Carriers Likely Not at Higher Risk of Adult-onset Dementia

Sanfilippo carriers likely are not at an increased risk of developing adult-onset dementia or other neurodegenerative conditions, despite earlier clinical evidence suggesting such a predisposition, a new study in mice has found.

All types of Sanfilippo are inherited in an autosomal recessive manner. This means that both copies — one from a person’s biological mother and one from the biological father — of any one of the four genes involved in the development of the disorder must carry a mutation for Sanfilippo to develop. A person who has only one faulty copy of the gene will not develop the disease, but is a carrier of it.

The research, conducted by scientists in Australia, was prompted by clinical evidence that carriers of genes that are involved in lysosomal storage disorders similar to Sanfilippo are predisposed to neurodegeneration later on in life. Now the team, from the South Australian Health and Medical Research Institute (SAHMRI), assessed this possible link in mice.

“By better understanding why deficiency in, or mutant forms of some but not all lysosomal proteins, leads to heightened risk or earlier onset of classical neurodegenerative disorders, novel disease‐causing mechanisms may be identified,” the researchers wrote.

The team compared mice carrying a mutation in one copy of SGSH — the gene responsible for Sanfilippo syndrome type A — with mice that were not carriers. All of the mice were assessed through their mid- and late-life stages for signs of neurodegeneration.

A series of behavioral tests were done to study the mice’s motor skills. Carrier mice showed impaired motor performance in the negative geotaxis test, which measures the ability to climb and coordinate movement, as compared with non-carrier mice. However, motor performance did not differ between carrier and non-carrier mice in any of the other behavioral tests.

Given those findings, it seems that carrying one copy of the mutated gene may not overly hasten neurological decline with age or, raise the risk of adult-onset dementia or other conditions, the researchers said.

Further analysis of brain tissue showed no features of common neurodegenerative disorders, to include adult-onset dementia or Parkinson’s disease. There was no evidence of a loss of dopamine — a type of chemical messenger that is lacking in Parkinson’s — or alpha-synuclein positive inclusion bodies, another Parkinson’s feature.

Sanfilippo syndrome is caused by the defective degradation of heparan sulfate, a complex sugar molecule, which leads to its accumulation within cells and tissues. As expected, compared with non-carrier mice, carrier mice had half the levels of sulfamidase, a lysosomal enzyme necessary to break down heparan sulfate. However, no heparan sulfate buildup was observed.

When the researchers looked at certain nerve cells in a region of the brain that controls movement, they observed that although carrier mice had no gross features of neurodegenerative disorders, these neurons did have discrete changes in structure. However, they were unable to test whether the changes in structure translated into changes in function.

According to the foundation, additional studies will be carried out by Nazzmer Nazri, a study co-author and a PhD student at the childhood dementia research group at Flinders University in Adelaide, South Australia.