• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Mucopolysaccharidosis Type I

Synonyms: Alpha-L-Iduronidase Deficiency, IDUA Deficiency, MPS I. Includes: Hurler Syndrome (MPS I H), Hurler-Scheie Syndrome (MPS I H/S), Scheie Syndrome (MPS I S)

, MD and , PhD candidate.

Author Information
, MD
Professor, Medical Genetics
University of British Columbia
Vancouver, BC, Canada
, PhD candidate
Medical Genetics
University of British Columbia
Vancouver, BC, Canada

Initial Posting: ; Last Update: July 21, 2011.

Summary

Disease characteristics. Mucopolysaccharidosis type I (MPS I) is a progressive multisystem disorder with features ranging over a continuum of severity. While affected individuals have traditionally been classified as having one of three MPS I syndromes, Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome, no biochemical differences have been identified and the clinical findings overlap; thus, affected individuals are best described as having either severe or attenuated MPS I, a distinction that influences therapeutic options.

Severe MPS I. Infants appear normal at birth. Typical early manifestations are nonspecific (e.g., umbilical or inguinal hernia, frequent upper respiratory-tract infections before age 1 year). Coarsening of the facial features may not become apparent until after age one year. Gibbus deformity of the lower spine is common. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is universal. By age three years, linear growth ceases. Intellectual disability is progressive and profound. Hearing loss is common. Death, typically caused by cardiorespiratory failure, usually occurs within the first ten years of life.

Attenuated MPS I. The severity and rate of disease progression range from serious life-threatening complications leading to death in the second to third decades to a normal life span complicated by significant disability from progressive joint manifestations. While some individuals have no neurologic involvement and psychomotor development may be normal in early childhood, learning disabilities can be present. Clinical onset is usually between ages three and ten years. Hearing loss and cardiac valvular disease are common.

Diagnosis/testing. The diagnosis of MPS I relies on the demonstration of deficient activity of the lysosomal enzyme α-L-iduronidase in peripheral blood leukocytes, cultured fibroblasts, or plasma. Increased glycosaminoglycan (GAG) (heparan and dermatan sulphate) urinary excretion is a useful preliminary test. IDUA is the only gene in which mutations are currently known to cause MPS I. Sequence analysis is expected to identify both IDUA mutations in most individuals with MPS I.

Management. Treatment of manifestations: Infant learning programs/special education for developmental delays; hats with visors/sunglasses to reduce glare; cardiac valve replacement as needed; physical therapy, orthopedic surgery as needed (joint replacement, atlanto-occipital stabilization, median nerve decompression for carpal tunnel syndrome); cerebrospinal fluid (CSF) shunting for hydrocephalus; tonsillectomy and adenoidectomy for Eustachian tube dysfunction and/or upper airway obstruction; tracheostomy for sleep apnea, pulmonary hypertension, right heart failure; PE tubes; surgical intervention for cervical myelopathy.

Prevention of primary manifestations: Hematopoietic stem cell transplantation (HSCT) in selected children with severe MPS I before age two years can increase survival, reduce facial coarseness and hepatosplenomegaly, improve hearing, and maintain normal heart function. HSCT does not significantly improve skeletal manifestations or corneal clouding. HSCT may slow the course of cognitive decline in children with mild, but not significant, cognitive impairment at the time of transplantation. Due to the morbidity and mortality associated with HSCT, it is currently recommended primarily for children with severe MPS I who may experience some reduction in CNS manifestations. Enzyme replacement therapy (ERT) with laronidase (Aldurazyme®), licensed for treatment of the non-CNS manifestations of MPS I, improves liver size, linear growth, joint mobility, breathing, and sleep apnea in persons with attenuated disease. The timing of the initiation of ERT is likely to influence the outcome.

Prevention of secondary complications: Bacterial endocarditis prophylaxis for those with cardiac involvement; special attention to anesthetic risks.

Surveillance: Early and continuous monitoring of head growth in infants and children; routine median nerve conduction velocity testing; and educational assessment of children with attenuated disease prior to primary school entry. Annual assessment by: orthopedic surgeon, neurologist (spinal cord involvement), ophthalmologist, cardiologist (including echocardiogram), audiologist, and otolaryngologist.

Evaluation of relatives at risk: Sibs of affected individuals should be evaluated either through assay of α-L-iduronidase enzyme activity or IDUA molecular genetic testing (if both disease-causing mutations in the family are known) in order to begin therapy as early in the course of disease as possible.

Genetic counseling. MPS I is inherited in an autosomal recessive manner. At conception, each child of a couple in which both parents are heterozygous for a disease-causing IDUA mutation has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk is possible if both disease-causing IDUA alleles have been identified in the family.

Diagnosis

Clinical Diagnosis

The specific findings of mucopolysaccharidosis type I (MPS I) at presentation vary by disease severity. Clinical findings alone are not diagnostic.

MPS I is often suspected in individuals with the following:

  • Coarse facial features
  • Hepatosplenomegaly
  • Characteristic skeletal and joint findings (gibbus deformity; limitation of joint range of motion)
  • Characteristic ocular findings (corneal clouding)

Testing

Glycosaminoglycan (GAG) urinary excretion. Testing for mucopolysacchariduria by analysis of urinary glycosaminoglycans (heparan and dermatan sulphate) is a useful preliminary test. Measurement of urinary GAGs may be quantitative (measurement of total urinary uronic acid) or qualitative (GAG electrophoresis to analyze the specific GAGs excreted).

  • Neither method can diagnose a specific lysosomal enzyme deficiency, including MPS I; however, an abnormality of either or both indicates the likely presence of an MPS disorder.
  • Both methods have reduced sensitivity, particularly when urine is dilute.
  • GAG electrophoresis can exclude and include certain MPS disorders; definitive diagnosis requires specific enzyme determination.

Alpha-L-iduronidase enzyme assay

  • Affected individuals. The diagnosis of MPS I in an affected individual relies on the demonstration of deficient activity of the lysosomal enzyme α-L-iduronidase, a glycosidase that removes non-reducing terminal α-L-iduronide residues during the lysosomal degradation of the glycosaminoglycans heparan sulphate and dermatan sulphate. Alpha-L-iduronidase enzyme activity can be measured in most tissues; typically, peripheral blood leukocytes, plasma, or cultured fibroblasts are used.
    • Almost all individuals with MPS I have no detectable enzyme.
    • Although not yet confirmed by rigorous testing, as little as 0.13% of normal α-L-iduronidase activity appears to be sufficient to produce a mild phenotype [Ashton et al 1992].
  • Carriers. Carrier testing by enzyme analysis alone can be problematic.
    • Relatives of a proband. When only one or neither IDUA mutation is known, carrier testing of immediate family members of affected individuals requires testing of obligate carriers within the family first in order to determine if their levels of IDUA enzyme activity are clearly distinguishable from normal. If so, the same analysis can be applied to other family members at risk of being carriers.
    • General population
      • The interpretation of α-L-iduronidase enzyme activity for carrier testing of individuals within the general population is difficult because of considerable overlap between the lower end of the normal range of α-L-iduronidase enzyme activity and the upper end of the heterozygous range [Neufeld & Muenzer 2001].
      • The presence of rare pseudodeficiency alleles also renders interpretation of α-L-iduronidase enzyme activity difficult. Pseudodeficiency relates to the finding of reduced or undetectable α-L-iduronidase enzymatic activity with the use of artificial substrates, but no evidence of altered glycosaminoglycan metabolism with the use of radiolabeled (35S) GAG [Aronovich et al 1996].

Molecular Genetic Testing

Gene. IDUA is the only gene in which mutations are currently known to cause MPS I.

Clinical testing

  • Targeted mutation analysis. Mutation panels may vary among testing laboratories, but may include p.Gln70*, p.Ala327Pro, p.Trp402*, p.Pro533Arg, and c.46_57del.
  • Sequence analysis. In a study involving 85 families with MPS I, a combination of targeted mutation analysis and mutation scanning identified both IDUA mutations in 81 (95%) families, one IDUA mutation in three (3.5%) families, and none in one (1.1%) family, with an overall mutation detection rate of 97% for mutant alleles [Beesley et al 2001]. To date more than 100 IDUA mutations have been identified in individuals with MPS I.
  • Deletion/duplication analysis. No exonic or whole IDUA deletions or duplications have been reported to cause MPS I; thus, the usefulness of such testing is unknown.

Table 1. Summary of Molecular Genetic Testing Used in MPS I

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1, 2
IDUATargeted mutation analysisp.Gln70*, p.Ala327Pro, p.Trp402*, p.Pro533Arg, c.46_57del 3100% for the targeted variants 3
Sequence analysisSequence variants 4 including those in mutation panelsUnknown, but should be ~100%
Deletion / duplication analysis 5Partial- or whole-gene deletions or duplicationsNone known 6

1. The ability of the test method used to detect a mutation that is present in the indicated gene.

2. Although no published data are available for mutation detection frequency using sequence analysis, Beesley et al [2001] determined that both mutations could be identified in >95% of affected individuals using a combination of targeted mutation analysis for the most common mutations and mutation scanning.

