Signs and Symptoms

MPS I is a heterogeneous disease spanning a spectrum of severity. Severe MPS I patients may suffer from a number of progressively debilitating symptoms, including cognitive impairment. Their maximum lifespan is approximately eight to ten years.[1] Individuals at the opposite end of the disease spectrum have physical symptoms that can be severe as well, but they generally retain normal intellect and stature, and may have a normal lifespan. Because the disease generally affects many organ systems and can present in a variety of ways, diagnosis and treatment of MPS I disease may require the collaboration of and communication between geneticists, neurologists, pediatricians, developmental specialists, surgeons, cardiologists, gastroenterologists, physical therapists, and primary care providers.

General Physical Appearance

The physical appearance for MPS I is variable, and may include the following general physical characteristics:

  • coarse facial features
  • broad mouth, square jaw, and receding chin
  • large tongue
  • excess facial and body hair
  • large, scaphocephalic head (see picture below)

Patient with MPS I at age 4 years

Patient with MPS I at age 4 years (Photo courtesy of the National MPS Society, Inc)

  • corneal clouding
  • short neck
  • stocky build with short trunk
  • joint deformities (see picture below)

Joint contractures deformity in a patient with MPS I

Joint contractures in a patient with MPS I (Photo courtesy of the National MPS Society, Inc.)

Nervous System

Developmental Delay and Severe Cognitive Impairment

Patients with MPS I manifest a wide range of intellectual involvement. Some MPS I patients may suffer progressive and profound mental retardation, while others may show little or no intellectual dysfunction.[3] By 18 months, developmental delay is usually apparent. From this point on, patients generally do not progress in development but plateau for a number of years followed by a slow decline in intellectual capabilities.

Structural CNS Manifestations

In addition to the direct CNS effects of MPS I, hydrocephalus is common in MPS I patients. An associated increase in intracranial pressure may lead to brain compression, and rapidly increasing pressure may be the cause of acute developmental decline in some patients. Symptoms may be difficult to assess and progression can be insidious and is often under-appreciated. Lumbar puncture with opening pressure is a preferred method for assessing the degree of pressure elevation. Shunting procedures may be beneficial.[4] Another recognized complication is spinal cord compression, which can result from thickening of the dura or subluxation of vertebrae.

Peripheral Nervous System

Some patients with MPS I may have poor hand function, in part as a result of carpal tunnel syndrome. This syndrome is due to pressure on the median nerve as a result of thickened ligaments within the wrist. It may cause pain and numbness in the fingertips, but most patients lack these typical symptoms.[5][6][7] Diagnosis of carpal tunnel syndrome is often missed because its onset is insidious and often presents with few or no symptoms except thenar atrophy. Patients should be evaluated for this, as they may benefit from carpal tunnel release.

Skeletal System

Skeletal and joint manifestations (including gibbus deformity of the back, or dorsolumbar kyphosis) represent the major features for patients with less severe forms of MPS I.[3] In severe cases, skeletal involvement in MPS I patients can be detected in the first year of life by radiological methods.[8]Kyphosis, scoliosis, and severe back pain are also common in MPS I patients. Almost all patients experience progressive arthropathy affecting all joints, and eventually leading to the loss of (or severe restriction of) range of motion. MPS I is also associated with different degrees of growth retardation, typically involving the trunk more than the limbs.

Dysostosis lumbar vertebra

Dysostosis lumbar vertebra
(Photo courtesy of Dr. E. Wraith)

Dysostosis metacarpal bones

Dysostosis metacarpal bones
(Photo courtesy of Dr. E. Wraith)

Dysostosis skull

Dysostosis skull
(Photo courtesy of Dr. E. Wraith)

Respiratory System

Chronic rhinitis and rhinorrhea without obvious infections are common features of MPS I. Storage within the oro-pharynx with associated enlargement of the tongue, tonsils, and adenoids can lead to significant upper airway complications.[9] In addition, a narrowed trachea, thickened vocal cords, and redundant tissue in the upper airway may contribute to airway obstruction and can result in sleep apnea.[9][10][11][12]

Lung volumes are often reduced because of the small thorax and hepatosplenomegaly limiting excursion of the diaphragm. Recurrent respiratory infections are common, and respiratory insufficiency is a major cause of mortality.

