DESCRIPTION

Hurler syndrome is the most severe phenotype within a spectrum of lysosomal storage disorders known as mucopolysaccharidosis I due to deficiency of the enzyme -L-iduronidase. Current terminology applies the term severe MPSI for what has been known as Hurler syndrome and attenuated MPS I for Hurler-Scheie and Scheie syndromes.

EPIDEMIOLOGY

Incidence

Incidence is ~1/100,000 live births. The majority MPS I are the severe form (50–80%), although that may be related to a higher rate of diagnosis in the severe form vs. attenuated forms.

RISK FACTORS

Genetics

Autosomal recessive, caused by 1 of 110 known mutations in IDUA gene, localized on chromosome 4p16.3. The specific mutation is believed to determine phenotype.

PATHOPHYSIOLOGY

• Patients are unable to degrade the glycosaminoglycans dermatan sulfate and heparan sulfate which provide structural support of the extracellular matrix and cartilaginous structures, including heart valves, joints.
• -l-iduronidase enzyme deficiency results in the increase of both heparan and dermatan sulfate in the interstitium.
• Cardiomyopathy and valvar insufficiency occur as glycosaminoglycan accumulates in the myocardium, expands the spongiosa of cardiac valves, and proliferates within the myointima of the epicardial coronary arteries.
• The increase in undegraded glycosaminoglycans results in increased ventricular wall thickness, systolic and diastolic dysfunction with the clinical picture of an infiltrative restrictive cardiomyopathy and CHF.
• Diffuse narrowing of the coronary arteries may occur rather than the focal disease seen in atherosclerotic disease and may result in MI.

ETIOLOGY

Genetic; caused by a deficiency of the lysosomal enzyme -l-iduronidase

Outline

• Description
• Epidemiology
  • Incidence
• Risk Factors
  • Genetics
• Pathophysiology
• Etiology

History

• Afflicted individuals appear normal at birth, and are typically diagnosed at 6 mo–2 yr of age depending on the severity of the phenotype.
• Patients with the severe phenotype (Hurlers) usually die of obstructive airway symptoms and respiratory infection within the 1st decade of life.
• Cardiac involvement usually presents as premature coronary artery disease with MI, pulmonary HTN with hypoxemia, left-sided valvular (mitral and aortic) insufficiency, pseudohypertrophic cardiomyopathy, and endocardial fibroelastosis, CHF, and also various conduction abnormalities.

Physical Exam

• Infants with Hurler syndrome usually present in the first 2 yrs after birth with severe mental retardation, hepatosplenomegaly, skeletal deformities, and corneal clouding.
• Progressive coarsening of facial features, short stature

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• Elevated concentrations of heparan and dermatan sulfate in the urine are sensitive for detecting the enzyme defect but are not a reliable indicator of severity.
• Definitive diagnosis is based on deficient -l-iduronidase activity in leucocytes, fibroblasts, serum, or blood. Prenatal diagnosis is based on enzyme testing or, if the family mutation is known, DNA analysis.

Imaging

• Echo is used to estimate cardiac involvement by assessing LV wall thickness, valve function, and diastolic and systolic function.
• A radiographic skeletal survey is recommended and will demonstrate a characteristic MPS pattern known as dysostosis multiplex.

DIFFERENTIAL DIAGNOSIS

• Scheie syndrome
• Hunter syndrome
• Hurler-Scheie syndrome
• Sanfilippo A-D syndromes
• Morquio syndrome
• Maroteaux-Lamy syndrome
• Sly syndrome
• Hyaluronidase syndrome

Outline

• History
• Physical Exam
• Diagnostic Tests & Interpretation
  • Lab
  • Imaging
• Differential Diagnosis

• Enzyme replacement therapy (ERT) with recombinant ()-l-iduronidase also has been FDA approved.
• Relatively low risk but ERT cannot cross the blood–brain barrier and does not affect neurologic involvement.
• ERT is usually recommended for patients 2 yr of age, patients with neurologic impairment (development quotient 70) and for those with the attenuated phenotypes.
• ERT may be used as a supplement to HSCT.
• Treatment of cardiac involvement may include diuretics for CHF, antihypertensive medications.

• Multidisciplinary team evaluation determines phenotype and assesses development to determine risk/benefits of therapy.
• Hematopoietic stem-cell (HSCT) and umbilical cord-blood transplantation effective in stabilizing the neurologic condition, increasing life span, allowing regression of myocardial wall involvement, and reducing hepatosplenomegaly.
• The risks of transplant are high and currently recommended primarily for children 2 yr with minimal neurologic involvement (developmental quotients 70) in whom maximum benefit is expected.
• HSCT does not prevent progression of heart valve involvement and only stabilizes neurologic involvement.

SURGERY

Some case reports of aortic and mitral valve surgery

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

Annual cardiac evaluations using echo recommended to assess for valvular disease, heart failure, cor pulmonale, and cardiomyopathy

DIET

No restrictions

PATIENT EDUCATION

Activity: Limited

PROGNOSIS

Most patients with the severe MPS I phenotype (Hurlers) die before age 10 yr, usually of respiratory complications. Myocardial involvement has been demonstrated to regress with treatment (HSCT or ERT).

COMPLICATIONS

Respiratory failure, CHF

Outline

• Follow-Up Recommendations
  • Patient Monitoring
• Diet
• Patient Education
• Prognosis
• Complications

CODES

ICD9

• 277.5 Mucopolysaccharidosis
• 425.7 Nutritional and metabolic cardiomyopathy

SNOMED

• 65327002 mucopolysaccharidosis, MPS-I-H (disorder)
• 86995005 dilated cardiomyopathy secondary to mucopolysaccharidosis (disorder)

ADDITIONAL READING

• Braunlin EA, Berry JM, Whitley CB. Cardiac findings after enzyme replacement therapy for Mucopolysaccharidosis I. Am J Cardiol. 2006;9:416–418.
• Clarke LA, Wraith JE, Beck M, et al. Efficacy and safety of laronidase in treatment of Mucopolysacchidosis I. Pediatrics. 2009;123:229–240.
• Hirth A, Berg A, Greve G. Successful treatment of severe heart failure in an infant with Hurler syndrome. J Inherit Metab Dis. 2007;30:820.
• Muenzer J, Fisher. Advances in the treatment of mucopolysaccharidosis type 1. N Engl J Med. 2004;350(19):1932–1934.
• Muenzer J, Wraith JE, Clarke LA. Mucopolysaccaridosis I: Management and treatment guidelines. Pediatrics. 2009;123:19–29.

SEE ALSO

• Hunter syndrome
• Hurler-Scheie syndrome
• Morquio syndrome
• Sanfilippo syndrome
• Scheie syndrome
• Sly syndrome

Linda A. Pape