3. Mutation panels may vary among testing laboratories.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions, missense, nonsense, and splice site mutations.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.

6. No IDUA deletions or duplications have been reported to cause MPS I; therefore, the mutation detection rate is unknown and may be low.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. When MPS is clinically suspected, a combination of initial clinical evaluation and laboratory testing should enable definitive diagnosis of MPS I and distinction from MPS II and MPS III.

Clinical evaluation

  • Evaluation of the extent of visceral findings (i.e. facial coarseness, hepatosplenomegaly, and joint restriction)
  • Skeletal survey to evaluate for dysostosis multiplex
  • Ophthalmologic examination to evaluate for corneal clouding

Laboratory evaluation

  • Analysis of urinary glycosaminoglycans (GAG) followed by GAG electrophoresis to determine the specific species of GAG excreted
  • Assay of α-L-iduronidase enzyme activity in white blood cells, plasma, or fibroblasts
  • Enzyme analysis; recommended as the first diagnostic test
  • Identification of the IDUA mutations to help confirm the diagnosis; targeted mutation analysis is performed first in some laboratories, followed by sequence analysis of the entire coding region if neither or only one mutation is identified.

Carrier testing for at-risk relatives is best performed using molecular genetic testing if both disease-causing alleles have been identified in an affected family member.

Note: When only one or neither IDUA mutation is known, carrier testing of immediate family members of affected individuals requires testing of obligate carriers within the family first in order to determine if their levels of α-L-iduronidase enzyme activity are clearly distinguishable from normal controls. If so, the same analysis can be applied to other family members at risk of being carriers.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Predictive testing. Alpha-L-iduronidase enzyme activity alone cannot predict the severity of MPS I. If molecular testing of an affected individual identifies two recurrent mutant alleles known to be associated with a particular clinical course, prognostication of severe versus attenuated phenotype may be possible. As many non-recurrent alleles have been identified, the ability to accurately predict phenotype based on results of molecular genetic testing may be difficult, particularly early in the course of disease. (See Genotype-Phenotype Correlations.)

Prenatal diagnosis for at-risk pregnancies is best performed by molecular genetic testing when both mutant IDUA alleles have been identified in the family because assay of α-L-iduronidase enzyme activity can be problematic, particularly in laboratories with limited experience.

Preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior identification of both IDUA disease-causing mutations in the family.

Clinical Description

Natural History

Mucopolysaccharidosis type I (MPS I), a progressive multisystem disorder with features ranging over a wide continuum, is considered the prototypic lysosomal storage disease. While affected individuals have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no biochemical differences have been identified [Muenzer 2004] and the clinical findings overlap; thus, affected individuals are best described as having either severe or attenuated MPS I, a distinction that influences therapeutic options. The greatest variability is observed in individuals with attenuated MPS I.

An accurate determination of the proportion of individuals with severe or attenuated MPS I has not been published. Conservative estimates suggest that at least 80% of individuals with MPS I fall at the severe end of the spectrum; however, because of their increased longevity individuals with attenuated disease make up a larger fraction of individuals with MPS I than those with severe disease. It is speculated that individuals with attenuated disease may be underdiagnosed and, thus, skew the estimated proportion of severe to attenuated disease.

Severe MPS I (Hurler Syndrome)

Severe MPS I is characterized by a chronic and progressive disease course involving multiple organs and tissues [reviewed in Clarke 1997, Neufeld & Muenzer 2001, Muenzer et al 2009]. Infants with severe MPS I appear normal at birth but may have inguinal or umbilical hernias. The mean age of diagnosis for severe MPS I is approximately nine months; most affected children are diagnosed before age 18 months. Death, caused by cardiorespiratory failure, usually occurs within the first ten years of life.

Craniofacial and physical appearance. Coarsening of the facial features, caused by storage of GAGs in the soft tissues of the orofacial region and facial bone dysostosis, becomes apparent within the first two years. Thickening of the alae nasi, lips, ear lobules, and tongue becomes progressively more evident. Thickening of the calvarium results in macrocephaly. Scaphocephaly is common. Facial and body hypertrichosis are often seen by age 24 months, at which time the scalp hair is coarse, straight, and thatch-like.

Hepatosplenomegaly. Protuberance of the abdomen caused by progressive hepatosplenomegaly is common [Clarke 1997]. Although organ size may be massive, storage of glycosaminoglycans in the liver and spleen does not lead to organ dysfunction.

Skeletal. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is seen in all individuals with severe MPS I. Children have significant early bone involvement. Mild dysostosis, particularly of the hip, as well as thickening of the ribs, can be detected on radiographs at birth. Gibbus deformity (dorsolumbar kyphosis) often becomes clinically apparent within the first 14 months; it has been reported as early as age six months [Mundada & D'Souza 2009].

By age three years linear growth ceases. Defective ossification centers of the vertebral bodies lead to flattened and beaked vertebrae and subsequent spinal deformity. Complications may include spinal nerve entrapment, acute spinal injury, and atlanto-occipital instability.

The clavicles are short, thickened, and irregular. Long bones are short with wide shafts; the knees are prone to valgus and varus deformities. Endochondral growth plates are thickened and disordered. Typically, the pelvis is poorly formed. The femoral heads are small and coxa valga is common. Involvement of the femoral heads and acetabula leads to progressive and debilitating hip deformity. Progressive arthropathy leading to severe joint deformity is universal; joint stiffness is common by age two years.

Phalangeal dysostosis and synovial thickening lead to a characteristic claw hand deformity. Carpal tunnel syndrome and interphalangeal joint involvement commonly lead to poor hand function. Carpal tunnel syndrome is often missed because of its insidious onset; it often presents with few symptoms or signs other than thenar atrophy.

Ophthalmologic. Corneal clouding occurs in all individuals with MPS I. Progression can lead to severe visual impairment. Open-angle glaucoma may occur. Retinal degeneration resulting in decreased peripheral vision and night blindness is common. Blindness can result from a combination of retinal degeneration, optic nerve compression and atrophy, and cortical damage.

Cardiovascular. Cardiac involvement is seen in all individuals with severe MPS I. Cardiac involvement is evident by echocardiography much earlier than observed clinically. Progressive thickening and stiffening of the valve leaflets can lead to mitral and aortic regurgitation, which may become hemodynamically significant in the later stages of disease. Mitral valve regurgitation is the more common valvular disease in individuals with severe MPS I [Neufeld & Muenzer 2001]. As lysosomal storage continues in the heart, cardiomyopathy, sudden death from arrhythmia, coronary artery disease, and cardiovascular collapse may occur. A small subset of individuals with severe MPS I has an early-onset fatal endocardiofibroelastosis.

Hearing loss. Hearing loss which is common in severe MPS I is correlated to the severity of somatic disease. Hearing loss results from frequent middle ear infection from Eustachian tube dysfunction caused by storage of GAGs within the oro-pharynx, dysostosis of the ossicles of the middle ear, scarring of the tympanic membrane, and damage to the eighth nerve.

ENT (otolaryngologic). Chronic recurrent rhinitis and persistent copious nasal discharge without obvious infection are common. Storage of GAGs within the oro-pharynx with associated enlargement of the tonsils and adenoids can contribute to upper airway complications, along with narrowed trachea, thickened vocal cords, redundant tissue in the upper airway, and an enlarged tongue. This upper airway involvement leads to noisy breathing, particularly at night, and is a main component of obstructive sleep apnea, a common complication particularly in the later stages of disease. CNS involvement can also contribute to sleep apnea.

The voice may be deep and gravelly.

Gastrointestinal system. Inguinal hernias should be repaired surgically with the expectation that they may recur. Umbilical hernias are generally not treated unless they are exceedingly large and cause problems.

For unknown reasons, many children with severe MPS I periodically experience loose stools and diarrhea, sometimes alternating with periods of severe constipation. These problems may or may not diminish with age; they are exacerbated by muscle weakness and physical inactivity, as well as antibiotic use for other problems [Clarke & MacFarland 2001]. Wegrzyn et al [2005] suggested that atypical gastrointestinal microbial infections may underlie gastrointestinal disturbance in the MPSs. The prevalence of such infections is unknown.

Hydrocephaly. Communicating high-pressure hydrocephalus is common in severe MPS I. Impaired resorption of CSF causes an increase in intracranial pressure, leading to brain compression. Increase in intracranial pressure can cause rapid cognitive decline in some individuals. Symptoms may be difficult to assess and progression insidious. The degree to which hydrocephalus contributes to the neurologic deterioration in children with severe MPS I is unknown.

