How Hurler syndrome is diagnosed
Diagnosing Hurler syndrome (severe mucopolysaccharidosis type I, MPS I-H) involves putting together the clinical picture, laboratory tests and genetic results. Because early haematopoietic stem cell transplantation (HSCT) can protect brain function, the goal is to move from suspicion to confirmed diagnosis as quickly and safely as possible, while also distinguishing severe MPS I-H from attenuated forms of MPS I.
This page explains each step of the diagnostic pathway for families and healthcare professionals, from first concerns through to enzyme assays and IDUA gene testing.
From concern to confirmed diagnosis
Although individual countries use different protocols, most diagnostic pathways follow the same broad steps:
Clinical suspicion
Based on symptoms and examination
Screening tests
Looking for an MPS disorder
Confirmatory tests
Proving MPS I and identifying variants
Severity assessment
Determining if HSCT is appropriate
Recognising a possible MPS I-H case
The process usually starts when someone notices a pattern of problems rather than a single symptom. Early red flags include:
- Hernias and a gradually enlarged abdomen
- Coarse facial features, large tongue, bigger head
- Frequent ear, nose and throat infections, noisy breathing, snoring
- Joint stiffness and a small bump in the lower spine
- Delayed motor or language development
For clinicians, the key is to consider an MPS disorder whenever multisystem features appear together in a baby or young child.
Initial investigations and MPS screening
These tests help support the suspicion of an MPS disorder and guide which specific enzyme tests to request.
Urine glycosaminoglycans (GAGs)
The first laboratory test is often urine GAGs. This looks for increased levels of glycosaminoglycans, especially dermatan and heparan sulphate, which are typically raised in MPS I.
Key points:
- A markedly elevated GAG level strongly supports an MPS diagnosis
- Normal or mildly raised levels do not fully exclude MPS, especially in young infants
- Many centres now use GAG fractionation or mass spectrometry
Other baseline tests
Depending on local practice, clinicians may also arrange:
- Basic blood tests, including liver function
- Abdominal ultrasound for liver and spleen enlargement
- Skeletal survey to look for dysostosis multiplex
- Echocardiogram to assess heart valves and function
These tests are not diagnostic alone, but help build the overall picture and identify risks before anaesthesia or transplant.
Enzyme assay and IDUA gene analysis
Once an MPS disorder is suspected, the next step is to confirm MPS I specifically.
Alpha-L-iduronidase (IDUA) enzyme assay
The definitive biochemical test for MPS I is measurement of alpha-L-iduronidase activity. This can be performed in leukocytes, plasma, cultured fibroblasts or dried blood spots, depending on the laboratory.
Interpretation:
•Very low or absent IDUA activity confirms MPS I.
•Modestly reduced activity may reflect carrier status, pseudodeficiency or attenuated phenotypes and needs careful interpretation.
•Enzyme assays for other MPS types help ensure the correct subtype is identified.
IDUA gene sequencing
After enzyme testing, molecular genetic analysis of the IDUA gene is performed to identify the exact disease-causing variants. This:
•Confirms that MPS I is due to biallelic pathogenic IDUA variants.
•Helps distinguish MPS I from extremely rare technical issues in enzyme assays.
•Provides information for carrier testing, prenatal diagnosis and preimplantation genetic testing.
Some variants are strongly associated with severe disease, although genotype alone cannot always predict phenotype.
Low IDUA activity
MPS I confirmed
IDUA gene variants identified
IDUA gene variants identified
Babies identified through newborn screening
In some countries, MPS I is part of the newborn screening panel. In these cases, the pathway begins with a low IDUA result on a dried blood spot.
Typical steps after a positive newborn screen:
Repeat or second-tier testing to exclude false positives and pseudodeficiency.
Confirmatory enzyme assay in leukocytes and sometimes additional GAG analysis.
IDUA gene sequencing to identify the variants.
Early clinical assessment by a metabolic team to look for signs of severe MPS I-H versus attenuated disease.
Key message: For infants with clear biochemical and genetic evidence of severe MPS I-H, referral for HSCT assessment should be treated as time critical, often within the first few weeks or months of life.
Assessing disease severity after diagnosis
Once MPS I is confirmed, clinicians must determine whether the child has severe MPS I-H or an attenuated form, because this guides treatment decisions. This assessment uses:
Age at symptom onset and speed of progression
Pattern of somatic features
Including skeletal, cardiac and respiratory involvement
Neurodevelopmental status at diagnosis
Genotype analysis
Particularly whether known severe or mixed variants are present
In some centres, formal severity scoring systems or algorithms are used, especially for screen-detected infants.
For this site, the focus is on children who meet criteria for severe MPS I-H, for whom early HSCT is usually recommended.
What the diagnostic journey looks like for families
The first weeks and months after suspicion can feel overwhelming. Although each country is different, many families experience a similar sequence:
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1You or a doctor notice a pattern of symptoms and order initial tests.
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2You are referred to a specialist metabolic or genetics centre.
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3Your child has a detailed clinical assessment and further tests, including blood, urine, imaging and often hearing and heart checks.
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4Enzyme and genetic tests confirm MPS I, and the team explains whether the features fit Hurler syndrome.
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5If severe MPS I-H is confirmed, you are referred urgently to a transplant team to discuss HSCT, usually along with ERT.
Reassurance: It is normal to feel that everything is happening very fast. You can ask for information in writing, request to record key discussions, and bring family members or friends to appointments for support.
Diagnostic algorithm in practice
For Healthcare Professionals
Turnaround times and test availability vary widely. The unifying principle is to avoid delay in involving a specialist metabolic centre when the pattern of features is suggestive.
Suspect Hurler syndrome or other MPS
If a child has multisystem features (hernia, coarse facies, hepatosplenomegaly, joint stiffness, developmental delay, ENT problems).
Contact metabolic service and arrange initial tests
•Urine GAGs
•Basic bloods, abdominal ultrasound
•Skeletal survey, echocardiogram if readily available
Order IDUA enzyme assay
If urine GAGs are raised or suspicion remains high, order IDUA enzyme assay in leukocytes or dried blood spots, according to local protocol.
Perform genetic testing
If IDUA activity is low, perform IDUA gene sequencing and consider enzyme assays for other MPS types if needed.
Talking about results with families
Sometimes the diagnosis is clear and rapid. In other cases, there may be:
Borderline enzyme results
Variants of uncertain significance
Unclear clinical picture
In these situations, it is important to:
•Be honest that some results are not black and white.
•Explain which tests are clear, which are uncertain and what the plan is.
•Arrange regular follow up and repeat assessments rather than giving false reassurance or unnecessary alarm.
•Offer access to genetic counselling for detailed discussions about inheritance and family planning.
Talking about results with families
Sometimes the diagnosis is clear and rapid. In other cases, there may be: