Mucopolysaccharidoses And Alpha-mannosidosis Management: Neurology

Prof. Scarpa begins by describing the pathophysiology of central nervous system (CNS) involvement in lysosomal storage disorders. Unlike earlier models focused on simple substrate accumulation, he outlines a more complex cascade involving toxic protein build-up, mitochondrial dysfunction, neuroinflammation, cytokine release, and eventual apoptosis. CNS symptoms in MPS and alpha-mannosidosis vary widely but often include cognitive regression, sleep disturbances, hyperactivity, seizures, and behavioral issues—especially in younger children.

Prof. Scarpa highlights how glycosaminoglycan (GAG) accumulation leads to structural brain changes identifiable through MRI. These include enlarged perivascular spaces, white matter abnormalities, atrophy, hydrocephalus, and J-shaped sella turcica—features that can signal neurological involvement even in early stages. The spine is frequently affected, with dural thickening, cervical stenosis, and spinal cord compression commonly observed, particularly in MPS types I, II, IV, and VI. He emphasizes that spinal MRIs should be performed in flexion-extension positions to detect dynamic compression.

Carpal tunnel syndrome is discussed as a red flag for underlying metabolic disorders in children—an uncommon finding in general pediatrics that should prompt investigation for MPS. He also explains the role of behavioral and cognitive assessments, particularly in identifying early symptoms in children under five. Signs such as hyperactivity, hyperorality, lack of fear, aggression, and sleep disturbance are among the earliest markers of CNS involvement.

Treatment options are limited for CNS symptoms. Enzyme replacement therapy (ERT), administered intravenously, does not cross the blood-brain barrier due to molecular size. While hematopoietic stem cell transplantation (HSCT) is effective in MPS I Hurler syndrome when performed early, its benefit in other MPS types is limited. Newer therapeutic avenues, including intrathecal ERT, receptor-mediated enzyme delivery, gene therapy using viral vectors, and small molecules targeting the CNS, are under investigation but not yet established in clinical practice.

Prof. Scarpa concludes by urging clinicians to be vigilant in recognizing early neurological signs and to pursue diagnosis and intervention swiftly to improve outcomes, particularly as innovative therapies evolve.

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