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Mucopolysaccharidosis Type I

Synonyms: Alpha-L-Iduronidase Deficiency, IDUA Deficiency, MPS I
, MD
Professor, Medical Genetics
University of British Columbia
Vancouver, BC, Canada

Initial Posting: ; Last Update: February 11, 2016.

Summary

Clinical 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 easily measurable 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 and often noted within the first year. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is universal. By age three years, linear growth decreases. 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 and cardiorespiratory disease. 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 is established in a proband with suggestive clinical and laboratory findings and either identification of biallelic pathogenic variants in IDUA on molecular genetic testing or detection of deficient activity of the lysosomal enzyme α-L-iduronidase.

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, early median nerve decompression for carpal tunnel syndrome based on nerve conduction studies before clinical manifestations develop); 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) is considered as standard of care for children with severe MPS I. Outcome from HSCT is significantly influenced by disease burden at the time of diagnosis (and thus, by the age of the patient). HSCT can increase survival, improve growth, reduce facial coarseness and hepatosplenomegaly, improve hearing, and alter the natural history of cardiac and respiratory symptomatology. HSCT has lesser effects on the skeletal and joint 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.
  • 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 (for evidence of spinal cord compression), ophthalmologist, cardiologist (including echocardiogram), audiologist, and otolaryngologist.

Evaluation of relatives at risk: Early diagnosis prior to significant disease manifestations is warranted in relatives at risk 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 IDUA pathogenic variant 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 are possible if both pathogenic IDUA variants have been identified in the family.

GeneReview Scope

Mucopolysaccharidosis Type I: Included Phenotypes
  • Severe MPS I (Hurler syndrome)
  • Attenuated MPS I (Hurler-Scheie syndrome / Scheie syndrome)

For synonyms and outdated names see Nomenclature.

Diagnosis

Suggestive Findings

Mucopolysaccharidosis type I (MPS I) should be suspected in individuals with the following clinical and supportive laboratory findings.

Clinical findings

  • Coarse facial features
  • Early frequent upper-respiratory infections including otitis media
  • Inguinal or umbilical hernia
  • Hepatosplenomegaly
  • Characteristic skeletal and joint findings (gibbus deformity; limitation of joint range of motion)
  • Characteristic ocular findings (corneal clouding)

Note: Clinical findings vary by disease severity. Clinical findings alone are not diagnostic.

Supportive laboratory findings. Analysis of urinary glycosaminoglycans (GAG) (i.e., heparan and dermatan sulfate) may be quantitative (measurement of total urinary uronic acid) or qualitative (GAG electrophoresis to analyze the specific GAGs excreted).

  • Neither the quantitative nor the qualitative method can diagnose a specific lysosomal enzyme deficiency, including MPS I; however, an abnormality detected by either or both methods indicates the likely presence of an MPS disorder.
  • GAG electrophoresis can exclude and include certain MPS disorders; however, definitive diagnosis requires additional testing (see Establishing the Diagnosis).
  • Both methods have reduced sensitivity, particularly when urine is dilute.

Establishing the Diagnosis

The diagnosis of MPS I is established in a proband with the suggestive clinical and laboratory findings above and either identification of biallelic pathogenic variants in IDUA on molecular genetic testing (see Table 1) or detection of deficient activity of the lysosomal enzyme α-L-iduronidase.

Molecular testing approaches can include single-gene testing and use of a multi-gene panel.

  • Single-gene testing. Sequence analysis of IDUA is performed first followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. Of note, no exon or whole-IDUA deletions or duplications have been reported to cause MPS I; thus, the usefulness of such testing is unknown.
  • A multi-gene panel that includes IDUA and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the altered gene at the most reasonable cost.

Table 1.

Summary of Molecular Genetic Testing Used in MPS I

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
IDUASequence analysis 395%-97% 4
Gene-targeted deletion/duplication analysis 5None reported
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

The detection rate for pathogenic variants detectable by sequence analysis in 85 [Beesley et al 2001] and 102 [Bertola et al 2011] individuals with MPS I was 95%-97%.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

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 on the standard samples that are used for diagnostics.
  • Studies using fibroblasts from individuals with MPS I have revealed that as little as 0.13% of normal α-L-iduronidase activity appears to be sufficient to produce a mild phenotype [Ashton et al 1992, Oussoren et al 2013]. The overlapping range of residual IDUA activity noted in fibroblasts of individuals with severe and attenuated disease precludes this measure from being clinically useful.
  • The presence of 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].

