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Mucopolysaccharidosis Type I

Synonyms: Alpha-L-Iduronidase Deficiency, IDUA Deficiency, MPS I

, MD.

Author Information

Initial Posting: ; Last Update: February 25, 2021.

Estimated reading time: 41 minutes

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. Affected individuals are best described as having either a phenotype consistent with either severe (Hurler syndrome) 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, as is progressive arthropathy involving most joints. By age three years, linear growth decreases. Intellectual disability is progressive and profound but may not be readily apparent in the first year of life. Progressive cardiorespiratory involvement, hearing loss, and corneal clouding are common. Without treatment, death (typically from cardiorespiratory failure) usually occurs within the first ten years of life.
  • Attenuated MPS I. Clinical onset is usually between ages three and ten years. The severity and rate of disease progression range from serious life-threatening complications leading to death in the second to third decade, 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 and psychiatric manifestations can be present later in life. Hearing loss, cardiac valvular disease, respiratory involvement, and corneal clouding are common.

Diagnosis/testing.

The diagnosis of MPS I is established in a proband with suggestive clinical and laboratory findings by: detection of deficient activity of the lysosomal enzyme α-L-iduronidase (IDUA) in combination with elevation of glycosaminoglycan levels; and/or identification of biallelic pathogenic variants in IDUA on molecular genetic testing. Identification of the causative IDUA variants plays an important role in the determination of phenotype.

Management.

An essential component of management is the determination of whether the proband has severe or attenuated MPS I. This requires detailed clinical and laboratory assessment and can be challenging in very young individuals.

Treatment of manifestations: Infant learning programs/special education for developmental delay; physical therapy, orthopedic surgery as needed, joint replacement for progressive arthropathy, atlanto-occipital stabilization; spinal cord decompression for cervical myelopathy; cerebrospinal fluid shunting for hydrocephalus; early median nerve decompression for carpal tunnel syndrome based on nerve conduction studies before clinical manifestations develop; special attention to anesthetic risks; hats with visors/sunglasses to reduce glare, corneal transplantation for ophthalmologic involvement; cardiac valve replacement as needed and bacterial endocarditis prophylaxis for those with cardiac involvement; tonsillectomy and adenoidectomy for eustachian tube dysfunction and/or upper airway obstruction; ventilating tubes; hearing aids as needed; CPAP for sleep apnea; gastrointestinal management for diarrhea and constipation.

Prevention of primary manifestations

  • Hematopoietic stem cell transplantation (HSCT) for children with severe MPS I. Outcome is significantly influenced by disease burden at the time of diagnosis (and thus, by the age of the individual). HSCT can improve cognitive outcomes, increase survival, improve growth, reduce facial coarseness and hepatosplenomegaly, improve hearing, prevent hydrocephalus, and alter the natural history of cardiac and respiratory symptomatology. HSCT has lesser effects on the skeletal and joint manifestations, corneal clouding, and cardiac involvement. HSCT alters the course of cognitive decline in children with severe MPS I; cognitive outcome is greatly influenced by the degree of 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, and mobility and joint range of motion; slows progression of respiratory disease; and improves sleep apnea in persons with attenuated disease. The age of initiation of ERT influences the outcome.

Surveillance: Annual assessment by a team of physicians with knowledge of the multisystem nature of MPS I. Specialists and assessments: orthopedic surgery including annual assessment of median nerve conduction velocity; ophthalmology, cardiology (including echocardiography), respiratory with assessment of pulmonary function and sleep studies, audiology, and otolaryngology. Assessment for constipation and/or hernias as needed. Early and continuous monitoring of head growth in infants and children with imaging as needed; assessment for evidence of spinal cord compression by neurologic examination; developmental assessment annually; and psycho-educational assessment of children with attenuated disease prior to primary school entry.

