MPS VII - Sly Syndrome
Mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome, is an ultra-rare lysosomal storage disorder caused by a deficiency of the enzyme β-glucuronidase (GUSB). This enzyme is responsible for breaking down several glycosaminoglycans (GAGs), including dermatan sulfate, heparan sulfate, and chondroitin sulfate. Without sufficient enzyme activity, these GAGs accumulate in lysosomes, impairing normal cell and tissue function and leading to multi-system disease.
MPS VII is one of the rarest MPS subtypes but is notable for its wide spectrum of severity, ranging from severe neonatal forms (including non-immune hydrops fetalis) to later-onset, slowly progressive cases.
Key Facts
- • Prevalence: Fewer than 1 in 250,000 live births
- • Inheritance: Autosomal recessive
- • Affected enzyme: β-glucuronidase (GUSB)
- • Also known as: Sly syndrome
Causes and Pathophysiology
In healthy individuals, β-glucuronidase breaks down GAGs in the lysosome so they can be recycled or eliminated. In MPS VII, loss of GUSB activity leads to the build-up of:
Dermatan sulfate
affects connective tissue, heart, and joints.
Heparan sulfate
affects the brain and nervous system
Chondroitin sulfate
affects cartilage and bone development
This multi-GAG accumulation explains why MPS VII impacts multiple organ systems, including the brain, skeleton, eyes, heart, and lungs.
Signs and Symptoms
The clinical spectrum is highly variable, ranging from severe forms present at birth to milder childhood-onset forms.
Severe forms (often present at birth):
- Non-immune hydrops fetalis (life-threatening fluid accumulation in the foetus)
- Respiratory distress
- Liver and spleen enlargement
Childhood-onset forms:
- Short stature and skeletal abnormalities (dysostosis multiplex)
- Coarse facial features
- Joint stiffness and reduced mobility
- Spinal deformities (kyphosis, scoliosis)
- Enlarged liver and spleen
- Corneal clouding and vision loss
- Cardiac valve disease
- Hearing loss
- Developmental delay or cognitive impairment (more common in severe cases)
Diagnosis
Diagnosis typically involves:
Urinary GAG analysis
Elevated dermatan sulfate, heparan sulfate, and chondroitin sulfate.
Enzyme assay
Demonstrates low or absent β-glucuronidase activity.
Genetic testing
Confirms GUSB mutations.
Prenatal testing
Possible in families with known mutations.
Current Treatment Landscape
Enzyme Replacement Therapy (ERT)
– Intravenous vestronidase alfa is approved in some regions for MPS VII and can reduce GAG levels and improve endurance. However, like other ERTs, it does not effectively reach the brain or avascular cartilage.
Supportive Care
– Orthopaedic surgery, respiratory therapy, cardiac monitoring, vision and hearing aids.
Unmet Needs
- CNS-penetrating therapies to address neurological symptoms in severe cases.
- Early intervention to prevent irreversible organ and skeletal damage.
- One-time treatment options to replace life-long infusions.
Dawn Therapeutics’ Approach
Dawn Therapeutics is developing a gene therapy solution for MPS VII designed to provide:
- Lifelong enzyme production from a single administration.
- Systemic distribution to reach connective tissue, bone, heart, lungs, and liver.
- CNS access potential for neurological symptom management in severe cases.
- Reduced treatment burden compared with weekly ERT infusions.
By targeting both systemic and neurological disease features, our approach has the potential to dramatically improve quality of life for individuals with MPS VII.