Intellect. Although early psychomotor development may be normal, developmental delay is usually obvious by age 18 months. A measurable decrease in intellectual capacity occurs monthly thereon (as graded by the Bayley Mental Development Index) [Krivit et al 1999]. Subsequently, most children do not progress developmentally but plateau for a number of years, followed by a slow decline in intellectual capabilities. By the time of death at age eight to ten years, most children are severely intellectually disabled.

Children with severe MPS I develop only limited language skills, likely related to the triad of developmental delay, chronic hearing loss, and enlarged tongue [Neufeld & Muenzer 2001].

In contrast to MPS II and MPS III, the severe developmental effects in children with MPS I are associated with placid rather than aggressive behavior. Seizures appear to be uncommon even at the end stages of disease [Clarke 1997].

Heparan sulphate is found in abundance in the brain as part of the extracellular matrix. Deficiency of α-L-iduronidase in individuals with MPS I results in glycosaminoglycan accumulation in the lysosomes of neurons, leading to secondary accumulation of glycolipids that form zebra bodies through a yet-unknown mechanism. The glycosaminoglycan storage and secondary glycolipid storage presumably lead to severe intellectual disability and hydrocephalus.

Attenuated MPS I (Hurler-Scheie Syndrome / Scheie Syndrome)

If development is normal at age 24 months and if moderate somatic involvement is evident, an individual should be classified as having attenuated MPS I. Onset of disease in children with attenuated MPS I is variable, usually occurring between ages three and ten years. The rate of disease progression can range from serious life-threatening complications leading to death in the second to third decades, to a normal life span (albeit with significant disease morbidity). The rarity of MPS I and specifically attenuated MPS I lead to difficulty in developing characteristic phenotypic descriptions [Thomas et al 2010].

Although development may be normal in early childhood, children with attenuated MPS I may have detectable learning disabilities. No correlation between the degree of somatic disease and intellectual deficits in attenuated MPS I has been observed [Vijay & Wraith 2005].

Craniofacial and physical appearance. The physical appearance of individuals with attenuated MPS I varies. Coarseness of facial features is less obvious than in severe MPS I. Findings can include a short neck, broad mouth, square jaw, and micrognathia.

Children with attenuated MPS I have variable degrees of growth retardation.

Hepatosplenomegaly. A variable degree of hepatomegaly is seen in individuals with attenuated MPS I.

Skeletal. Skeletal and joint manifestations are the most significant source of disability and discomfort for individuals with attenuated disease who may have severe bone involvement but no cognitive impairment [Clarke 1997, Vijay & Wraith 2005]. The MPS I Registry showed that more than 85% of persons with attenuated MPS I have dysostosis, primarily in the vertebrae and femur [Thomas et al 2010]. Kyphosis, scoliosis, and severe back pain are common. Spondylolisthesis of the lower spine leading to spinal cord compression can occur.

Progressive arthropathy affecting all joints and eventually leading to loss of or severe restriction in range of motion is universal. Carpel-tunnel syndrome was present at a median age of 13.1 years in approximately 67% of persons with attenuated MPS I included in the MPS I Registry [Thomas et al 2010]. Poor hand function resulting from the characteristic claw hand deformity, carpal tunnel syndrome, and interphalangeal joint stiffness is often observed. Most individuals do not have early symptoms of carpal tunnel syndrome (see Management).

More than 90% of persons with attenuated MPS I included in the MPS I Registry had pes cavus, genu valgum, and “toe-walking” [Thomas et al 2010].

Ophthalmologic. Corneal clouding, exhibited by approximately 82% of children with attenuated MPS I, was identified at a median age of 9.1 years [Thomas et al 2010]. Corneal clouding can lead to significant visual disability. Glaucoma, retinal degeneration, and optic atrophy can occur.

Cardiovascular. Cardiac involvement is estimated to occur in approximately 88% of children with attenuated MPS I at a median age of 11.7 years [Thomas et al 2010]. Cardiac involvement can present as progressive disease of the mitral and aortic valves with regurgitation and/or stenosis, for which valve replacement may be necessary. Aortic valvular disease is more likely to occur in children with attenuated MPS I than in those with severe MPS I [Neufeld & Muenzer 2001]; however, in some individuals, all valves are affected. In a group of 78 persons with attenuated MPS I, 40% had involvement of one valve and 60% had involvement of two or more valves [Thomas et al 2010].

Coronary disease may also be a feature of attenuated MPS I.

Hearing loss. Moderate to severe hearing loss develops in many individuals with attenuated MPS I, particularly children with significant somatic disease. Hearing impairment, most commonly in the high frequency range, is likely caused by a combination of Eustachian tube dysfunction, dysostosis of the ossicles of the middle ear, and eighth nerve involvement.

ENT (otolaryngologic). Rhinorrhea is common.

Sleep apnea as a result of obstructive airway disease and possibly CNS involvement occurs in attenuated MPS I.

Gastrointestinal system. Hernias were present in approximately 65% of persons with attenuated MPS I included in the MPS I Registry [Thomas et al 2010]. Many have also had inguinal hernias during infancy, often requiring repeated surgical correction.

Respiratory system. Progressive pulmonary disease may manifest as abnormalities of forced vital capacity. Respiratory complications (and cardiac involvement) are one of the leading causes of premature death.

Hydrocephaly. The risk of communicating hydrocephalus and its complications are lower in attenuated MPS I than severe MPS I. However, hydrocephalus may occur with insidious onset.

Other neurologic findings. Arachnoid cysts may develop. The predictive power of changes noted on MRI does not seem to be significant in individuals with attenuated MPS I [Neufeld & Muenzer 2001, Matheus et al 2004].

Progressive compression of the spinal cord with resulting cervical myelopathy caused by thickening of the dura (hypertrophic pachymeningitis cericalis) is common in individuals with attenuated MPS I. Cervical myelopathy may present initially as reduced activity or exercise intolerance and may not be recognized until the injury is irreversible [Neufeld & Muenzer 2001].

Intellect. In attenuated MPS I intellect may be normal or nearly normal. If intellectual abilities decline, the course is more protracted than in individuals with severe disease.

Genotype-Phenotype Correlations

Enzyme assay alone is unable to predict the severity of MPS I.

Up to 70% of mutations are recurrent and thus may be helpful in phenotype prediction; however, because many non-recurrent alleles have been identified, the ability to accurately predict phenotype based on genotype is limited. A 2003 comprehensive review of genotype-phenotype correlations illustrates the limitations related to the frequency of private mutations at this locus [Terlato & Cox 2003].

In general, a “severe” IDUA allele is one that results in the severe MPS I phenotype when it is present either in the homozygous state or compound heterozygous state with a previously characterized “severe” allele. Any combination of two “severe” alleles leads to severe MPS I.

In contrast, attenuated MPS I is usually associated with one “severe” allele and a second allele that permits some residual enzyme activity.

Nomenclature

The use of the binary classification of severe MPS I and attenuated MPS I is now generally accepted and more accurately reflects the phenotypes of MPS I than previous naming systems, which divided the attenuated form into intermediate and mild.

Prevalence

MPS I is seen in all populations at a frequency of approximately 1:100,000 for the severe form and 1:500,000 for the attenuated form [Lowry et al 1990, Meikle et al 1999, Poorthuis et al 1999].

Differential Diagnosis

Lysosomal storage disease. Findings in individuals with mucopolysaccharidosis type I (MPS I) overlap those of other lysosomal diseases, particularly other mucopolysaccharide diseases including MPS II, MPS IVA, multiple sulfatase deficiency, mucolipidosis I (sialidosis type II), mucolipidosis II (I-cell disease), mucolipidosis III alpha/beta, and alpha-mannosidosis. Clinical findings and biochemical testing can distinguish them.

Note that deficient α-L-iduronidase enzyme activity may be observed in mucolipidosis II (I-cell disease) and pseudo-Hurler polydystrophy (mucolipidosis III alpha/beta). In these conditions, the enzyme α-L-iduronidase is synthesized in adequate amounts but is not transported to the lysosome because of a defect in the receptor-mediated lysosomal targeting process.

Juvenile idiopathic arthritis. Persons with attenuated MPS I may present with non-inflammatory arthritis at any age; thus, MPS I should be considered in the differential diagnosis of juvenile idiopathic arthritis [Cimaz et al 2006]. Clinical evaluation for the pattern of joint involvement and other manifestations of MPS I should allow identification of individuals with attenuated MPS I presenting with non-inflammatory arthritis.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with mucopolysaccharidosis type I (MPS I), the following evaluations are recommended:

  • Skeletal survey to determine the involvement of the spine and degree and extent of joint involvement
  • Ophthalmologic examination with measurement of visual acuity and intraocular pressure, slit lamp examination of the cornea, and assessment of retinal function by electroretinography and visual field testing
  • Cardiac evaluation with echocardiography to assess ventricular size and function
  • Hearing assessment
  • ENT assessment and consideration of ventilating tubes for recurrent otitis media
  • Consideration of sleep study
  • Cranial imaging, preferentially MRI, including assessment of possible hydrocephalus
  • Assessment of spinal cord and peripheral nerve involvement
  • Developmental assessment

Treatment of Manifestations

Supportive or symptomatic management can improve the quality of life for affected individuals and their families.

