Limitations of current treatments in Hurler syndrome (MPS I-H)
Haematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) have transformed the outlook for children with Hurler syndrome (severe mucopolysaccharidosis type I, MPS I-H). Many patients now live into adolescence and adulthood, and some aspects of the disease are significantly improved. However, these treatments are not a cure. Important problems remain in the brain, skeleton, heart, lungs, eyes and day to day functioning, especially in patients who have already had a transplant.
This page explains where current treatments fall short, why there is still a major unmet medical need, and why ongoing research and support are so important for people living with Hurler syndrome.
HSCT and ERT change the outlook – but do not cure the disease
For many children with severe MPS I-H, early HSCT greatly improves survival compared with the natural history and can preserve part of their neurocognitive function. ERT with laronidase improves or stabilises many body symptoms in both severe and attenuated forms of MPS I.
However, long term studies and patient reports show that even after “successful” treatment:
- Many patients still have significant physical disability and organ damage.
- Most need multiple operations and long term specialist care.
- There is still a heavy emotional, social and financial burden on families.
This gap between what current treatments can do and what patients still need is at the heart of the unmet medical need in Hurler syndrome.
Long term burden after transplant
Large follow up studies of children with Hurler syndrome who had HSCT in childhood show that, despite good engraftment and improved survival, residual disease burden remains high.
Common long term problems include:
One long term cohort described the burden of disease after HSCT as still “enormous”, even though transplant clearly improves survival and many organ features. Around 80 percent of patients may become wheelchair dependent later in life.
Skeletal and joint disease
Progressive kyphosis and scoliosis, hip dysplasia, joint contractures
Cardiac and respiratory disease
Valve disease, thickened heart muscle, sleep apnoea, airway problems
Eye and ear problems
Corneal clouding, visual impairment, hearing loss
Functional impact
Difficulties with balance, endurance, fine motor skills and daily activities
When ERT is recommended
ERT with laronidase has an important role but also clear limitations:
Cannot adequately treat the brain
The infused enzyme does not cross the blood–brain barrier in meaningful amounts.
It therefore cannot reliably prevent neurocognitive decline in severe MPS I-H if used alone.
Attenuated MPS I (Hurler–Scheie / Scheie)
Established skeletal deformities, corneal clouding and advanced valve disease usually improve little with ERT alone.
Many patients still need orthopaedic and other surgeries despite years of treatment.
Infusion burden
Weekly hospital or home infusions over many years place a major time and logistical burden on families.
Central lines or ports can be needed and carry their own risks of infection and thrombosis.
Attenuated MPS I (Hurler–Scheie / Scheie)
Many patients develop antibodies to laronidase, which can cause infusion reactions.
This may reduce biochemical response in some cases.
In some countries, ERT is not routinely approved after HSCT because of concerns about donor cell rejection and cost, further limiting options for post-transplant patients.
A generation living with residual disease
A particular concern is the group of patients who have already had HSCT and are now living into their second and third decades of life.
Key issues for this group include:
- HSCT has already given them the best available chance to protect the brain.
- ERT may not be available or may be restricted post-transplant in some health systems.
- Many still have severe musculoskeletal, cardiac, respiratory and sensory problems that progress over time.
“There is no universal therapy available to treat the residual disease post-HSCT”, and this is a key target for new systemic gene therapy approaches.
Those who cannot access or tolerate transplant
Despite international recommendations, not every child with severe MPS I-H receives HSCT:
Some are diagnosed too late for HSCT to be safe or effective.
Others have advanced organ damage that makes transplant too risky.
In some regions there is no local access to experienced transplant or metabolic centres, or families cannot travel.
For these children, ERT and supportive care can help some aspects of the disease but cannot change the underlying prognosis in the same way as early HSCT. This adds to the global unmet need.
Why early diagnosis and newborn screening matter
Early diagnosis through newborn screening programs can identify children before symptoms appear, enabling timely intervention with HSCT when it’s most effective.
