK.
Orphanet J Rare Dis. 2008;3:24. PubMed abstract / Full Text

Muenzer J.
The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations.
J Pediatr. 2004;144(5 Suppl):S27-34. PubMed abstract

Muenzer J, Wraith JE, Clarke LA.
Mucopolysaccharidosis I: management and treatment guidelines.
Pediatrics. 2009;123(1):19-29. PubMed abstract / Full Text

Thomas JA, Jacobs S, Kierstein J, Van Hove J.
Outcome after three years of laronidase enzyme replacement therapy in a patient with Hurler syndrome.
J Inherit Metab Dis. 2006;29(6):762. PubMed abstract

Tolar J, Grewal SS, Bjoraker KJ, Whitley CB, Shapiro EG, Charnas L, Orchard PJ.
Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler syndrome.
Bone Marrow Transplant. 2008;41(6):531-5. PubMed abstract / Full Text