Infants with severe MPS I require a stimulating environment to promote early learning, as some skills may be retained during the period of general deterioration.

Skeletal. Physical therapy is a critical aspect of MPS I therapy [Tylki-Szymanska et al 2010a]. Range of motion exercises appear to offer some benefits in preserving joint function, and should be started early. Once significant joint limitation has occurred, increased range of motion may not be achieved without hematopoietic stem cell transplantation (HSCT).

Various orthopedic approaches can be undertaken, particularly in individuals with attenuated disease. Joint replacement and atlanto-occipital stabilization may be necessary. These procedures must be performed at appropriate times in the individual's clinical course and must take into account the presence of other disease complications.

Carpal tunnel syndrome should be treated especially in individuals with attenuated MPS I and individuals with severe MPS I who have had HSCT. Most individuals lack typical symptoms (pain, tingling, or numbness) until severe compression occurs [Haddad et al 1997, Van Heest et al 1998, Bahadir et al 2009]; thus, nerve conduction studies should be used early in the course of disease to identify persons with carpal tunnel syndrome at a time when surgical release may be most beneficial. Surgical decompression of the median nerve results in variable restoration of motor hand activity [Van Heest et al 1998]. Intervention at an early stage, prior to severe nerve damage, optimizes outcome; repeated surgery may be required [Neufeld & Muenzer 2001].

Ophthalmologic. Wearing peaked caps or eye shades can help reduce glare resulting from corneal clouding. Corneal transplantation is successful for individuals with attenuated disease, although donor grafts eventually become cloudy. Individuals with clear grafts may still experience poor vision because of involvement of the retina and/or optic nerve [Neufeld & Muenzer 2001].

Cardiovascular. Cardiac valve replacement should be considered early.

Hearing loss. Tonsillectomy and adenoidectomy correct Eustachian tube dysfunction and decrease upper airway obstruction. Early placement of ventilating tubes is recommended in severely affected individuals. Hearing aids should also be considered.

ENT (otolaryngologic). Sleep apnea may require tracheotomy or high-pressure continuous positive airway pressure (CPAP) with supplemented oxygen. Tracheostomy is often required to maintain the airway and control pulmonary hypertension and right heart failure.

Gastrointestinal system. Some gastrointestinal symptoms (diarrhea and constipation) can be controlled by diet, including control of the amount of roughage. Increased roughage and the conservative use of laxatives may ease constipation.

Hydrocephaly. Cerebrospinal fluid (CSF) pressure and progressive ventricular enlargement indicate a shunting procedure. Ventriculoperitoneal shunting in individuals with MPS I who have moderate to severe hydrocephalus is generally palliative and improves quality of life.

Other. Progressive compression of the spinal cord with resulting cervical myelopathy should be aggressively and quickly evaluated in individuals with attenuated disease or those who have had HSCT. Early surgical intervention may prevent severe complications.

Prevention of Primary Manifestations

Hematopoietic Stem Cell Transplantation (HSCT)

HSCT should be used only in carefully selected children with extensive pretransplantation clinical assessment and counseling in whom systematic long-term monitoring will be possible [Neufeld & Muenzer 2001]. Adults have not undergone HSCT.

Failure to achieve stable engraftment and graft-versus-host disease represent significant barriers to successful HSCT for many children [Peters et al 1996, Peters et al 1998a, Peters et al 1998b]; thus, the procedure carries a high risk of morbidity and mortality [Neufeld & Muenzer 2001]. Pulmonary and cardiac complications post-HSCT appear to be significant [Gassas et al 2003].

In general, the outcome of children undergoing HSCT is varied and depends on the degree of clinical involvement and the child's age at the time of transplantation. It is generally recommended that HSCT be performed before age two years to maximize benefit.

HSCT has been successful in reducing the progression of some findings in children with severe MPS I [Vellodi et al 1997, Guffon et al 1998, reviewed in Neufeld & Muenzer 2001, Souillet et al 2003, Staba et al 2004]. Although the heterogeneity of the disease makes the outcomes of HSCT somewhat difficult to interpret, available data show that:

  • Successful HSCT reduces facial coarseness, and hepatosplenomegaly, improves hearing, and maintains normal heart function;
  • The skeletal manifestations and corneal clouding continue to progress at the same rate in children treated with HSCT and in untreated children [Weisstein et al 2004, Taylor et al 2008];
  • The degree to which HSCT relieves neurologic complications other than progressive intellectual decline is not clear: a few reports suggest improvement [Munoz-Rojas et al 2008, Valayannopoulos et al 2010] whereas others do not. In children undergoing HSCT before evidence of significant developmental delay (i.e., usually between ages 12 and 18 months), HSCT appears to slow the course of cognitive decline. Children showing significant cognitive impairment prior to undergoing HSCT do not show correction of existing impairment.

Survival is increased roughly 67% compared to those not receiving HSCT [Moore et al 2008].

HSCT is not curative and does not ameliorate cardiac valvular or skeletal manifestations.

In individuals predicted to have severe MPS I based on the presence of known severe mutations, use of HSCT resulted in stabilization and improvement of myocardial function with regression of hypertrophy and normalization of chamber dimensions [Braunlin et al 2003]. In that cohort, HSCT did not appear to show significant effects on the presence and progression of valvular involvement.

In part because of increased longevity after HSCT, treated individuals develop increasing pain and stiffness of the hips and knees, carpal tunnel syndrome, spinal cord compression, and progressive thoracolumbar kyphosis [reviewed in Neufeld & Muenzer 2001]. As a result, various orthopedic procedures intended to maintain function and gait have been performed post-HSCT [Masterson et al 1996, Tandon et al 1996].

Pathophysiology. The beneficial effect of HSCT is thought to result from the replacement of deficient macrophages by marrow-derived donor macrophages (Kupffer cells; pulmonary, splenic, nodal, tonsilar, and peritoneal macrophages; and microglial cells) that constitute an ongoing source of normal enzyme capable of gaining access to the various sites of storage [Guffon et al 1998, Prasad & Kurtzberg 2010]. As existing damage is not reversed, early HSCT is critical for optimal effect.

One hypothesis regarding the failure of HSCT in treating skeletal manifestations is the relatively poor vascularity of bone tissues [Taylor et al 2008].

Enzyme Replacement Therapy (ERT)

Laronidase (Aldurazyme®) is currently licensed in the US, Europe, and Canada for use in treating non-CNS manifestations of MPS I. The current dose regime involves premedication with an anti-inflammatory and antihistamine drugs and intravenous weekly infusion of 100 U/kg of Aldurazyme® over four hours.

The potential effect of Aldurazyme® on the progression of somatic findings and (more importantly) the effect that Aldurazyme® may have when started very early in the treatment of an individual with attenuated disease remain to be answered. The latter is particularly important as early diagnosis is critical. Aldurazyme® does not cross the blood-brain barrier and thus is not expected to influence the CNS disease in severely affected individuals.

The phase I open label study included ten individuals with attenuated MPS I treated with human α-L-iduronidase and studied over one year. This study showed improvement in liver size, growth, joint mobility, breathing, and sleep apnea. Increased ability to perform daily functions was reported [Kakkis et al 2001]. A six-year follow-up of five of the treated individuals showed sustained improvements in joint range of motion and sleep apnea and no progression of heart disease, but evidence of progression of valvular involvement [Sifuentes et al 2007].

The phase III double-blind placebo-controlled study included 45 individuals with attenuated MPS I treated for 52 weeks with a 26-week placebo phase [Wraith et al 2005]. This study showed statistically significant improvements in pulmonary function and a six-minute walk test and clear biologic effect with reduction in urinary GAG excretion and liver volume. Patients who had significant sleep apnea at the start of the study improved significantly.

Other case reports representing smaller numbers of treated patients show variable responsiveness to treatment. The heterogeneity of treated patients published to date complicates any conclusions that can be drawn. It appears that the ability of ERT to reverse disease symptoms in individuals with attenuated disease relates closely to the burden of disease prior to commencement of treatment.

All published reports indicate that ERT is well tolerated. Although most individuals treated in either clinical trial developed IgG antibodies, no apparent clinical effects have been reported. These antibodies may, however, hinder therapeutic benefit by promoting more rapid clearance of the enzyme. Follow-up of individuals who were part of the Phase I and Phase III studies indicates that immune tolerance is eventually reached [Kakavanos et al 2003, Wraith et al 2005].

The phase III extension trial included 40 of the individuals from the phase III trial for an additional four years of treatment [Clarke et al 2009].

