History of Hurler Syndrome (MPS I-H)
Hurler syndrome, or mucopolysaccharidosis type I-H (MPS I-H), has been recognised for just over a century. From the first clinical descriptions of affected children in 1919, through the discovery of the underlying enzyme defect, to the introduction of haematopoietic stem cell transplantation (HSCT), enzyme replacement therapy (ERT) and newborn screening, the story of Hurler syndrome reflects the wider evolution of rare disease medicine.
This page gives a concise historical overview, to help families, clinicians and researchers understand how current practice has developed and why there is still a need for new therapies.
The first descriptions of Hurler syndrome
Hurler syndrome is named after Dr Gertrud Hurler, a German paediatrician who, in 1919, described two children with coarse facial features, corneal clouding, short stature, skeletal abnormalities and developmental impairment. Her report, published around 1920, was based on cases first presented by her mentor Professor Meinhard von Pfaundler at the Munich Paediatric Society. (Life in the Fast Lane • LITFL)
In the early decades, the condition was sometimes referred to as “gargoylism”, reflecting the striking facial and skeletal features seen in affected children. This terminology is now considered outdated and potentially stigmatising and has been replaced by the more precise name mucopolysaccharidosis type I-Hurler.
“Hurler syndrome was first clinically described in 1919 by Dr Gertrud Hurler, based on two children with progressive skeletal and developmental problems.”
Recognising a systemic metabolic disease
By the mid twentieth century, clinicians recognised that children with Hurler syndrome did not only have skeletal and facial features but also progressive heart, lung, liver and neurological involvement. Researchers showed that these patients excreted large amounts of mucopolysaccharides in their urine, and the condition was grouped with other disorders of mucopolysaccharide metabolism under the term mucopolysaccharidoses (MPS).
In 1962, Scheie described a much milder form of MPS I with later onset and minimal neurological involvement. Clinicians began to use three clinical labels: Hurler (MPS I-H) for the severe form, Hurler-Scheie for intermediate disease and Scheie for attenuated disease. Today, because there is a continuous spectrum, many experts simply classify MPS I as severe (Hurler) or attenuated.
Hurler (severe MPS I)
Early onset, progressive disease
Hurler-Scheie (intermediate)
Moderate severity, variable presentation
Scheie (attenuated MPS I)
Later onset, minimal neurological involvement
Historical clinical subtypes of MPS I
Identifying the biochemical cause
Hurler syndrome is caused by disease causing variants in the IDUA gene, located on chromosome 4. More than 200 different IDUA mutations have been reported, and the specific combination of variants in an individual partly influences disease severity, although genotype phenotype correlations are not always straightforward.
From the 1960s and 1970s, advances in biochemistry and cell biology led to the recognition that MPS I disorders were lysosomal storage diseases. Researchers showed that Hurler syndrome is caused by a deficiency of the lysosomal enzyme alpha L iduronidase (IDUA). This enzyme is responsible for breaking down the glycosaminoglycans dermatan sulphate and heparan sulphate. Deficiency of IDUA leads to progressive storage of these GAGs in lysosomes throughout the body.
The IDUA gene was later mapped to chromosome 4p16.3, and more than 200 disease causing mutations have since been identified. This helped confirm Hurler syndrome as an autosomal recessive inherited condition and paved the way for modern diagnostics, including enzyme assays and molecular genetic testing.
- Dermatan sulphate
- Heparan sulphate
Haematopoietic stem cell transplantation and changing natural history
Before the 1980s, treatment for Hurler syndrome was largely supportive and the natural history was poor. Most children died in early childhood, commonly from respiratory or cardiac complications.
In 1981, the first haematopoietic stem cell transplant (bone marrow transplant) was performed in a child with MPS I. Donor cells provided a source of functional IDUA enzyme, which could be taken up by recipient tissues. Over the following decades, HSCT became the standard disease modifying treatment for children with severe MPS I-H and significantly altered the natural history of the disease. Long term follow up studies have shown improved survival and preservation of neurocognitive function when HSCT is performed early in life, although many patients still have significant skeletal and cardiorespiratory problems.
Enzyme replacement therapy and the modern treatment era
From the late 1990s and early 2000s, enzyme replacement therapy (ERT) with recombinant human alpha L iduronidase (laronidase) was developed and introduced into clinical practice for MPS I. ERT infusions can reduce GAG storage in many organs and improve endurance, pulmonary function and quality of life, particularly in attenuated MPS I and in combination with HSCT for Hurler syndrome.
For children with severe MPS I-H, ERT is often started before HSCT to stabilise cardiorespiratory status and reduce peri transplant risk, and may be continued afterwards. Despite these advances, long term data show that many transplanted patients live with significant residual disease, especially skeletal deformities, joint stiffness and airway problems, which has driven the search for therapies that can better reach bone and brain.
Key goals of ERT
• Reduce GAG storage in organs
• Improve endurance and pulmonary function
• Enhance quality of life
• Stabilise cardiorespiratory status
Hurler-Scheie (intermediate)
• Limited bone penetration
• Incomplete brain delivery
• Skeletal deformities persist
• Joint stiffness and airway problems
Newborn screening for MPS I
As evidence grew that early HSCT offers the best chance of preserving neurocognitive function, attention turned to newborn screening so that MPS I-H could be identified before symptoms become advanced. Pilot programmes in the 2000s and 2010s showed that it is technically feasible to measure IDUA activity in dried blood spots using tandem mass spectrometry or fluorimetric assays.
Several regions, including parts of the United States, Taiwan, Brazil, Mexico and some European countries, have since implemented newborn screening for MPS I, often as part of broader lysosomal storage disease panels. Screening policies vary by country and remain under active review. In the United Kingdom, for example, national screening committees have concluded that more data are needed before routine newborn screening for MPS I is adopted.
USA
Taiwan
Brazil
Mexico
Europe (selected)
Note for UK users: Newborn screening for MPS I is not yet universal in the United Kingdom. National screening committees continue to review evidence.
Emerging approaches in the twenty first century
The limitations of HSCT and ERT, particularly for skeletal and neurological disease, have led to the development of gene and cell based therapies for MPS I-H. Experimental strategies include ex vivo gene modified stem cell transplantation and in vivo gene therapy using viral vectors to deliver a working IDUA gene. Early clinical and preclinical studies suggest that these approaches may provide more stable enzyme delivery and better access to the brain and skeleton, although they remain investigational and are not yet part of standard care.
This new era builds directly on the historical understanding of Hurler syndrome – from the first clinical descriptions, through the recognition of lysosomal storage, to the success and limitations of HSCT and ERT. Ongoing research aims to change the long term outlook for children and adults living with MPS I-H.
- Early descriptions by Dr Gertrud Hurler established Hurler syndrome as a distinct clinical entity.
- The discovery of IDUA deficiency and classification as MPS I linked clinical features to a clear biochemical cause.
- HSCT and ERT transformed survival and neurocognitive outcomes but did not fully normalise health.
- 4 Newborn screening and early treatment aim to intervene before irreversible damage occurs.
- Ongoing research into gene and cell based therapies seeks to address unmet needs and improve quality of life across the lifespan.
Understanding this journey helps families and clinicians appreciate how far care has come, and why participation in registries, research and advocacy remains so important.
What is Hurler syndrome?
Learn about the fundamentals of Hurler syndrome and how it affects the body.
Natural history and prognosis
Understand the progression and outlook for individuals with Hurler syndrome.
Treatments and care today
Explore current treatment options and care approaches for MPS I-H.