Evaluation of relatives at risk: Early diagnosis prior to significant disease manifestations is warranted in relatives at risk in order to initiate 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 disease-causing 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

Scenarios

Scenario 1 – Abnormal Newborn Screening (NBS) Result

Note: The approach to NBS for mucopolysaccharidosis type I (MPS I) is currently in evolution. Although single-tier α-L-iduronidase (IDUA) enzyme activity measurement was the original and remains the most common approach taken in the United States, the potential adoption of a second tier involving measurement of dried blood spot glycosaminoglycans is currently underway by some centers. The addition of the second tier greatly increases the positive predictive value of NBS for MPS I [Clarke et al 2020].

  • Single-tier NBS for mucopolysaccharidosis type I (MPS I) is primarily based on quantification of IDUA enzyme activity on dried blood spots.
  • IDUA enzyme activity values below the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing and clinical evaluation. Follow-up biochemical testing includes confirmation of deficiency of IDUA enzyme activity in blood as well as demonstration of elevation in urinary glycosaminoglycan levels.
  • Positive NBS results should be reviewed by a clinical specialist with experience in MPS I to ensure that the appropriate additional laboratory testing and clinical assessment is performed and correctly interpreted to determine whether this a true positive NBS result and to definitively establish the diagnosis of MPS I.

Scenario 2 – Symptomatic Individual

A symptomatic individual who has findings associated with either attenuated MPS I or severe untreated MPS I (Hurler syndrome) may present because of any of the following: NBS not performed, false negative NBS result, and/or caregivers not compliant with the recommended assessment plan following a positive NBS result.

Supportive (particularly when multiple findings are present) but nonspecific clinical findings and preliminary laboratory findings can include the following.

Clinical findings

  • Coarse facial features
  • Early frequent upper respiratory infections including otitis media
  • Inguinal or umbilical hernia
  • Hepatosplenomegaly
  • Characteristic skeletal findings (gibbus deformity, limitation of joint range of motion)
  • Noninflammatory arthropathy
  • Characteristic ocular findings (corneal clouding)
  • Hydrocephalus
  • Developmental delay

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

Preliminary laboratory findings. Analysis of urine glycosaminoglycans (GAG) (i.e., heparan and dermatan sulfate) may be quantitative (measurement of total urinary GAGs or specific GAG disaccharides) 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.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

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

Note:

  • Identification of biallelic IDUA variants of uncertain significance (or identification of one known IDUA pathogenic variant and one IDUA variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.
  • Due to the presence of IDUA pseudodeficiency, the establishment of the diagnosis of MPS I requires the demonstration of BOTH deficiency of IDUA enzyme activity AND elevation of urine GAGs.

Molecular Testing

When NBS results and/or clinical and preliminary laboratory findings suggest the diagnosis of MPS I, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of IDUA is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. Typically, if only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications; however, to date such variants have only rarely been reported.
  • An MPS multigene panel that includes IDUA and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Mucopolysaccharidosis Type I

Gene 1MethodProportion of Probands with Disease-Causing Variants 2 Detectable by Method
IDUA Sequence analysis 397% 4
Gene-targeted deletion/duplication analysis 5Rare 6
1.
2.

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

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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 two pathogenic variants detectable by sequence analysis in 556 patients was 97% [Clarke et al 2019].

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may 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.

6.

Whole-gene deletions and intragenic deletions of exons 1-2 and exon 14 have been reported [Breen et al 2016, Jahic et al 2019].

IDUA Enzyme Activity

IDUA enzyme activity can be measured in most tissues; typically, peripheral blood leukocytes, plasma, or cultured fibroblasts are used.

  • All individuals with MPS I have no or very little IDUA enzyme activity detected by the standard methods used for diagnostics.
  • Detailed studies using fibroblasts from individuals with MPS I have revealed that as little as 0.13% of normal IDUA enzyme activity appears to be sufficient to produce a mild phenotype [Ashton et al 1992, Oussoren et al 2013]. The overlapping range of residual IDUA enzyme 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 IDUA enzyme activity difficult. Pseudodeficiency relates to the finding of reduced or undetectable IDUA enzyme 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 having Hurler-Scheie syndrome, and 10% as having Scheie syndrome; 8.6% were classified as either unknown or indeterminate. The potential ascertainment bias of registry data and the lack of a clear definition of phenotypic features for each of the subcategories should be considered in interpretation of the data [D'Aco et al 2012].