  • Urinary GAG levels decreased 60%-70% before the reduction rate plateaued after 12 weeks (with 15% of patients achieving normal values).
  • Hepatic volume normalized in 92%.
  • Respiratory function either improved slightly or remained constant.
  • Shoulder joint mobility increased gradually, with larger increases being seen in persons with more severe disease.
  • Timed walk measurements remained largely constant.
  • Quality of life index improved in most (especially with respect to pain).
  • Visual acuity improved in 24% although corneal clouding was unchanged.
  • Growth resumed in approximately 70%; although the growth rate increased with treatment, the final height was still reduced.

The most common reactions were of an immune nature; most were not serious, indicating that Aldurazyme® is generally well tolerated. IgG antibodies to Aldurazyme® were produced in 93% of patients, in inverse correlation to urinary GAG excretion levels; they were not, however, directly related to adverse immune reactions.

Other studies have shown:

  • Improvement in height and cranial diameter with earlier administration of Aldurazyme® (age <1 year) as compared to later administration (age ≥3 years), despite no measurable improvement in growth rate when treatment was started at age one year [Tylki-Szymanska et al 2010b]
  • Improvement of learning performance in one of three patients and noticeable alteration of MRI profile after 3.5-4.5 years of ERT in 3/3 persons with attenuated disease [Valayannopoulos et al 2010]; however, many more individuals would need to be treated to confirm this.
  • Clear differences between early initiation (age 5 months) and late initiation (age 5 years) of ERT in sibs with attenuated MPS I [Coppa et al 2010].

Pathophysiology. The effectiveness of ERT depends on the ability of recombinant enzymes (supplied intravenously) to enter cells and to localize to the lysosome, the appropriate intracellular site [Russell & Clarke 1999].

Prevention of Secondary Complications

Bacterial endocarditis prophylaxis is advised for individuals with cardiac abnormalities [Neufeld & Muenzer 2001].

Individuals with MPS I present major anesthetic risks, including death [Moores et al 1996]. It is appropriate for affected individuals to undergo general anesthesia in centers staffed by anesthesiologists experienced in managing individuals with a mucopolysaccharidosis [Neufeld & Muenzer 2001]. The following are important considerations:

  • Dysostosis multiplex can lead to instability of the spine, including the atlanto-axial joint. Careful positioning and avoidance of hyperextension of the neck are necessary.
  • Induction of anesthesia for any purpose can be difficult because of the difficulty of maintaining an adequate airway. Smaller than anticipated endotracheal tubes may be required for endotracheal intubation because the trachea may be narrowed and the vocal cords thickened.
  • Intubation may require fiber-optic laryngoscopy.
  • Recovery from anesthesia may be slow and postoperative airway obstruction is a common problem.

Surveillance

Persons with MPS I, regardless of disease severity and mode of treatment, should be actively followed at a center that is experienced with the care of individuals with MPS disease.

  • Aggressive orthopedic management for all patients regardless of treatment choices and disease severity; yearly or more frequent assessment by an experienced orthopedic surgeon is recommended.
  • Routine median nerve conduction velocity testing because of the high incidence of carpal tunnel syndrome [Van Heest et al 1998]
  • Annual ophthalmologic assessment with assessment of corneal status and retinal function
  • Cardiac assessment including annual echocardiogram
  • Annual assessment by an audiologist as well as by an otolaryngologist to determine the degree and cause of hearing impairment
  • Early and continuous monitoring of head growth by measuring occipito-frontal circumference (OFC) in infants and children
    • Cranial ultrasound examination and other brain imaging studies are recommended if a rapid increase in OFC occurs.
    • MRI can show ventriculomegaly, but imaging studies often cannot reliably distinguish between brain atrophy and brain compression.
    • Lumbar puncture with measurement of opening pressure of CSF is a preferred method for assessing the degree of pressure elevation [Neufeld & Muenzer 2001].
  • Annual assessment of spinal cord involvement by neurologic examination with consideration of spinal MRI studies when indicated
  • Developmental assessment in all patients; consideration of psycho-educational assessment of children with attenuated disease prior to primary school entry

Evaluation of Relatives at Risk

Sibs of affected individuals should be identified either through assay of enzyme activity or molecular genetic testing of IDUA if both disease-causing mutations in the family are known in order to initiate therapy as early in the course of disease as possible.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

With the success of ERT for MPS I demonstrated by clinical trials, an increased effort is underway to improve responsiveness to ERT and to develop other forms of therapy directed at areas/organs that may not be responsive to ERT, such as skeletal and neurologic involvement.

Combined ERT and HSCT. Whether long-term combined ERT and HSCT may improve the outcome of a severely affected individual is of interest.

Pre-HSCT enzyme replacement therapy (ERT). The use of enzyme replacement therapy (ERT) prior to HSCT should be considered. It has been suggested that pre-HSCT ERT could alleviate existing pulmonary and cardiac manifestations, thus reducing transplantation complications [Tolar et al 2008]. Whether ERT begun prior to HSCT and continued in the peri-HSCT period reduces the frequency of these complications has not been systematically reviewed; however, several trials have supported the safety of peri-HSCT ERT and shown that anti-α-L-Iduronidase antibodies do not seem to be problematic for graft rejection [Tolar et al 2008, Soni et al 2007].

Delivery of enzyme to the CNS. Intravenous infusion of recombinant proteins does not lead to transfer of proteins across the blood-brain barrier. Various means to provide enzyme to the CNS are currently being researched. These approaches include CSF instillation of enzyme via direct injection, continuous pumps, microcapsule implants, and production of chimeric recombinant proteins, enabling passage across the blood-brain barrier.

A clinical trial of intrathecal ERT is currently underway in patients who have evidence of spinal cord involvement. To date, this method has reduced CSF GAG levels and CSF pressure [Munoz-Rojas et al 2008].

Stabilization of mutant enzyme with substrate analogs. It is now generally accepted that lysosomal enzymes must be processed through a complex intracellular sorting mechanism prior to transport to the lysosome. Many point mutations underlying lysosome enzyme deficiencies lead to disease by altering the folding of the protein after translation, such that the misfolded protein cannot be transported to the lysosome. Small molecule substrate analogs have been shown to stabilize mutant lysosomal proteins in tissue culture and thus enable transport of these enzymes to the lysosome. Once in the lysosome, these mutant enzymes are likely able to metabolize enough substrate to alter the disease course. As most individuals with attenuated MPS I have at least one IDUA allele containing a missense mutation, the development of substrate analogs for alpha-L-iduronidase may lead to new forms of therapy for this disorder.

Substrate deprivation. Decreasing the quantity of stored substrate in lysosomal disorders is currently being investigated for the treatment of Gaucher disease [Cox et al 2003]. Potential use of similar molecules that may decrease the production of GAGs or other substances that are stored in MPS disease may have a future role in treatment [Piotrowska et al 2006]. These approaches are still in the animal model phase, with attempts such as silencing of key GAG synthetic enzymes [Kaidonis et al 2010] to certain GAGs.

Gene- and cell-based therapy. Advances in both gene- and stem cell-based therapies for genetic diseases could potentially influence treatment of MPS I [Punnett et al 2004, Di Domenico et al 2005].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Mucopolysaccharidosis type 1 (MPS 1) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with MPS I are obligate heterozygotes (carriers) for a disease-causing IDUA mutation. Individuals with severe disease do not reproduce.

Other family members. Each sib of an obligate heterozygote is at a 50% risk of being a carrier.

Carrier Detection

Measurement of α-L-iduronidase enzyme activity in leukocytes is not a reliable method of carrier determination (see Testing, Alpha-L-iduronidase enzyme assay, Carriers).

Molecular genetic testing of IDUA can be used to identify carriers among at-risk family members when both mutations have been identified in an affected family member.

Molecular genetic testing of IDUA to determine carrier status can be offered to both parents of an affected deceased child with MPS I in whom no molecular testing of IDUA was performed and for whom no DNA samples are available. If both parents are found to be carriers, the diagnosis of MPS I in the proband is confirmed and carrier testing can be offered to family members. If only one parent has an identifiable IDUA mutation, carrier testing using molecular genetic techniques would be available to that parent's family members.

Molecular genetic testing is also possible for carrier testing in the unrelated reproductive partners of individuals known to have an IDUA mutation. Normal molecular genetic test results in an individual at a general population risk can reduce but not eliminate the probability of his/her being a carrier.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

In cases in which the molecular basis of MPS I is known, prenatal diagnosis should be performed by molecular genetic testing as enzyme activity measurements, particularly those performed by laboratories with limited experience, have potential inherent difficulties.

Molecular genetic testing. If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Biochemical genetic testing. Prenatal testing is possible for pregnancies at increased risk for MPS I by measuring α-L-iduronidase enzyme activity in cultured cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or CVS at about ten to 12 weeks' gestation.

