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J Inherit Metab Dis. 2010 Aug;33(4):347-62. doi: 10.1007/s10545-010-9075-9. Epub 2010 Apr 29.

Pathophysiology of neuropathic lysosomal storage disorders.

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Department of Paediatrics, Centre for Rare Diseases, University of Padova, Via Giustiniani 3, 35128, Padova, Italy.


Although neurodegenerative diseases are most prevalent in the elderly, in rare cases, they can also affect children. Lysosomal storage diseases (LSDs) are a group of inherited metabolic neurodegenerative disorders due to deficiency of a specific protein integral to lysosomal function, such as enzymes or lysosomal components, or to errors in enzyme trafficking/targeting and defective function of nonenzymatic lysosomal proteins, all preventing the complete degradation and recycling of macromolecules. This primary metabolic event determines a cascade of secondary events, inducing LSD's pathology. The accumulation of intermediate degradation affects the function of lysosomes and other cellular organelles. Accumulation begins in infancy and progressively worsens, often affecting several organs, including the central nervous system (CNS). Affected neurons may die through apoptosis or necrosis, although neuronal loss usually does not occur before advanced stages of the disease. CNS pathology causes mental retardation, progressive neurodegeneration, and premature death. Many of these features are also found in adult neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. However, the nature of the secondary events and their exact contribution to mental retardation and dementia remains largely unknown. Recently, lysosomal involvement in the pathogenesis of these disorders has been described. Improved knowledge of secondary events may have impact on diagnosis, staging, and follow-up of affected children. Importantly, new insights may provide indications about possible disease reversal upon treatment. A discussion about the CNS pathophysiology involvement in LSDs is the aim of this review. The lysosomal involvement in adult neurodegenerative diseases will also be briefly described.

[Indexed for MEDLINE]

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