Table 2.

Mucopolysaccharidosis Type I: Comparison of Phenotypes by Select Features

Feature% of Persons w/Feature 1
Severe MPS IAttenuated MPS I
Course facial features100%10%
Macrocephaly50%20%
Hepatosplenomegaly100%80%
Dysostosis multiplex100%100%
Ophthalmologic issues100%100%
Cardiac involvement100%100%
Hearing loss100%50%
Upper airway involvement100%80%
Hydrocephalus25%5%
Intellectual disability100%10%
1.

The age of the affected individual considerably affects the phenotypic features.

Severe MPS I (Hurler Syndrome)

Severe MPS I is characterized by a chronic and progressive disease course involving multiple organs and tissues [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 ten months; most affected children are diagnosed before age 18 months [Giugliani et al 2020]. In untreated individuals, death due to cardiorespiratory failure usually occurs within the first ten years of life.

Craniofacial and physical appearance. Coarsening of the facial features, caused by storage of glycosaminoglycans (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. Although organ size may be massive, storage of GAGs 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 soon after birth but findings may be interpreted as within normal limits at this early age. Gibbus deformity (dorsolumbar kyphosis) often becomes clinically apparent within the first ten months; it has been reported as early as age six months [Mundada & D'Souza 2009].

MPS I registry data show that by age six months the median growth for individuals with severe MPS I begins to deviate from normal, falling below the third percentile of normal by age four years [Viskochil et al 2019]. 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; significant and functionally impactful 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 from hydrocephalus.

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 and stenosis, 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 oropharynx, 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 oropharynx 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 a deep and gravelly voice, and is a main component of obstructive sleep apnea, a common complication of MPS I. CNS involvement can also contribute to sleep apnea.

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.

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 medical complications.

Hydrocephaly. Communicating high-pressure hydrocephalus is common in individuals with severe MPS I. Impaired resorption of cerebrospinal fluid 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) [Shapiro et al 2018]. 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.

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.

Pathophysiology. The metabolic and physiologic bases of the various symptoms in MPS I are complex and involve the direct cellular effect of lysosomal storage of GAGs, inflammatory pathway activation, alteration of extracellular matrix composition and function, interference of other lysosomal and endosomal pathways, cell signaling, and alteration of autophagy.

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

If development is normal by age 24 months and if moderate somatic involvement is evident (e.g., mild hepatomegaly, relatively normal joint range of motion, mild dysostosis on skeletal x-rays, mild corneal clouding), 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, but recognition of the diagnosis may be delayed [Giugliani et al 2020].

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

Children with attenuated MPS I have variable growth restriction that may not be apparent until later childhood [Viskochil et al 2019].

Hepatosplenomegaly is variable 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 [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. Carpal tunnel syndrome was present at a median age of nine years 11 months in 138 individuals with attenuated MPS I included in the MPS I Registry [Viskochil et al 2017]. 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).

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. Significant 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]. Virtually all individuals with MPS I will have evidence of cardiac valvular thickening. 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 central nervous system involvement occurs in individuals with 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 among 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, Valayannopoulos et al 2010].

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.

Intellect. Although development may be normal in early childhood, children and adults with attenuated MPS I may have detectable learning disabilities. No correlation between the degree of multiorgan disease and intellectual deficits in attenuated MPS I has been observed [Shapiro et al 2015]. If intellectual abilities decline, the course is more protracted than in individuals with severe disease.

Prognosis. The rate of disease progression can range from serious life-threatening complications leading to death in the second to third decade, to a normal life span (albeit with significant disease morbidity).

Genotype-Phenotype Correlations

There is a close correlation of genotype to phenotype in MPS I based on data from 538 individuals within the international MPS I registry [Clarke et al 2019]. Complete loss of IDUA enzyme activity, often due to homozygosity or compound heterozygosity of the common p.Gln70Ter or p.Trp402Ter pathogenic variants, is associated with severe MPS I. Any combination of two "severe" variants leads to severe MPS I. In individuals with severe MPS I, 68% (257/380) had two variants that would be predicted to severely disrupt gene transcription or translation, 76 of the remaining 123 individuals (20%, 76/380) had recurrent variants, and 47 (12.4%, 47/380) had at least one unique variant.