Note: (1) Difficulty with prenatal diagnosis for MPS I may result from the low α-L-iduronidase enzyme activity in normal chorionic villi [Young 1992]; however, difficulties in interpreting borderline low α-L-iduronidase enzyme activity can be overcome by assaying enzyme activity in cultured rather than uncultured CVS cells [Neufeld & Muenzer 2001], provided analysis for possible maternal contamination is performed. (2) Measurement of glycosaminoglycans or α-L-iduronidase enzyme activity in amniotic fluid is complicated by high glycosaminoglycan excretion in fetuses and is thus not useful for prenatal testing. (3) Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Carrier status documented in only one parent. When one parent is a known heterozygote and the other parent has inconclusive enzymatic activity and no disease-causing IDUA mutation on molecular genetic testing, or when the mother is a known heterozygote and the father is unknown and/or unavailable for testing, options for prenatal testing can be explored in the context of formal genetic counseling.

Preimplantation genetic diagnosis (PGD) by polar body analysis for MPS I has been reported [Tomi et al 2006] and may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Canadian Society for Mucopolysaccharide and Related Diseases, Inc.
    PO Box 30034
    North Vancouver British Columbia V7H 2Y8
    Canada
    Phone: 800-667-1846 (toll free); 604-924-5130
    Fax: 604-924-5131
    Email: info@mpssociety.ca
  • National MPS Society
    PO Box 14686
    Durham NC 27709-4686
    Phone: 877-677-1001 (toll-free); 919-806-0101
    Fax: 919-806-2055
    Email: info@mpssociety.org
  • Society for Mucopolysaccharide Diseases (MPS)
    MPS House Repton Place
    White Lion Road
    Amersham Buckinghamshire HP7 9LP
    United Kingdom
    Phone: +44 0845 389 9901
    Email: mps@mpssociety.co.uk
  • MPS I Registry
    Genzyme Corporation
    500 Kendall Street
    Cambridge MA 02142
    Phone: 800-745-4447 ext 15500 (toll-free); 617-591-5500
    Fax: 617-374-7339
    Email: help@mpsiregistry.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Mucopolysaccharidosis Type I: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
IDUA4p16​.3Alpha-L-iduronidaseIDUA homepage - Mendelian genesIDUA

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Mucopolysaccharidosis Type I (View All in OMIM)

252800ALPHA-L-IDURONIDASE; IDUA
607014HURLER SYNDROME
607015HURLER-SCHEIE SYNDROME
607016SCHEIE SYNDROME

Normal allelic variants. IDUA is approximately 19 kb with 14 exons; the cDNA open reading frame (ORF) is about 2 kb [Scott et al 1995]. An Alu repetitive sequence and a highly polymorphic VNTR (variable number of tandem repeats) are normal variants reported in intron 2 [Scott et al 1991, Scott et al 1992].

Pathologic allelic variants. The Human Gene Mutation database currently lists more than 110 IDUA mutations. Known mutations include nonsense, missense, and splice site mutations, small deletions, and insertions. It is expected that more intragenic mutations that are null and lead to severe disease will be discovered; mutations causing attenuated MPS I are expected to be limited in number [Neufeld & Muenzer 2001].

Table 2. Selected IDUA Pathologic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change Reference Sequences
c.46_57del12p.Ser16_Ala19delNM_000203​.3
NP_000194​.2
c.208C>Tp.Gln70*
c.223G>Ap.Ala75Thr
c.266G>Ap.Arg89Gln
c.386-2A>G
(474-2A>G)
--
c.653T>Cp.Leu218Pro
c.590-7A>G
(c.678-7A>G)
--
c.979G>Cp.Ala327Pro
c.1029C>Ap.Tyr343*
c.1081G>Ap.Ala361Thr
c.1205G>Ap.Trp402*
c.1598C>Gp.Pro533Arg
c.1960T>Gp.X654Gly

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Table 3. Common Pathologic Variants in Persons with MPS I

Ethnic Background/ Geographic Location% of Persons with MPS I in whom the Common Pathologic Variant was Identified Number of Affected Individuals/ Families StudiedOther Pathologic Alleles with Apparent High Frequencies (%)Reference
p.Gln70*p.Trp402*
Europeans35%37%46Bunge et al [1994]
Netherlands & Germany19%48%
Norway & Finland62%19%
Italian13%11%27p.Pro533Arg (11%)
p.Gly51Asp (9.3%)
p.Ala327Pro (5.6%)
Gatti et al [1997]
North American of European ancestry 117%43%Scott et al [1995]
Central Europe p.Ala327Pro (11%)Scott et al [1995]
Czechoslovakia47%19Vazna et al [2009]
Russian68%Voskoboeva et al [1998]
Australasia55%
Britain7%
Scandinavia65%Bunge et al [1994]
Japanp.Arg89Gln (24%)
c.704ins5 (18%) 2
Yamagishi et al [1996]

1. The most common pathogenic alleles in individuals of European background with MPS I are p.Tryp402* and p.Gln70*.

2. The p.Arg89Gln and c.704ins5 alleles seem to be most frequent in the Japanese population (24% and 18%, respectively), while the p.Trp402* and p.Gln70* alleles may be completely absent [Yamagishi et al 1996]; data, however, are limited.

Normal gene product. Alpha-L-iduronidase is a glycosidase that removes non-reducing terminal α-L-iduronide residues during the lysosomal degradation of heparan sulfate and dermatan sulfate, which are glycosaminoglycans in mammalian cells [Neufeld & Muenzer 2001]. IDUA encodes a peptide of 653 amino acids. The protein sequence is thought to contain six N-glycosylation sites [Zhao et al 1997].

Abnormal gene product. Most of the alleles leading to attenuated MPS I are missense mutations. Exceptions are:

  • p.Tyr343*, a premature stop codon that is used as an acceptor splice site, thereby generating an in-frame deletion [Lee-Chen & Wang 1997] and p.X654Gly, which predicts an extension of α-L-iduronidase at its carboxyl end that may effect a change in the conformation and/or stability of the enzyme
  • A base substitution in p.Arg89Gln that may change the ability of α-L-iduronidase to affect catalysis; its deleterious effect appears to be potentiated by a polymorphism, p.Ala361Thr [Leroy 2003].
  • An interesting mutation that results in mild MPS I: a base substitution in intron 5 (c.590-7A>G) that creates a new splice site and produces a frameshift; however, because the old splice site is not obliterated, some normal enzyme is produced.

