Brain Changes and Underlying Molecular Mechanisms of MPS Disorders Reviewed

While toxic accumulation of large sugar molecules, called heparan sulfate, are present in certain mucopolysaccharidosis (MPS) disorders with brain involvement, it is still unclear whether this molecule is the primary cause of brain damage or a secondary aspect of other processes, a recent review highlights.

Scientific data suggests that additional studies are necessary to identify the mechanisms underlying brain involvement in MPS, along with biomarkers that provide reliable information about central nervous system (CNS, spinal cord and brain) damage in these disorders.

The review, “Anatomical changes and pathophysiology of the brain in mucopolysaccharidosis disorders,” was published in the journal Molecular Genetics and Metabolism.

MPS disorders are characterized by deficiencies in lysosomal enzymes involved in the degradation of large sugar molecules called glycosaminoglycans (GAGs). MPS I, II, III (Sanfilippo syndrome), and VII patients display accumulation of heparan sulfate — one of the major types of GAGs — and CNS involvement, suggesting that toxic accumulation of heparan sulfate is involved in CNS damage.

CNS damage in MPS can manifest as impaired cognition, behavioral difficulties, epileptic seizures, sleeping problems, and/or fluid accumulation in the brain (hydrocephalus).

In 2016, an international group 39 MPS experts gathered in Stockholm, Sweden to discuss CNS changes associated with heparan sulfate accumulation in MPS I, II, III, and VII patients.

Post-mortem analysis of tissue samples has shown that while brain lesions are present in all these patients, they seem to be more abundant in MPS II patients with cognitive difficulties and to increase over time. Also, brain atrophy is observed more frequently in people with MPS II and III.

Reduced integrity of the blood-brain barrier — the protective membrane that restricts the passage of large molecules from the blood into the brain — also has been reported in patients with Sanfilippo syndrome, suggesting that problems in this membrane may contribute to CNS changes.

Also, several types of brain cells, cells of the blood-brain barrier, and brain blood vessels, have been shown to display abnormalities in this patient population.

MPS I, II, and III patients have up to six times higher GAGs levels in the brain than healthy people, supporting the idea that CNS changes may result from GAGs accumulation, particularly accumulation of heparan sulfate.

However, experts noted that brain changes also have been reported in other types of MPS not associated with heparan sulfate accumulation or cognitive impairment.

So, while many studies point to heparan sulfate accumulation as the trigger of neurodegeneration in these types of MPS, it remains unclear how it can lead to different features of brain damage and cognitive symptoms between them.

The knowledge about the mechanisms behind MPS disorders and their differences have been greatly provided by mouse models of these diseases.

Studies in these mouse models, cells grown in the lab, and in MPS patients have suggested that accumulation of heparan sulfate triggers production of pro-inflammnatory molecules (those involved in inflammatory processes), affects the function of mitochondria — cells’ powerhouses and waste disposal centers — increases the production of reactive oxygen species (oxygen-related molecules that cause oxidative stress and cell damage) and leads to nerve cell dysfunction and impaired nerve cell communication.

The experts also noted that while several molecules associated with these processes in MPS disorders potentially could be useful biomarkers of disease status and progression, to date, no biomarker allows the identification and monitoring of neurodegeneration and the prediction of disease progression in MPS disorders.

With a clear dysregulation of inflammation in MPS disease, and its association with impaired cognition in other neurodegenerative diseases, researchers suggest that an inflammation/immune system-related biomarker could reflect treatment response in the brain.

The authors concluded that additional studies are necessary to identify biomarkers of neurodegeneration and the underlying mechanisms in MPS with CNS involvement.