Attenuated MPS I is usually associated with at least one missense variant; registry data showed that 95.6% (151/158) of individuals with attenuated MPS I had at least one missense variant. It is postulated that the missense variant permits some residual enzyme activity.

Exceptions include the following variants associated with attenuated MPS I:

  • p.Tyr343Ter. A premature stop codon that is used as an acceptor splice site, thereby generating an in-frame deletion [Lee-Chen & Wang 1997]
  • p.Ter654Gly predicts an extension of α-L-iduronidase at its carboxyl end that may change the conformation and/or stability of the enzyme.
  • p.Ter654Arg predicts an extension of α-L-iduronidase at its carboxyl end that may change the conformation and/or stability of the enzyme.
  • c.590-7G>A. A base substitution in intron 5 creates a new splice site and produces a frameshift; however, because the old splice site is not obliterated, some normal enzyme is produced.

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 (Hurler syndrome) or attenuated MPS I, a distinction that influences therapeutic options.

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 disorders, including those summarized in Table 3. Clinical findings and biochemical testing can distinguish them.

Table 3.

Genes and Disorders of Interest in the Differential Diagnosis of Mucopolysaccharidosis Type I

Gene 1DiffDx DisorderMOIClinical FindingsBiochemical Findings
IDS MPS II XLSimilar to MPS I but no corneal involvementDeficiency of iduronate-2-sulfatase
GUSB MPS VIIARSimilar to MPS IDeficiency of β-D-glucuronidase
ARSB MPS VIARSimilar to MPS IDeficiency of galactosamine-4-sulfatase
GNPTAB ML II & ML IIIα/β (See GNPTAB-Related Disorders.)ARSimilar to MPS I↑ α-L-iduronidase enzyme activity may be observed in ML II & ML IIIα/β. 2
MAN2B1 Alpha-mannosidosis ARMild dysostosisDeficiency of alpha mannosidase
NEU1 Mucolipidosis I (sialidosis type II) (OMIM 256550)ARCoarse features, myoclonus, seizuresDeficiency of neuraminidase
SUMF1 Multiple sulfatase deficiency ARSimilar to MPS IFormylglycine-generating enzyme
GALNS MPS IVA ARShort stature, chest deformityDeficiency of galactosamine-6-sulfatase
GLB1 MPS IVBARShort stature, chest deformityDeficiency of β-D-galactosidase

AR = autosomal recessive; DiffDx = differential diagnosis; ML = mucolipidosis; MOI = mode of inheritance; MPS = mucopolysaccharidosis; XL = X-linked

1.

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

2.

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 noninflammatory arthritis at any age; thus, MPS I should be considered in the differential diagnosis of juvenile idiopathic arthritis [Cimaz & Mauro 2015]. 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 noninflammatory arthritis.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and determination of phenotype (i.e., severe or attenuated) in an individual diagnosed with mucopolysaccharidosis type I (MPS I), the evaluations summarized in Table 4 and Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis of Mucopolysaccharidosis Type I in a Newborn

EvaluationComment
Consultation w/metabolic physician / biochemical geneticist & specialist metabolic dietitian 1Referral to specialist center w/experience in mgmt of inherited metabolic/genetic diseases is strongly recommended.
Molecular genetic testing for IDUA variantsGenotype of patient is an important component of determining phenotype.
Developmental assessment
  • Consultation w/PT, OT, & speech therapist
  • Consider referral to developmental pediatrician. Experience with the nuances of developmental assessment of children with MPS or other multisystem disorders is critical.
Consultation w/social workerTo ensure understanding of the diagnosis & assess parental / affected person's coping skills & resources
Genetic counseling by genetics professionals 2To inform affected persons & families re nature, MOI, & implications of MPS I to facilitate medical & personal decision making

MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist

1.

After a new diagnosis of MPS I in a child, the closest hospital and local pediatrician should also be informed.