References

Literature Cited

  1. Aronovich EL, Pan D, Whitley CB. Molecular genetic defect underlying alpha-L-iduronidase pseudodeficiency. Am J Hum Genet. 1996;58:75–85. [PMC free article: PMC1914939] [PubMed: 8554071]
  2. Ashton LJ, Brooks DA, McCourt PA, Muller VJ, Clements PR, Hopwood JJ. Immunoquantification and enzyme kinetics of alpha-L-iduronidase in cultured fibroblasts from normal controls and mucopolysaccharidosis type I patients. Am J Hum Genet. 1992;50:787–94. [PMC free article: PMC1682646] [PubMed: 1550122]
  3. Bahadir C, Kurtulus D, Cihandide E. Mucopolysaccharidosis type-IS presenting with onset of carpal tunnel syndrome at adolescence. J Clin Rheumatol. 2009;15:402–4. [PubMed: 19955999]
  4. Beesley CE, Meaney CA, Greenland G, Adams V, Vellodi A, Young EP, Winchester BG. Mutational analysis of 85 mucopolysaccharidosis type I families: frequency of known mutations, identification of 17 novel mutations and in vitro expression of missense mutations. Hum Genet. 2001;109:503–11. [PubMed: 11735025]
  5. 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;92:882–6. [PubMed: 14516901]
  6. Bunge S, Kleijer WJ, Steglich C, Beck M, Zuther C, Morris CP, Schwinger E, Hopwood JJ, Scott HS, Gal A. Mucopolysaccharidosis type I: identification of 8 novel mutations and determination of the frequency of the two common alpha-L-iduronidase mutations (W402X and Q70X) among European patients. Hum Mol Genet. 1994;3:861–6. [PubMed: 7951228]
  7. Cimaz R, Vijay S, Haase C, Coppa GV, Bruni S, Wraith E, Guffon N. Attenuated type I mucopolysaccharidosis in the differential diagnosis of juvenile idiopathic arthritis: a series of 13 patients with Scheie syndrome. Clin Exp Rheumatol. 2006;24:196–202. [PubMed: 16762159]
  8. Clarke LA. Clinical diagnosis of lysosomal storage diseases. In: Applegarth DA, Dimmick JE, Hall JG, eds. Organelle Diseases. Clinical Features, Diagnosis, Pathogenesis and Management. London, UK: Chapman and Hall Medical; 1997:37-71.
  9. Clarke L, MacFarland J. Mucopolysaccharidosis-I (MPS-I). The Canadian Society for Mucopolysaccharide and Related Diseases, Inc. Clarke LA, Kaweski C, Di Ilio L, Hahn S, eds. Vancouver: Ticky Graphics and Printing; 2001.
  10. Clarke LA, Wraith JE, Beck M, Kolodny EH, Pastores GM, Muenzer J, Rapoport DM, Berger KI, Sidman M, Kakkis ED, Cox GF. Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I. Pediatrics. 2009;123:229–40. [PubMed: 19117887]
  11. Coppa GV, Buzzega D, Zampini L, Maccari F, Galeazzi T, Pederzoli F, Gabrielli O, Volpi N. Effect of 6 years of enzyme replacement therapy on plasma and urine glycosaminoglycans in attenuated MPS I patients. Glycobiology. 2010;20:1259–73. [PubMed: 20538645]
  12. Cox TM, Aerts JM, Andria G, Beck M, Belmatoug N, Bembi B, Chertkoff R, Vom Dahl S, Elstein D, Erikson A, Giralt M, Heitner R, Hollak C, Hrebicek M, Lewis S, Mehta A, Pastores GM, Rolfs A, Miranda MC, Zimran A. Advisory Council to the European Working Group on Gaucher Disease; The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement. J Inherit Metab Dis. 2003;26:513–26. [PubMed: 14605497]
  13. Di Domenico C, Villani GR, Di Napoli D, Reyero EG, Lombardo A, Naldini L, Di Natale P. Gene therapy for a mucopolysaccharidosis type I murine model with lentiviral-IDUA vector. Hum Gene Ther. 2005;16:81–90. [PubMed: 15703491]
  14. Gassas A, Sung L, Doyle JJ, Clarke JT, Saunders EF. Life-threatening pulmonary hemorrhages post bone marrow transplantation in Hurler syndrome. Report of three cases and review of the literature. Bone Marrow Transplant. 2003;32:213–5. [PubMed: 12838287]
  15. Gatti R, DiNatale P, Villani GR, Filocamo M, Muller V, Guo XH, Nelson PV, Scott HS, Hopwood JJ. Mutations among Italian mucopolysaccharidosis type I patients. J Inherit Metab Dis. 1997;20:803–6. [PubMed: 9427149]
  16. Guffon N, Souillet G, Maire I, Straczek J, Guibaud P. Follow-up of nine patients with Hurler syndrome after bone marrow transplantation. J Pediatr. 1998;133:119–25. [PubMed: 9672523]
  17. Haddad FS, Jones DH, Vellodi A, Kane N, Pitt MC. Carpal tunnel syndrome in the mucopolysaccharidoses and mucolipidoses. J Bone Joint Surg Br. 1997;79:576–82. [PubMed: 9250742]
  18. Kaidonis X, Liaw WC, Roberts AD, Ly M, Anson D, Byers S. Gene silencing of EXTL2 and EXTL3 as a substrate deprivation therapy for heparan sulphate storing mucopolysaccharidoses. Eur J Hum Genet. 2010;18:194–9. [PMC free article: PMC2987189] [PubMed: 19690583]
  19. Kakavanos R, Turner CT, Hopwood JJ, Kakkis ED, Brooks DA. Immune tolerance after long-term enzyme-replacement therapy among patients who have mucopolysaccharidosis I. Lancet. 2003;361:1608–13. [PubMed: 12747881]
  20. Kakkis ED, Muenzer J, Tiller GE, Waber L, Belmont J, Passage M, Izykowski B, Phillips J, Doroshow R, Walot I, Hoft R, Neufeld EF. Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med. 2001;344:182–8. [PubMed: 11172140]
  21. Krivit W, Peters C, Shapiro EG. Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy, mannosidosis, fucosidosis, aspartylglucosaminuria, Hurler, Maroteaux-Lamy, and Sly syndromes, and Gaucher disease type III. Curr Opin Neurol. 1999;12:167–76. [PubMed: 10226749]
  22. Lee-Chen GJ, Wang TR. Mucopolysaccharidosis type I: identification of novel mutations that cause Hurler/Scheie syndrome in Chinese families. J Med Genet. 1997;34:939–41. [PMC free article: PMC1051126] [PubMed: 9391892]
  23. Leroy JG. Disorders of lysosomal enzymes: clinical phenotypes. In: Royce PM, Steinman B, eds. Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects. 2 ed. Hoboken, NJ: John Wiley & Sons; 2003.
  24. Lowry RB, Applegarth DA, Toone JR, MacDonald E, Thunem NY. An update on the frequency of mucopolysaccharide syndromes in British Columbia. Hum Genet. 1990;85:389–90. [PubMed: 2118475]
  25. Masterson EL, Murphy PG, O'Meara A, Moore DP, Dowling FE, Fogarty EE. Hip dysplasia in Hurler's syndrome: orthopaedic management after bone marrow transplantation. J Pediatr Orthop. 1996;16:731–3. [PubMed: 8906643]
  26. Matheus MG, Castillo M, Smith JK, Armao D, Towle D, Muenzer J. Brain MRI findings in patients with mucopolysaccharidosis types I and II and mild clinical presentation. Neuroradiology. 2004;46:666–72. [PubMed: 15205860]
  27. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249–54. [PubMed: 9918480]
  28. 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. [PMC free article: PMC2553763] [PubMed: 18796143]
  29. Moores C, Rogers JG, McKenzie IM, Brown TC. Anaesthesia for children with mucopolysaccharidoses. Anaesth Intensive Care. 1996;24:459–63. [PubMed: 8862643]
  30. Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr. 2004;144(5) Suppl:S27–34. [PubMed: 15126981]
  31. Muenzer J, Wraith JE, Clarke LA. Mucopolysaccharidosis I: management and treatment guidelines. Pediatrics. 2009;123:19–29. [PubMed: 19117856]
  32. Mundada V, D'Souza N. Lumbar gibbus: early presentation of dysostosis multiplex. Arch Dis Child. 2009;94:930–1. [PubMed: 19933601]
  33. Munoz-Rojas MV, Vieira T, Costa R, Fagondes S, John A, Jardim LB, Vedolin LM, Raymundo M, Dickson PI, Kakkis E, Giugliani R. Intrathecal enzyme replacement therapy in a patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am J Med Genet A. 2008;146A:2538–44. [PubMed: 18792977]
  34. Neufeld E, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B, eds. The Metabolic and Molecular Basis of Inherited Disease. 8 ed. New York. NY: McGraw-Hill; 2001:3421-52.
  35. Peters C, Balthazor M, Shapiro EG, King RJ, Kollman C, Hegland JD, Henslee-Downey J, Trigg ME, Cowan MJ, Sanders J, Bunin N, Weinstein H, Lenarsky C, Falk P, Harris R, Bowen T, Williams TE, Grayson GH, Warkentin P, Sender L, Cool VA, Crittenden M, Packman S, Kaplan P, Lockman LA, Anderson J, Krivit W, Dusenbery K, Wagner J. Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome. Blood. 1996;87:4894–902. [PubMed: 8639864]
  36. Peters C, Shapiro EG, Anderson J, Henslee-Downey PJ, Klemperer MR, Cowan MJ, Saunders EF, deAlarcon PA, Twist C, Nachman JB, Hale GA, Harris RE, Rozans MK, Kurtzberg J, Grayson GH, Williams TE, Lenarsky C, Wagner JE, Krivit W. Hurler syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty-four children. The Storage Disease Collaborative Study Group. Blood. 1998a;91:2601–8. [PubMed: 9516162]
  37. Peters C, Shapiro EG, Krivit W. Hurler syndrome: past, present, and future. J Pediatr. 1998b;133:7–9. [PubMed: 9672503]
  38. Piotrowska E, Jakóbkiewicz-Banecka J, Barańska S, Tylki-Szymańska A, Czartoryska B, Wegrzyn A, Wegrzyn G. Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses. Eur J Hum Genet. 2006;14:846–52. [PubMed: 16670689]
  39. Poorthuis BJ, Wevers RA, Kleijer WJ, Groener JE, de Jong JG, van Weely S, Niezen-Koning KE, van Diggelen OP. The frequency of lysosomal storage diseases in The Netherlands. Hum Genet. 1999;105:151–6. [PubMed: 10480370]
  40. Prasad VK, Kurtzberg J. Cord blood and bone marrow transplantation in inherited metabolic diseases: scientific basis, current status and future directions. Br J Haematol. 2010;148:356–72. [PubMed: 19919654]
  41. Punnett A, Bliss B, Dupuis LL, Abdolell M, Doyle J, Sung L. Ototoxicity following pediatric hematopoietic stem cell transplantation: a prospective cohort study. Pediatr Blood Cancer. 2004;42:598–603. [PubMed: 15127414]
  42. Russell CS, Clarke LA. Recombinant proteins for genetic disease. Clin Genet. 1999;55:389–94. [PubMed: 10450855]
  43. Scott HS, Anson DS, Orsborn AM, Nelson PV, Clements PR, Morris CP, Hopwood JJ. Human alpha-L-iduronidase: cDNA isolation and expression. Proc Natl Acad Sci U S A. 1991;88:9695–9. [PMC free article: PMC52785] [PubMed: 1946389]
  44. Scott HS, Bunge S, Gal A, Clarke LA, Morris CP, Hopwood JJ. Molecular genetics of mucopolysaccharidosis type I: diagnostic, clinical, and biological implications. Hum Mutat. 1995;6:288–302. [PubMed: 8680403]
  45. Scott HS, Guo XH, Hopwood JJ, Morris CP. Structure and sequence of the human alpha-L-iduronidase gene. Genomics. 1992;13:1311–3. [PubMed: 1505961]
  46. Sifuentes M, Doroshow R, Hoft R, Mason G, Walot I, Diament M, Okazaki S, Huff K, Cox GF, Swiedler SJ, Kakkis ED. A follow-up study of MPS I patients treated with laronidase enzyme replacement therapy for 6 years. Mol Genet Metab. 2007;90:171–80. [PubMed: 17011223]
  47. Soni S, Hente M, Breslin N, Hersh J, Whitley C, Cheerva A, Bertolone S. Pre-stem cell transplantation enzyme replacement therapy in Hurler syndrome does not lead to significant antibody formation or delayed recovery of the endogenous enzyme post-transplant: a case report. Pediatr Transplant. 2007;11:563–7. [PubMed: 17631030]
  48. Souillet G, Guffon N, Maire I, Pujol M, Taylor P, Sevin F, Bleyzac N, Mulier C, Durin A, Kebaili K, Galambrun C, Bertrand Y, Froissart R, Dorche C, Gebuhrer L, Garin C, Berard J, Guibaud P. Outcome of 27 patients with Hurler's syndrome transplanted from either related or unrelated haematopoietic stem cell sources. Bone Marrow Transplant. 2003;31:1105–17. [PubMed: 12796790]
  49. Staba SL, Escolar ML, Poe M, Kim Y, Martin PL, Szabolcs P, Allison-Thacker J, Wood S, Wenger DA, Rubinstein P, Hopwood JJ, Krivit W, Kurtzberg J. Cord-blood transplants from unrelated donors in patients with Hurler's syndrome. N Engl J Med. 2004;350:1960–9. [PubMed: 15128896]
  50. Tandon V, Williamson JB, Cowie RA, Wraith JE. Spinal problems in mucopolysaccharidosis I (Hurler syndrome). J Bone Joint Surg Br. 1996;78:938–44. [PubMed: 8951011]
  51. Taylor C, Brady P, O'Meara A, Moore D, Dowling F, Fogarty E. Mobility in Hurler syndrome. J Pediatr Orthop. 2008;28:163–8. [PubMed: 18388709]
  52. Terlato NJ, Cox GF. Can mucopolysaccharidosis type I disease severity be predicted based on a patient's genotype? A comprehensive review of the literature. Genet Med. 2003;5:286–94. [PubMed: 12865757]
  53. Thomas JA, Beck M, Clarke JT, Cox GF. Childhood onset of Scheie syndrome, the attenuated form of mucopolysaccharidosis I. J Inherit Metab Dis. 2010;33:421–7. [PMC free article: PMC2903709] [PubMed: 20532982]
  54. 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;41:531–5. [PubMed: 18037941]
  55. Tomi D, Schultze-Mosgau A, Eckhold J, Schopper B, Al-Hasani S, Steglich C, Gal A, Axt-Fliedner R, Schwinger E, Diedrich K, Griesinger G. First pregnancy and life after preimplantation genetic diagnosis by polar body analysis for mucopolysaccharidosis type I. Reprod Biomed Online. 2006;12:215–20. [PubMed: 16478590]
  56. Tylki-Szymanska A, Marucha J, Jurecka A, Syczewska M, Czartoryska B. Efficacy of recombinant human alpha-L-iduronidase (laronidase) on restricted range of motion of upper extremities in mucopolysaccharidosis type I patients. J Inherit Metab Dis. 2010a;33:151–7. [PubMed: 20217237]
  57. Tylki-Szymanska A, Rozdzynska A, Jurecka A, Marucha J, Czartoryska B. Anthropometric data of 14 patients with mucopolysaccharidosis I: retrospective analysis and efficacy of recombinant human alpha-L-iduronidase (laronidase). Mol Genet Metab. 2010b;99:10–7. [PubMed: 19783188]
  58. Valayannopoulos V, Boddaert N, Barbier V, Le Merrer M, Caillaud C, de Lonlay P. Cognitive and neuroradiological improvement in three patients with attenuated MPS I treated by laronidase. Mol Genet Metab. 2010;100:20–3. [PubMed: 20106688]
  59. 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;23:236–43. [PubMed: 9556262]
  60. Vazna A, Beesley C, Berna L, Stolnaja L, Myskova H, Bouckova M, Vlaskova H, Poupetova H, Zeman J, Magner M, Hlavata A, Winchester B, Hrebicek M, Dvorakova L. Mucopolysaccharidosis type I in 21 Czech and Slovak patients: mutation analysis suggests a functional importance of C-terminus of the IDUA protein. Am J Med Genet A. 2009;149A:965–74. [PMC free article: PMC3526155] [PubMed: 19396826]
  61. Vellodi A, Young EP, Cooper A, Wraith JE, Winchester B, Meaney C, Ramaswami U, Will A. Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centres. Arch Dis Child. 1997;76:92–9. [PMC free article: PMC1717089] [PubMed: 9068295]
  62. Vijay S, Wraith JE. Clinical presentation and follow-up of patients with the attenuated phenotype of mucopolysaccharidosis type I. Acta Paediatr. 2005;94:872–7. [PubMed: 16188808]
  63. Voskoboeva EY, Krasnopolskaya XD, Mirenburg TV, Weber B, Hopwood JJ. Molecular genetics of mucopolysaccharidosis type I: mutation analysis among the patients of the former Soviet Union. Mol Genet Metab. 1998;65:174–80. [PubMed: 9787109]
  64. Wegrzyn G, Kurlenda J, Liberek A, Tylki-Szymanska A, Czartoryska B, Piotrowska E, Jakóbkiewicz-Banecka J, Wegrzyn A. Atypical microbial infections of digestive tract may contribute to diarrhea in mucopolysaccharidosis patients: a MPS I case study. BMC Pediatr. 2005;5:9. [PMC free article: PMC1142328] [PubMed: 15882450]
  65. Weisstein JS, Delgado E, Steinbach LS, Hart K, Packman S. Musculoskeletal manifestations of Hurler syndrome: long-term follow-up after bone marrow transplantation. J Pediatr Orthop. 2004;24:97–101. [PubMed: 14676543]
  66. Wraith EJ, Hopwood JJ, Fuller M, Meikle PJ, Brooks DA. Laronidase treatment of mucopolysaccharidosis I. BioDrugs. 2005;19:1–7. [PubMed: 15691212]
  67. Yamagishi A, Tomatsu S, Fukuda S, Uchiyama A, Shimozawa N, Suzuki Y, Kondo N, Sukegawa K, Orii T. Mucopolysaccharidosis type I: identification of common mutations that cause Hurler and Scheie syndromes in Japanese populations. Hum Mutat. 1996;7:23–9. [PubMed: 8664897]
  68. Young EP. Prenatal diagnosis of Hurler disease by analysis of alpha-iduronidase in chorionic villi. J Inherit Metab Dis. 1992;15:224–30. [PubMed: 1527990]
  69. Zhao KW, Faull KF, Kakkis ED, Neufeld EF. Carbohydrate structures of recombinant human alpha-L-iduronidase secreted by Chinese hamster ovary cells. J Biol Chem. 1997;272:22758–65. [PubMed: 9278435]