Auditory System

Moderate to severe hearing loss, which correlates with the severity of somatic disease, can occur in patients with MPS I. Hearing loss may be sensorineural or conductive, but is typically mixed.[13][14]

Ocular System

Corneal clouding occurs in all MPS I patients and can lead to significant visual disability. (See picture below.) Open-angle glaucoma is also a common complication, and retinal degeneration associated with loss of peripheral vision and night-blindness may occur.[13][14]

Corneal clouding, evident at 18 months

Corneal clouding, evident at 18 months
(Reproduced by permission of Hodder/Arnold Publishers)

Cardiovascular System

Clinical complications related to heart disease occur in some patients with MPS I, particularly during the later stages of the disease. Storage of certain glycosaminoglycans within and around the valve leaflets results in their thickening and stiffening, which can lead to progressive mitral and aortic regurgitation or stenosis – mitral regurgitation is the most common valvular disease in severely affected MPS I patients.[13][14]

MPS I heart valve

MPS I heart valve
(Photo courtesy of Dr. E. Wraith)

Normal heart valve

Normal heart valve
(Photo courtesy of Dr. E. Wraith)

Gastrointestinal System

A distended abdomen is commonly observed in patients with severe MPS I and is typically caused by the progressive enlargement of the liver and/or spleen.[15] (See picture below). Some children with MPS I suffer periodically from loose stools and diarrhea, sometimes alternating with periods of severe constipation due to storage within ganglion cells of the enteric nervous system. Hernias, both inguinal and umbilical, are common in patients with MPS I.[16]

Distended abdomen due to hernia, and Gibbus deformity in an 18-month infant

Distended abdomen due to hernia, and Gibbus deformity in an 18-month infant
(Photo courtesy of Dr. Emil Kakkis)

Abdominal distension

Abdominal distension
(Photo courtesy of Dr. E. Wraith)

Umbilical hernia

Umbilical hernia
(Photo courtesy of Dr. E. Wraith)

 

Indication

ALDURAZYME® (laronidase) is a prescription only medication indicated for patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for patients with the Scheie form who have moderate to severe symptoms. The risks and benefits of treating mildly affected patients with the Scheie form have not been established.

ALDURAZYME has been shown to improve pulmonary function and walking capacity. ALDURAZYME has not been evaluated for effects on the central nervous system manifestations of the disorder.

Important Safety Information

WARNING: Risk of anaphylaxis.

Life-threatening anaphylactic reactions have been observed in some patients during ALDURAZYME® infusions. Therefore, appropriate medical support should be readily available when ALDURAZYME is administered. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring.


Anaphylaxis and severe allergic reactions have been observed in patients during or up to 3 hours after ALDURAZYME infusions. Some of these reactions were life-threatening and included respiratory failure, respiratory distress, stridor, tachypnea, bronchospasm, obstructive airways disorder, hypoxia, hypotension, bradycardia, and urticaria. If anaphylactic or other severe allergic reactions occur, immediately discontinue the infusion of ALDURAZYME and initiate appropriate treatment. Caution should be exercised if epinephrine is being considered for use in patients with MPS I due to the increased prevalence of coronary artery disease in these patients. Interventions have included resuscitation, mechanical ventilatory support, emergency tracheotomy, hospitalization, and treatment with inhaled beta-adrenergic agonists, epinephrine, and IV corticosteroids.

In clinical studies and postmarketing safety experience with ALDURAZYME, approximately 1% of patients experienced severe or serious allergic reactions. In patients with MPS I, pre-existing upper airway obstruction may have contributed to the severity of some reactions. Due to the potential for severe allergic reactions, appropriate medical support should be readily available when ALDURAZYME is administered. Because of the potential for recurrent reactions, some patients who experience initial severe reactions may require prolonged observation.

The risks and benefits of re-administering ALDURAZYME following an anaphylactic or severe allergic reaction should be considered. Extreme care should be exercised, with appropriate resuscitation measures available, if the decision is made to re-administer the product.

Patients with an acute febrile or respiratory illness at the time of ALDURAZYME infusion may be at greater risk for infusion reactions. Careful consideration should be given to the patient’s clinical status prior to administration of ALDURAZYME and consider delaying ALDURAZYME infusion.