2.

Medical geneticist, certified genetic counselor, or certified advanced genetic nurse

Table 5.

Recommended Evaluations in Individuals with Mucopolysaccharidosis Type I

System/ConcernEvaluationComment
Skeletal Complete skeletal survey to determine degree & extent of joint involvement & involvement of spineHip dysplasia as well as spinal compression are common.
Ophthalmologic Ophthalmologic exam w/measurement of visual acuity & intraocular pressure, slit lamp exam of cornea, & assessment of retinal function by electroretinography & visual field testing if age allowsCorneal clouding is universal & older persons are at risk of glaucoma & retinal dysfunction.
Cardiovascular Cardiac eval w/echocardiography to assess ventricular size, function, & valvular diseaseValvular dysfunction is common; young persons can exhibit cardiomyopathy.
Hearing Hearing assessment
ENT (otolaryngologic) ENT assessment incl sleep studyChronic otitis is common as is upper airway obstruction w/large tonsils & adenoids.
Gastrointestinal Eval for hernias, stooling issues, & assessment of diet
Neurologic Cranial imaging, preferably MRI, incl assessment of possible hydrocephalusSeverely affected persons can have hydrocephalus early in life.
Assessment of spinal cord & peripheral nerve involvementSpinal cord compression can occur at any level, w/cervical compression most common.
Assessment for carpal tunnel syndromeCarpal tunnel compression is common & affected persons may not have primary symptoms.
Development Developmental assessment
Genetic counseling By genetics professionals 1To inform affected persons & families re nature, MOI, & implications of MPS I to facilitate medical & personal decision making
Family support/
resources
Assess need for:
1.

Medical geneticist, certified genetic counselor, or certified advanced genetic nurse

Treatment of Manifestations

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

Due to the multisystem involvement and progressive nature of this disorder, treatment of affected individuals is complex and requires the support of a multidisciplinary team consisting of metabolic/genetic physicians, specialist physicians including orthopedics, general surgery, ophthalmology, ENT, cardiology, neurosurgery, pulmonary, and developmental pediatrics, as well as specialists in neuropsychology, physiotherapy, occupational therapy, genetic counseling, and social work.

To determine the appropriate management for each individual, molecular, biochemical, and clinical assessments must be integrated into the decision-making process. A central component of management of MPS I is the initiation of treatment early in the natural history of disease, as symptoms and disease complications are difficult or impossible to reverse. It is essential to promptly determine whether the individual fits the phenotype of severe or attenuated MPS I, as the only therapeutic approach that has been demonstrated to alter the natural history of the central nervous system (CNS) manifestations characteristic of severe MPS I is hematopoietic stem cell transplantation (HSCT), and the age of initiation of HSCT directly influences the ultimate outcome of affected individuals. Additionally, the age of initiation of enzyme replacement therapy in individuals with attenuated MPS I influences the long-term outcome.

Hematopoietic Stem Cell Transplantation (HSCT)

HSCT is considered the 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 the age of the affected individual). Due to the morbidity and mortality associated with HSCT, it is currently recommended primarily for children with severe MPS I. HSCT is not curative but does significantly alter the natural history of the disorder. To date it is the only therapeutic approach that alters the natural history of neurocognitive disease in MPS I [Aldenhoven et al 2015a, Aldenhoven et al 2015b, Shapiro et al 2015, Kunin-Batson et al 2016]. HSCT has more limited impact on cardiac valvular and skeletal manifestations.

  • HSCT should be used only in carefully selected children with extensive pre-transplantation 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.
  • In general, the outcome of children undergoing HSCT is varied and depends on the degree of clinical involvement and age at the time of transplantation. It is generally recommended that HSCT be performed before age two years to maximize benefit.
  • Individuals who have received HSCT require continued multidisciplinary follow up and monitoring related to MPS I complications.

