Associated disorders

The IDUA gene is associated with autosomal recessive mucopolysaccharidosis type I (MPS I) (MedGen UID: 39698, 88566, 6453).

Lysosomal enzymes play an important house-keeping role in the cell by breaking down toxins and recycling used cellular components. The IDUA gene encodes the lysosomal enzyme alpha-L-iduronidase, which is involved in the catabolism of dermatan sulfate and heparan sulfate.

Mucopolysaccharidosis, MPS-I
MedGen UID: 88566

Clinical condition
IDUA (OMIM 252800) is the gene associated with mucopolysaccharidosis type I (MPS I; OMIM 60714) also known as Hurler syndrome. IDUA encodes a lysosomal enzyme called alpha-L-iduronidase, which is necessary for the breakdown of large sugar molecules glycosaminoglycans (GAGs). Mutations in the IDUA gene reduce or completely eliminate the activity of alpha-L-iduronidase, which leads to the accumulation of GAGs within cells (National Library of Medicine. Genetics Home Reference. Mucopolysaccharidosis type I. https://ghr.nlm.nih.gov/condition/mucopolysaccharidosis-type-i. Accessed June 2017).

There is a variable expression of the disorder, with Hurler syndrome at the most severe end of the spectrum, Sheie syndrome (OMIM 60716) at the mildest end, and Hurler-Scheie syndrome (OMIM 60715) in individuals with the intermediate phenotype (National Library of Medicine. Genetics Home Reference. Mucopolysaccharidosis type I. https://ghr.nlm.nih.gov/condition/mucopolysaccharidosis-type-i. Accessed June 2017).

Most affected individuals appear normal at birth, with signs and symptoms developing in 98% of infants within the first six months for the severe end of the spectrum and later in childhood for individuals with a milder presentation (PMID: 28193245). The main features include (PMID: 2031341):

  • macrocephaly with hydrocephalus
  • coarsening of facial features
  • short stature
  • hepatosplenomegaly
  • macroglossia (large tongue)
  • umbilical hernia
  • heart valve abnormalities

Vocal cords can also be involved causing a hoarse voice, while narrowing of the upper airway can result in frequent upper respiratory infections and sleep apnea. Corneal clouding can lead to vision loss, and repeated ear infections may cause hearing loss (National Library of Medicine. Genetics Home Reference. Mucopolysaccharidosis type I. https://ghr.nlm.nih.gov/condition/mucopolysaccharidosis-type-i. Accessed June 2017).

Affected individuals have short stature and joint contractures, which can be severe and limit mobility. X-rays of affected individuals show a characteristic pattern of skeletal abnormalities known as dysostosis multiplex. Spinal stenosis in the neck can cause damage to the spinal cord, and stenosis in the hands can cause carpal tunnel syndrome. Individuals with the severe form of MPS1 have intellectual disability, with the onset of delayed developmental milestones by one year of age or regression of development. Severely affected individuals also have a shortened lifespan (Saudubray J-M, et al.). Individuals with the attenuated forms tend to have longer lifespans and no or mild involvement of the central nervous system. The severe form of MPS1 is more common, but the attenuated forms (Scheie and Hurler-Scheie) may be underdiagnosed (PMID: 22234477).

As of February 2016, the Advisory Committee on Heritable Disorders in Newborns and Children has recommended that MPS I be added to the Recommended Uniform Screening Panel (RUSP). Early diagnosis leading to early treatment has been shown to improve cognition in MPS I (PMID: 25103575, 25624320, 28193245).

Differential diagnosis
There is overlap between MPS I and other lysosomal storage disorders. MPS II (OMIM 253220) can be difficult to distinguish clinically from MPS I, with the exception of corneal clouding, which only occurs in MPS I (Saudubray J-M, et al.). MPS VII (Sly disease; OMIM 253220) can present in utero as hydrops fetalis, but affected individuals who survive resemble patients with MPS I (Saudubray J-M, et al.). In addition, enzyme deficiency of alpha-L-iduronidase can be seen in mucolipidosis II (I cell disease; OMIM 252500) and mucolipidosis III alpha/beta (OMIM 252600; PMID: 20301341). Individuals with Hurler-Scheie or Scheie syndrome may also be misdiagnosed with juvenile idiopathic arthritis (PMID: 20301342).

Gene information
Pathogenic variants in IDUA result in alpha-L-iuronidase enzyme deficiency leading to accumulation of GAGs, heparan, and dermatan sulfate throughout the body and increased GAG levels in the urine. The accumulation GAGs leads to progressive organ damage. Over 200 IDUA pathogenic variants have been documented (Giugliani R, et al.). Some pathogenic variants are recurring, and some are more common among particular ethnic groups (PMID: 22976768, 27520059).

IDUA shows autosomal recessive inheritance.

Comprehensive baseline evaluations including neurologic, developmental, ophthalmologic, auditory, cardiac, respiratory, gastrointestinal, and musculoskeletal should be undertaken at the time of diagnosis and every 6-12 months (PMID: 19117856). Periodic assessments aid in evaluating efficacy of treatment interventions.

Enzyme replacement therapy (ERT) with laronidase (Aldurazyme®) has been shown to be effective in individuals with MPS I in ameliorating some of the symptoms of the disorder (PMID: 27033167). However, the enzyme does not cross the blood–brain barrier and so does not prevent cognitive decline. Evidence suggests that a hematopoietic stem cell transplant can provide some CNS protection if performed early in the disease course, and it is recommended in MPS I patients. There is also evidence that genotype–phenotype correlation may be useful in developing treatment options (PMID: 21831279). Also, clinical trials are assessing the benefits of intrathecal enzyme replacement to address the blood brain–barrier issues. (PMID: 26260077, 28211988).


  • National Library of Medicine. Genetics Home Reference. Mucopolysaccharidosis type I. https://ghr.nlm.nih.gov/condition/mucopolysaccharidosis-type-i. Accessed June 2017.
  • Saudubray J-M, et al., eds. Inborn Metabolic Diseases Diagnosis and Treatment. 6th ed. Berlin, Germany: Springer; 2016.
  • Giugliani R, et al. Lysosomal Disorders. In: Sarafoglou K, et al., eds. Pediatric Endocrinology and Inborn Errors of Metabolism. 2nd ed. McGraw-Hill Education; 2017.

Review date: June 2017

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
IDUA NM_000203.4