Sleep apnea is common in MPS I patients. Evaluation of airway patency should be considered prior to initiation of treatment with ALDURAZYME. Patients using supplemental oxygen or continuous positive airway pressure (CPAP) during sleep should have these treatments readily available during infusion in the event of an infusion reaction or extreme drowsiness/sleep induced by antihistamine use.

Caution should be exercised when administering ALDURAZYME to patients susceptible to fluid overload or patients with an acute underlying respiratory illness or compromised cardiac and/or respiratory function for whom fluid restriction is indicated. These patients may be at risk of serious exacerbation of their cardiac or respiratory status during infusions. Appropriate medical support and monitoring measures should be readily available during ALDURAZYME infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient.

Because of the potential for infusion reactions, patients should receive antipyretics and/or antihistamines prior to infusion. If an infusion-related reaction occurs, regardless of pre-treatment, decreasing the infusion rate, temporarily stopping the infusion, or administering additional antipyretics and/or antihistamines may ameliorate the symptoms.

The most serious adverse reactions reported with ALDURAZYME treatment during clinical trials were anaphylactic and allergic reactions.

In a 26-week, placebo-controlled clinical trial in patients 6 years and older, the most commonly reported infusion reactions regardless of treatment group were flushing, pyrexia, headache, and rash. Flushing occurred in 5 patients (23%) receiving ALDURAZYME; the other reactions were less frequent. Less common infusion reactions included angioedema (including face edema), hypotension, paresthesia, feeling hot, hyperhidrosis, tachycardia, vomiting, back pain, and cough. Other reported adverse reactions included bronchospasm, dyspnea, urticaria, and pruritus. In the open-label, uncontrolled extension phase of this clinical trial, the infusion reactions were similar, but also included abdominal pain or discomfort and injection site reaction. Less commonly reported infusion reactions included nausea, diarrhea, feeling hot or cold, vomiting, pruritus, arthralgia and urticaria. Additional common adverse reactions included, back pain and musculoskeletal pain.

In an open-label, uncontrolled clinical trial in patients 6 years and younger who received ALDURAZYME treatment for up to 52 weeks, the most commonly reported serious adverse events (regardless of relationship) in patients 6 years and younger, were otitis media (20%), and central venous catherization required for ALDURAZYME infusion (15%). The most commonly reported adverse reactions in patients 6 years and younger were infusion reactions reported in 35% (7 of 20) of patients and included pyrexia (30%), chills (20%), blood pressure increased (10%), tachycardia (10%), and oxygen saturation decreased (10%). Other commonly reported infusion reactions occurring in ≥5% of patients were pallor, tremor, respiratory distress, wheezing, crepitations (pulmonary), pruritus, and rash.

In postmarketing experience with ALDURAZYME, severe and serious infusion reactions have been reported, some of which were life-threatening, including anaphylactic shock. Adverse reactions resulting in death reported in the postmarketing setting with ALDURAZYME treatment included cardio-respiratory arrest, respiratory failure, cardiac failure, and pneumonia. These events have been reported in MPS I patients with significant underlying disease. Additional common adverse reactions included erythema and cyanosis. There have been a small number of reports of extravasation in patients treated with ALDURAZYME. There have been no reports of tissue necrosis associated with extravasation. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In clinical trials, 99 of 102 patients (97%) treated with ALDURAZYME were positive for IgG antibodies to ALDURAZYME. In the 2 trials of patients 6 years and older, 9 patients who experienced severe infusion reactions were tested for ALDURAZYME-specific IgE antibodies and complement activation. One of the nine patients had an anaphylactic reaction consisting of urticaria and airway obstruction and tested positive for both ALDURAZYME-specific IgE binding antibodies and complement activation. In the postmarketing setting, approximately 1% of patients experienced severe or serious infusion-allergic reactions and tested positive for IgE. Of these IgE-positive patients, some have discontinued treatment, but some have been successfully re-challenged. The clinical significance of antibodies to ALDURAZYME, including the potential for product neutralization, is not known.

Adverse events should be reported promptly to Sanofi Genzyme Medical Information at 800-745-4447, option 2.

You are encouraged to report negative side effects of prescription drugs to FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

ALDURAZYME is available by prescription only. To learn more, please see the Full Prescribing Information including Boxed Warning (PDF), visit www.ALDURAZYME.com or contact Sanofi Genzyme at 1-800-745-4447, option 2.