HSCT has been successful in reducing the rate of progression of some findings in children with severe MPS I. Although the heterogeneity of the disease makes the outcomes of HSCT somewhat difficult to interpret, available data indicate the following:

  • Successful HSCT improves survival [Lum et al 2017].
  • Successful HSCT reduces facial coarseness and hepatosplenomegaly, and improves hearing [van den Broek et al 2020a].
  • The skeletal manifestations and corneal clouding continue to progress in children treated with HSCT and in untreated children [van den Broek et al 2020b].
  • The degree to which HSCT relieves neurologic complications other than progressive intellectual decline is not clear. In children undergoing HSCT before evidence of significant developmental delay (i.e., usually age 12-18 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. The age of HSCT appears to influence the age of onset of carpal tunnel syndrome and cervical compression.
  • Cardiac disease remains a significant factor post HSCT: although HSCT has been shown to initially stabilize and improve myocardial function with regression of hypertrophy and normalization of chamber dimensions, long-term follow up shows continued progression of valvular involvement [Lum et al 2017].
  • 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.

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 [Prasad & Kurtzberg 2010]. As existing damage is not reversed, early HSCT is critical for optimal effect.

Enzyme Replacement Therapy (ERT)

Laronidase (Aldurazyme®) is currently licensed widely for use in treating non-CNS manifestations of MPS I. The current dose regime involves premedication with 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 effect of Aldurazyme® on the rate of disease progression and (more importantly) the effect when started very early in the treatment of an individual with attenuated disease remain to be comprehensively studied. This is largely due to the lack of unbiased long-term outcome data in large cohorts as well as the significant clinical heterogeneity of attenuated MPS I. Aldurazyme® does not cross the blood-brain barrier and thus is not expected to influence CNS disease. Comparative sib studies indicate improved outcomes when ERT is initiated early in the disease course.

Clinical trial extension data and various case series reports of outcome of ERT in individuals with attenuated MPS I who have established clinical disease at initiation of therapy reveal the following [Sifuentes et al 2007, Clarke et al 2009, Al-Sannaa et al 2015, Gabrielli et al 2016]:

  • ERT appears to be well tolerated.
  • Urinary glycosaminoglycan (GAG) levels show a prompt and sustained response within 12 weeks, with some individuals achieving normal values.
  • Hepatic and splenic volumes normalize in the majority of individuals.
  • Respiratory function stabilizes but does not improve.
  • Shoulder joint range of motion increases gradually within the first two years, then plateaus.
  • Mobility as measured by timed-walk measurements improves within the first two years, then can be variably affected by hip, knee, and spinal disease progression.
  • Corneal involvement continues.
  • Cardiac valvular disease progression continues.
  • Progressive arthropathy particular involving large joints (e.g., hips, knees) continues, as does involvement of the hands.
  • Carpal tunnel syndrome remains a potential disease complication.
  • Progressive spinal disease with cord compression particularly in the cervical region is common.
  • Quality of life index improves.

Pathophysiology. The effectiveness of ERT depends on the ability of recombinant enzymes (supplied intravenously) to enter cells and to localize to the lysosome where restoration of GAG catabolism ensues. The ability of intravenous ERT to access and be taken up by cells in all tissues is likely limited, particularly in tissues with poor vascular perfusion (e.g., joint, bone, cardiac valves, spinal cord). In addition, the ability of ERT to reverse the complex pathogenic cascades that are initiated early in the disease course and may ultimately be responsible for disease symptoms remains unknown.

Management of Primary Manifestations

Skeletal. Physical therapy is a critical aspect of MPS I therapy [Tylki-Szymanska et al 2010]. 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 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 [Van Heest et al 1998, Bahadir et al 2009, Viskochil et al 2017]; 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.

Surgical management. 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]. 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 fiberoptic laryngoscopy.
  • Recovery from anesthesia may be slow and postoperative airway obstruction is a common problem.

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

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 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 need for 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.

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.

Table 6.