Clinical Characteristics

Clinical Description

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 easily measurable 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. Data from the international MPS I registry available in 2011 showed that of the 891 individuals included in the registry 57% were classified as having Hurler syndrome, 23.5% as Hurler-Scheie syndrome, and 10% as Scheie syndrome; 8.6% were classified as either unknown or indeterminate. The potential ascertainment bias of registry data and the lack of clear definition of phenotypic features for each of the subcategories should be considered in interpretation of the data [D'Aco et al 2012].

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 decreases. 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 have 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 thereafter (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].

Pathophysiology. Heparan sulphate is found in abundance in the brain as part of the extracellular matrix. Deficiency of 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) results in glycosaminoglycan accumulation in the lysosomes of neurons, leading to secondary accumulation of glycolipids that form zebra bodies through an as-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) leads 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, wide 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 the characteristic 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 appear 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

Up to 70% of pathogenic variants are recurrent and thus may be helpful in phenotype prediction.

Complete loss of IDUA enzyme activity, often due to homozygosity or compound heterozygosity of the common p.Glu70Ter or p.Typ402Ter pathogenic variants, is associated with severe MPS I. Any combination of two “severe” variants leads to severe MPS I.

Attenuated MPS I is usually associated with one “severe” variant and a second pathogenic variant that permits some residual enzyme activity; however, because many non-recurrent pathogenic variants have been identified, the ability to accurately predict phenotype based on genotype is limited [Terlato & Cox 2003, Bertola et al 2011].

Nomenclature

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.

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 permit identification of individuals with attenuated MPS I presenting with non-inflammatory arthritis.

See Mucopolysaccharidoses: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Guidelines for the management of MPS I have been developed [Muenzer et al 2009].

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.

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 is considered standard of care for children with severe MPS I. Outcome from HSCT is significantly influenced by disease burden at the time of diagnosis (and thus, with the age of the patient). Due to the morbidity and mortality associated with HSCT, it is currently recommended primarily for children with severe MPS I.

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 [Aldenhoven et al 2015a, Aldenhoven et al 2015b]. Adults have not undergone HSCT.

Pulmonary and cardiac complications in the peri-transplant period appear to be significant predictors of transplant complications [Orchard et al 2010].

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, Neufeld & Muenzer 2001, Souillet et al 2003, Staba et al 2004, Aldenhoven et al 2015b]. 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 [Eisengart et al 2013, Aldenhoven et al 2015b]. 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.

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 pathogenic variants, 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. Note that the package insert provides details that may differ by country.

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.

A 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].

A 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].

A 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 finding.
  • 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

The recommended minimal schedule of assessments is highlighted in Muenzer et al 2009].

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 for evidence of spinal cord compression 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 molecular genetic testing of IDUA, if both pathogenic variants in the family are known, or assay of IDUA enzyme activity 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.

Pregnancy Management

Key elements of the management of women with MPS I who become pregnant involve assessment and frequent monitoring of cardiorespiratory as well as spinal cord involvement.

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.

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 and has been found to be safe. The efficacy of intrathecal ERT is unclear [Munoz-Rojas et al 2008, Dickson et al 2015a, Dickson et al 2015b].

Stabilization of mutated 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 single-nucleotide variants 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 mutated lysosomal proteins in tissue culture and thus enable transport of these enzymes to the lysosome. Once in the lysosome, these mutated 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 pathogenic missense variant, 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

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one IDUA pathogenic variant).
  • Heterozygotes are asymptomatic and are not at risk of developing the disorder.

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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of an IDUA pathogenic variant.

Carrier (Heterozygote) Detection

Molecular genetic testing of IDUA can be used to identify carriers among at-risk family members when both pathogenic variants 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 pathogenic variant, carrier testing using molecular genetic techniques would be available to that parent's family members.

Enzyme analysis. Measurement of α-L-iduronidase enzyme activity in leukocytes is not a reliable method of carrier determination.

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, are carriers, or are 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

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. Once the IDUA pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for MPS I are possible.

