The disease itself
Sanfilippo syndrome is caused by the accumulation of partially degraded heparan sulfate molecules in body’s tissues (heparan sulfate is a polysaccharide found in all animal tissues). This occurs as a consequence of a genetic mutation affecting the activity of an enzyme necessary for heparan sulfate degradation. Undigested molecules, which cannot be eliminated, impair normal brain development and further kill brain cells.
The first symptoms of the disease – delayed cognitive development associated with hyperactivity, autistic behavior and sleep disorders – usually appear before the ages of 3 years. Neurological damage subsequently causes intellectual deficiencies and reduced motor skills, leading to a loss of autonomy at about 10 years of age. There is also slight facial dysmorphia.
Sanfilippo syndrome is often diagnosed late. Incidence in France, UK and Greece has been documented in a retrospective epidemiological study conducted by the Institut Pasteur and the AP-HP in 2009 (Héron B et al. Incidence and natural history of mucopolysaccharidosis type III in France and comparison with United Kingdom and Greece. Am J Med Genet A. January, 2011). It varies from 0.6 to 1.2 diagnosed cases per 100,000 life births.
There are four types of Sanfilippo syndrome – A, B, C and D – and each type is caused by a different enzyme deficiency. Genetic transmission, the same for the four types, is recessive autosomic: a child has a risk of being affected if both parents carry a genetic mutation associated with the disease. The clinical expression of the two most common types – type A and type B – is identical.
Treatment and management
There is currently no treatment for the disease, while care of the symptoms is difficult. Supplying functional enzyme, especially to the brain very early in life is presumably the best strategy to modify the dramatic natural course of the disease.
At the Institut Pasteur
Jean-Michel Heard, researcher at the Institut Pasteur, now retired, developed the first human neuron model for Sanfilippo syndrome at the Institut Pasteur in July 2011. This model facilitates the understanding of cellular mechanisms responsible for the disease and the identification of therapeutic strategies. The procedure used by the scientists, involving stem cells, could also be applied to the modeling of other neurodegenerative diseases.
The Institut Pasteur has sponsored a gene therapy trial for Sanfilippo syndrome type B, which was initiated in 2013, enrolling four children from one and a half to four years old. The trial was conducted at the AP-HP, Paris-Sud University Hospitals (Pr Marc Tardieu). Results have been published in July 13, 2017 in the journal Lancet Neurology. After a 48-months follow-up of the treated children, scientists conclude that the treatment is safe and well tolerated. It is associated with a significant modification of the natural course of the disease. The improvement of neurocognitive performances appears to be correlated with treatment at early age. The endpoint of the protocol was reached 5 ½ years after intracerebral injection of the transgene. In May 2021, in a paper in Frontiers in Immunology, Marie Lise Gougeon of the Institut Pasteur demonstrated the persistent presence of transgene-specific memory lymphocytes and the absence of immunological tolerance to the transgene. However, the detection of the NAGLU enzyme is constant. The clinical and radiological results, currently submitted for publication, confirm the initial results: only the child treated before 2 years of age has significantly better cognitive performance than the untreated children.