Recommended Surveillance for Individuals with Mucopolysaccharidosis Type I

System/ConcernEvaluationFrequency
Skeletal Assessment by experienced orthopedic surgeonAt least annually
Median nerve conduction velocity testing to assess for carpal tunnel syndromeAnnually for 1st 10 yrs
Ophthalmologic Ophthalmologic assessment incl corneal status & retinal functionAnnually
Cardiac Cardiac assessment incl echocardiogram
Audiologic/ENT Assessment by audiologist & ENT physician to determine degree & cause of hearing impairment
Gastrointestinal Assessment for constipation &/or herniasAs needed
Neurologic Monitor head growth by measuring OFC.At each visit in infants & children
  • Cranial ultrasound exam & other brain imaging studies; MRI can show ventriculomegaly, but imaging studies often cannot reliably distinguish between brain atrophy & brain compression.
  • Lumbar puncture w/measurement of opening pressure of CSF is preferred method to assess degree of pressure elevation [Neufeld & Muenzer 2001].
If a rapid ↑ in OFC occurs
Assessment for evidence of spinal cord compression by neurologic exam w/consideration of spinal MRI studies when indicatedAnnually
Development Developmental assessmentAt least annually
In children w/attenuated disease: consider psycho-educational assessment.Prior to primary school entry

CSF = cerebrospinal fluid; OFC = occipitofrontal circumference

Evaluation of Relatives at Risk

Testing of all at-risk sibs of any age is warranted in order to initiate therapy as early in the course of disease as possible. For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening, either test for the familial IDUA pathogenic variants or measure IDUA enzyme activity and urinary GAG excretion.

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

Pregnancy Management

Women with MPS I who become pregnant require assessment and frequent monitoring of cardiorespiratory and 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. There have been limited observational data on the outcome of individuals with severe MPS I treated with long-term combined ERT and HSCT. Polgreen et al [2020] report on ten individuals who received long-term ERT post HSCT; growth may have been improved in the younger individuals.

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 individuals 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 α-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 including 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 [Di Domenico et al 2005].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Mucopolysaccharidosis type 1 (MPS I) 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., presumed to be carriers of one IDUA pathogenic variant disease-causing variant based on family history).
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an IDUA disease-causing variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
  • Heterozygotes are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for an IDUA disease-causing variant, each sib of an affected individual has at conception 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.
  • Although MPS I is a heterogeneous disorder, affected sibs will have a clinical course similar to the proband.
  • 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 disease-causing variant. Individuals with severe MPS I generally do not reproduce, but fertility is likely unaffected by the disease; thus, advances to treatments and improved outcomes may lead to pregnancies in the future.

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

Carrier Detection

Molecular genetic testing

  • If both IDUA disease-causing variants have been identified in an affected family member, molecular genetic testing can be used to identify carriers among at-risk family members.
  • 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 disease-causing variant, carrier testing using molecular genetic techniques would be available to the carrier 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/preimplantation genetic 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 Testing

In families in which the molecular basis of MPS I is known, prenatal testing 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

  • Both IDUA disease-causing variants identified in an affected family member. Once both IDUA pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MPS I are possible.
  • 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 disease-causing 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.

Biochemical genetic testing. Measurement of α-L-iduronidase enzyme activity in cultured cells obtained by amniocentesis or CVS was formerly used for prenatal diagnosis; however, the presence of IDUA pseudodeficiency as well as a lack of laboratories available to accurately perform this assay has led to the current use of molecular methods [Clarke 2021].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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
  • MPS Society
    MPS House Repton Place
    White Lion Road
    Amersham Buckinghamshire HP7 9LP
    United Kingdom
    Phone: 0345 389 9901
    Email: mps@mpssociety.org.uk
  • 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
  • Newborn Screening in Your State
    Health Resources & Services Administration
  • 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-Specific DatabasesHGMDClinVar
IDUA 4p16​.3 Alpha-L-iduronidase IDUA database IDUA IDUA

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Mucopolysaccharidosis Type I (View All in OMIM)

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

Molecular Pathogenesis

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

Mechanism of disease causation. Loss of function

IDUA-specific laboratory technical considerations. The presence of rare pseudodeficiency alleles 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]. Pilot studies of newborn screening for MPS I have identified three additional IDUA pseudodeficiency variants: p.Ala79Thr, p.His82Gln, and p.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 to date. It is conceivable that pathogenic variants could affect the function of both IDUA and SLC26A6 and thus lead to a complex phenotype.