References

  1. Neufeld EF, Muenzer J. The Mucopolysaccharidoses. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. eds. The Online Metabolic and Molecular Bases of Inherited Disease New York, NY: McGraw-Hill; 2014. http://ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62642135. Accessed April 11, 2017.
  2. Neufeld EF, Muenzer J. The Mucopolysaccharidoses. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. eds. The Online Metabolic and Molecular Bases of Inherited Disease New York, NY: McGraw-Hill; 2014. http://ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62642135. Accessed April 11, 2017.
  3. Clarke LA. Clinical diagnosis of lysosomal storage diseases. In: Organelle Diseases. Clinical Features, Diagnosis, Pathogenesis and Management. Applegarth DA, Dimmick JE, Hall JG, editors. London: Chapman and Hall Medical; 1997. p. 37.
  4. Neufeld EF, Muenzer J. The Mucopolysaccharidoses. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. eds. The Online Metabolic and Molecular Bases of Inherited Disease New York, NY: McGraw-Hill; 2014. http://ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62642135. Accessed April 11, 2017.
  5. Wraith JE, Alani SM Carpal tunnel syndrome in the mucopolysaccharidoses and related disorders. Arch Dis Child 1990;65:962.
  6. Haddad FS, Jones DH, Vellodi A., Kane N., Pitt MC Carpal tunnel syndrome in the mucopolysaccharidoses and the mucolipidoses. J Bone Joint Surg Br 1997;79:576.
  7. Van Heest AE, House J, Krivit W, Walker K. Surgical treatment of carpal tunnel syndrome and trigger digits in children with mucopolysaccharide storage disorders. J Hand Surg (Am) 1998;23:236.
  8. Neufeld EF, Muenzer J. The Mucopolysaccharidoses. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. eds. The Online Metabolic and Molecular Bases of Inherited Disease New York, NY: McGraw-Hill; 2014. http://ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62642135. Accessed April 11, 2017.
  9. Neufeld EF, Muenzer J. The Mucopolysaccharidoses. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. eds. The Online Metabolic and Molecular Bases of Inherited Disease New York, NY: McGraw-Hill; 2014. http://ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62642135. Accessed April 11, 2017.
  10. Myer, C.M.D. Airway obstruction in Hurler's syndrome - Radiographic features. Int J Pediatr Otorhinolaryngol; 1990. 22: 91.
  11. Peters, M.E., Arya, S., Langer, L.O., Gilbert, E.F., Carlson, R., and Adkins, W. Narrow trachea in mucopolysaccharidoses. Pediatr Radiol; 1985. 15: 225.
  12. Shapiro, J., Strome, M., and Crocker, A.C. Airway obstruction and sleep apnea in Hurler and Hunter syndromes. Ann Otol Rhinol Laryngol; 1985. 94: 458.
  13. Clarke LA. Clinical diagnosis of lysosomal storage diseases. In: Organelle Diseases. Clinical Features, Diagnosis, Pathogenesis and Management. Applegarth DA, Dimmick JE, Hall JG, editors. London: Chapman and Hall Medical; 1997. p. 48.
  14. Neufeld EF, Muenzer J. The Mucopolysaccharidoses. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. eds. The Online Metabolic and Molecular Bases of Inherited Disease New York, NY: McGraw-Hill; 2014. http://ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62642135. Accessed April 11, 2017.
  15. Clarke LA. Clinical diagnosis of lysosomal storage diseases. In: Organelle Diseases. Clinical Features, Diagnosis, Pathogenesis and Management. Applegarth DA, Dimmick JE, Hall JG, editors. London: Chapman and Hall Medical; 1997. p. 46.
  16. Clarke, L.A. and MacFarland, J. Mucopolysaccharidosis-I (MPS-I). The Canadian Society for Mucopolysaccharide and Related Diseases, Inc., Clarke, L.A., Kaweski, C., Di Ilio, L., and Hahn, S. (eds.). Ticky Graphics & Printing, Vancouver; 2001.

Resources & Support

Information on MPS I disease is limited because of its rarity. Learn more about MPS I Registry, a global resource dedicated to improving the understanding of MPS I disease.

Complete Prescribing Information

View full prescribing information including boxed warning.