Excerpt from Lysosomal Storage Disease

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Lysosomes are subcellular organelles responsible for the physiologic turnover of cell constituents containing catabolic enzymes requiring a low optimum pH to function.

Lysosomal storage diseases describe a heritable group of rare heterogeneous human disorders characterized by the accumulation of undigested macromolecules intralysosomally, which results in an increase in the size and number of these organelles and ultimately in cellular dysfunction and clinical abnormalities.

Many lysosomal storage diseases exist, some of which will be discussed in detail later in this article. Lysosomal storage diseases are generally classified by the accumulated substrate and they include sphingolipidoses, glycoproteinoses, mucolipidoses, mucopolysaccharidoses (MPSs), and others.

The concept of lysosomal storage disease has been expanded to include deficiencies in lysosomal enzymes, deficiencies in the noncatalytic lysosomal proteins, and more general abnormalities in lysosomal function occurring in the lysosome.

New developments in 2005-2007

Therapy is increasingly promising, albeit expensive. Enzyme replacement therapy appears extraordinarily effective for patients with Gaucher disease types I and III, Fabry disease, and Hurler-Scheie syndrome. In persons with Gaucher disease, a chemokine, CCL18, has been identified as a biomarker for clinical development that reflects disease severity and treatment responsiveness.¹ Additional acid alpha-glucosidase deficiency has shown to be helpful for Pompe disease.² 

Idursulfase for the treatment of mucopolysaccharidosis II (Hunter syndrome) has been shown to help abate this disease and is now on the market in the United States and the European Union.¹⁸ Laronidase seems to be a promising agent for treating mucopolysaccharidosis type I, as shown by the reduction in the urinary excretion of GAGs and the associated improvements in vital capacity and in the performance of defined physical tasks.³ 

New developments and tests for disease can be followed by reviewing the Online Mendelian Inheritance in Man⁴ and GeneTests⁵ Web sites.

Manifestations

Although these abnormalities result in substrate accumulation, the underlying mechanisms relating to the pathologic effects are not entirely clear. However, the distribution of the accumulating material does determine which organs are affected. In particular, neurons that are incapable of cell division are commonly impaired because of the accumulation of undegraded material and lack of cell turnover. Cells of the mononuclear phagocyte system are especially rich in lysosomes and so are frequently affected by lysosomal storage diseases.

Lysosomal storage diseases may result in a severe neurodegenerative phenotype. Milder or later onset phenotypes have been identified and are related to residual enzyme activity. Such subtypes and variants show that even at low enzyme activity levels (as low as 1-5% of normal), a severe neurologic course can be modified into a milder, often nonneurologic, phenotype.

Pathophysiology

Recent advances in molecular genetics have shifted the focus both in gene products and genes themselves. The defective genes in most of these genetic diseases have been isolated and characterized and the specific mutations identified. At the gene level, genetic heterogeneity is complex despite similar phenotypes, biochemistry, and enzyme defects.

In 2003, Peters noted that hematopoietic cell transplantation (HCT) has been used as effective therapy for selected inherited metabolic diseases (IMDs), including Hurler (MPS IH) and Maroteaux-Lamy (MPS VI) syndromes, childhood-onset cerebral X-linked adrenoleukodystrophy (X-ALD), globoid-cell leukodystrophy, metachromatic leukodystrophy, alpha-mannosidosis, osteopetrosis, and others.⁶ It is a promising treatment for a variety of lysosomal storage diseases, which otherwise can be fatal.

Testing

In general, according to Parkinson-Lawrence et al in 2006, immune assays provide a direct practical application for the early detection, diagnosis, and prognosis of those with lysosomal storage disorder.⁷ Multiplexing of these assays may provide a platform to allow newborn screening for multiple lysosomal storage disorders.

Please click here to view the full topic text: Lysosomal Storage Disease