Table 7.

Notable IDUA Variants

Reference SequencesDNA Nucleotide Change (Alias 1)Predicted Protein ChangeComment [Reference] 2
NM_000203​.3
NP_000194​.2
c.235G>Ap.Ala79ThrPseudodeficiency variants
c.246C>Gp.His82Gln
c.667G>Ap.Asp223Asn
c.787A>Tp.Arg263Trp
c.965T>Ap.Val322Glu
c.1081G>Ap.Ala361Thr
c.1757C>Tp.Ser586Phe
c.152G>Ap.Gly51AspCommon pathogenic variant in Italy
c.208C>Tp.Gln70TerCommon variant in Europe & Russia; assoc w/severe MPS I
c.266G>Ap.Arg89Gln
  • Common pathogenic variant in Japan; causes attenuated MPS I
  • May change ability of α-L-iduronidase to affect catalysis
  • Deleterious effect appears to be potentiated by a polymorphism, p.Ala361Thr [Leroy 2003].
c.613_617dupTGCTC
(704ins5)
p.Glu207AlafsTer29Common pathogenic variant in Japan
c.590-7G>A--Variant causes attenuated MPS I; creates alternate splice site, but (as old splice site is not obliterated) some normal enzyme is produced.
c.979G>Cp.Ala327ProCommon pathogenic variant in Europe
c.1029C>Ap.Tyr343TerVariant causes attenuated MPS I; premature stop codon used as an acceptor splice site, generating an in-frame deletion [Lee-Chen & Wang 1997].
c.1205G>Ap.Trp402TerCommon pathogenic variant in persons of European ancestry & Australasia
c.1598C>Gp.Pro533ArgCommon pathogenic variant in Italy
c.1960T>Gp.Ter654GlyVariants cause attenuated MPS I; predict extension of α-L-iduronidase at the carboxyl end that may change conformation &/or stability of enzyme.
c.1960T>Cp.Ter654Arg

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

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

1.

Variant designation that does not conform to current naming conventions

2.

See Table 8 for common pathogenic variants by ethnic background and/or geographic location.

Table 8.

Common Pathogenic Variants in Persons with Mucopolysaccharidosis Type I by Ethnic Background and/or Geographic Location

Ethnic Background or Geographic Location% of Persons w/MPS I in whom the Common Pathogenic Variant Was Identified# of Affected Persons or Families StudiedOther Pathogenic Alleles w/Apparent High Frequencies (%)Reference
p.Gln70Terp.Trp402Ter
European 135%37%46 Bunge et al [1994]
Italian13%11%27p.Pro533Arg (11%) Gatti et al [1997]
p.Gly51Asp (9.3%)
p.Ala327Pro (5.6%)
North American & European ancestry 19%46%Clarke et al [1994], Bertola et al [2011]
Czech & Slovak 217%30%19 Vazna et al [2009]
Russian44%4%25 Voskoboeva et al [1998]
Britain10%43%291 Ghosh et al [2017]
Japan19p.Arg89Gln (24%) 3 Yamagishi et al [1996]
c.613_617dupTGCTC (18%) 3
1.

The most common pathogenic alleles in individuals of European background with MPS I are p.Trp402Ter and p.Gln70Ter.

2.

Includes persons from the Czech Republic and Slovakia

3.

The p.Arg89Gln and c.613_617dupTGCTC alleles appear to be most frequent in the Japanese population, while the p.Trp402Ter and p.Gln70Ter alleles may be completely absent [Yamagishi et al 1996]; data, however, are limited.

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

  • 25 February 2021 (sw) Comprehensive update posted live
  • 11 February 2016 (bp) Comprehensive update posted live
  • 21 July 2011 (me) Comprehensive update posted live
  • 21 September 2007 (me) Comprehensive update posted live
  • 6 August 2004 (me) Comprehensive update posted live
  • 13 June 2003 (cd) Revision: Resources
  • 31 October 2002 (me) Review posted live
  • 14 March 2002 (cp) Original submission

References

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