Suggested Reading

  1. Arn P, Wraith JE, Underhill L (2009) Characterization of surgical procedures in patients with mucopolysaccharidosis type I: findings from the MPS I Registry. J Pediatr. 154:859-64.e3. [PubMed: 19217123]
  2. Tomatsu S, Montaño AM, Oguma T, Dung VC, Oikawa H, de Carvalho TG, Gutiérrez ML, Yamaguchi S, Suzuki Y, Fukushi M, Sakura N, Barrera L, Kida K, Kubota M, Orii T. Dermatan sulfate and heparan sulfate as a biomarker for mucopolysaccharidosis I. J Inherit Metab Dis. 2010;33:141–50. [PubMed: 20162367]

Chapter Notes

Author History

Lorne A Clarke, MD (2002-present)
Jonathan Heppner (2011-present)
Cheryl L Portigal, MSc; University of British Columbia, Vancouver (2002-2004)

Revision History

  • 21 July 2011 (me) Comprehensive update posted live
  • 21 September 2007 (me) Comprehensive update posted to live Web site
  • 6 August 2004 (me) Comprehensive update posted to live Web site
  • 13 June 2003 (cd) Revision: Resources
  • 31 October 2002 (me) Review posted to live Web site
  • 14 March 2002 (cp) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1162PMID: 20301341
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...