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 ~15-18 weeks' gestation) or CVS (at ~10-12 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 IDUA pathogenic variant 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.

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
  • My46 Trait Profile
  • 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: 0345 389 9901
    Email: mps@mpssociety.co.uk
  • RegistryNXT!
    Phone: 888-404-4413
    Email: RegistryNXT.helpdesk@us.imshealth.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

GeneChromosome LocusProteinLocus SpecificHGMD
IDUA4p16​.3Alpha-L-iduronidaseIDUA databaseIDUA

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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

Gene structure. IDUA is approximately 19 kb with 14 exons; the cDNA open reading frame (ORF) is about 2 kb [Scott et al 1995]. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. 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].

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]. Recent pilot studies of newborn screening (NBS) for MPS I have identified three additional IDUA pseudodeficiency alleles: p.Ala79Thr, p.His82Gln, and Val322Glu [Pollard et al 2013].

It has been observed that IDUA contains an overlapping transcript coding for a putative sulfate transporter termed Sat-1 (SLC26A6). No pathogenic variants of SLC26A6 have been reported in humans as of yet. It is conceivable that pathogenic variants could affect the function of both IDUA and SLC26A6 and thus lead to a complex phenotype.

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

Table 2.

Selected IDUA Variants

Variant ClassificationDNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
Benignc.236C>Tp.Ala79ThrNM_000203​.3
NP_000194​.2
c.246C>Gp.His82Gln
c.965T>Ap.Val322Glu
c.1081G>Ap.Ala361Thr
Pathogenicc.46_57del12p.Ser16_Ala19del
c.208C>Tp.Gln70Ter
c.223G>Ap.Ala75Thr
c.266G>Ap.Arg89Gln
c.386-2A>G
(474-2A>G)
--
c.653T>Cp.Leu218Pro
c.590-7G>A--
c.979G>Cp.Ala327Pro
c.1029C>Ap.Tyr343Ter
c.1205G>Ap.Trp402Ter
c.1598C>Gp.Pro533Arg
c.1960T>Gp.Ter654Gly

Note on variant classification: Variants listed in the table have been provided by the author. 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 Pathogenic Variants in Persons with MPS I

Ethnic Background/ Geographic Location% of Persons w/MPS I in whom the Common Pathogenic Variant was Identified# of Affected Individuals / Families StudiedOther Pathogenic Alleles w/Apparent High Frequencies (%)Reference
p.Gln70Terp.Trp402Ter
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 Europep.Ala327Pro (11%)Scott et al [1995]
Czech & Slovak 247%19Vazna et al [2009]
Russian68%Voskoboeva et al [1998]
Australasia55%
Britain7%
Scandinavia65%Bunge et al [1994]
Japanp.Arg89Gln (24%)
c.613_617dupTGCTC 3 (18%) 4
Yamagishi et al [1996]
1.

The most common pathogenic alleles in individuals of European background with MPS I are p.Tryp402Ter and p.Gln70Ter.

2.

Includes persons from Czechoslovakia, the Czech Republic, and Slovakia

3.

Also known as 704ins5 [Yamagishi et al 1996]

4.

The p.Arg89Gln and c.613_617dupTGCTC alleles appear to be most frequent in the Japanese population (24% and 18%, respectively), while the p.Trp402Ter and p.Gln70Ter 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 pathogenic missense variants. Exceptions are:

  • p.Tyr343Ter, a premature stop codon that is used as an acceptor splice site, thereby generating an in-frame deletion [Lee-Chen & Wang 1997] and p.Ter654Gly, which predicts an extension of α-L-iduronidase at its carboxyl end that may change 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 pathogenic variant that results in mild MPS I: a base substitution in intron 5 (c.590-7G>A) 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

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Suggested Reading

  • Arn P, Wraith JE, Underhill L. Characterization of surgical procedures in patients with mucopolysaccharidosis type I: findings from the MPS I Registry. J Pediatr. 2009;154:859–64.e3. [PubMed: 19217123]
  • 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, PhD; University of British Columbia (2011-2016)
Cheryl L Portigal, MSc; University of British Columbia (2002-2004)

Revision History

  • 11 February 2016 (bp) Comprehensive update posted live
  • 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
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