The toughest organs to treat
Reviews of MPS I treatments consistently identify certain organ systems as the hardest to treat with HSCT and ERT:
Brain and nervous system
Limited enzyme delivery and ongoing concerns about subtle cognitive, behavioural and mental health issues in some survivors.
Skeleton and joints
Poor vascular supply and complex growth patterns mean current therapies only partly modify disease, leading to progressive deformity and pain.
Heart and circulation
Thickened, dysfunctional valves and potential coronary artery involvement can progress despite HSCT or ERT, with few targeted treatments.
Eyes and vision
HSCT has little impact on existing corneal clouding; ERT is also limited here, and some patients need corneal transplant.
The residual disease burden in MPS I is driven largely by insufficient enzyme levels in the CNS, eyes, heart and bones, even after HSCT or ERT.
Beyond biology – real world barriers
Most patients tolerate laronidase well, but some develop:
Even when HSCT and ERT are available, families face other challenges:
Delayed diagnosis
Symptoms are non-specific in early childhood and newborn screening is not universal, so many children are diagnosed late.
Complex care pathways
Coordinating metabolic, transplant, cardiac, respiratory, orthopaedic, ENT, eye, dental and rehabilitation care is demanding.
Unequal access
Availability of HSCT, ERT, specialist teams and emerging therapies varies widely between countries and even regions.
Psychological and social impact
Surveys of families highlight exhaustion, anxiety about the future, financial strain and difficulties accessing support services.
Voices from families
Families consistently report:
- The emotional toll of managing a chronic, progressive condition
- Financial pressure from frequent medical appointments and travel
- Difficulty balancing care needs with work and other family responsibilities
- The need for better support services and coordinated care
These factors mean that even “best available” care on paper may not translate into optimal outcomes in real life.
Why we still urgently need better treatments
From research and patient experiences, several themes are clear:
- HSCT and ERT have changed the story of Hurler syndrome but have not finished it.
- A whole generation of post-HSCT patients lives with substantial residual disease, especially in bones, joints, heart, lungs, eyes and function.
- There is no universal therapy to address this burden, especially once transplant has already been done.
- New approaches, including systemic and CNS-targeted gene and cell therapies, are being developed to fill these gaps.
This is why ongoing research, clinical trials, patient advocacy and charitable support are so important. Better treatments have the potential not just to extend life but to improve quality of life, independence and participation for people with Hurler syndrome at every age.
Key limitations to keep in mind when planning care
For clinicians, important points include:
- HSCT and ERT should be presented as disease modifying but not curative options.
- Long term follow up must actively look for and manage progressive skeletal, cardiac, respiratory, ocular and ENT disease, even after apparently successful HSCT.
- Adults and older adolescents with Hurler syndrome are an understudied and underserved group, with limited evidence based guidance and substantial unmet need.
- There is a need for standardised outcomes and registries that capture what matters to patients – pain, fatigue, function, mental health and participation, not only laboratory and imaging measures.
- Clinicians should be aware of and, where appropriate, refer to clinical trials and emerging therapies that aim to address CNS, skeletal and residual systemic disease.
Key points about limitations of current treatments
HSCT and ERT are life changing but not curative for Hurler syndrome.
Long term studies show considerable residual disease burden in most transplanted patients, particularly affecting bones, joints, heart, lungs, eyes and function.
ERT does not adequately treat the brain or skeleton and is not always available after HSCT, leaving important gaps in care.
Many children never receive HSCT because of late diagnosis, advanced disease or lack of access, and for them current options are especially limited.
These limitations create a clear unmet medical need, especially for post-HSCT patients and adults with Hurler syndrome, and underline the importance of continued research, advocacy and financial support.
What to read next
Current treatments overview
Haematopoietic stem cell transplant (HSCT)
Process, benefits and risks
Enzyme replacement therapy (ERT)
Weekly infusions, benefits and limitations