Lysosomal dysfunction, cellular pathology and clinical symptoms: basic principles ARNOLD J. J. REUSER & MAARTEN R. DROST Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands, and Department of Movement Sciences, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands Abstract Between 40 and 50 lysosomal storage disorders are known at present. Fine details of the pathogenic process involved are in general not known. This overview highlights the basic principles of lysosomal pathogenesis and the clinical consequences of defective genes involved in lysosomal functions. The subject is discussed in the context of the possibility of prevention and reversal of cellular and organ damage by enzyme replacement therapy. Also presented is a mechanical model for the muscle pathology observed in Pompe disease. Direct mechanical effects of the non-contractile inclusions Á / glycogen-loaded lysosomes Á / seem to be a key factor in the loss of force during both early and late stages of the disease. Conclusion: Each lysosomal storage disorder and each patient with a given lysosomal disorder has unique molecular, pathological and clinical features. But, the order of pathological events is largely the same. Mutations in a gene cause lysosomal dysfunction which, in turn, results in cellular pathology affecting organ structure and function. Clinical symptoms are the ultimate manifestation. The reversibility of symptoms with enzyme replacement therapy will vary according to the disease, as well as the nature and stage of organ pathology. Key Words: Cellular pathology, lysosomal storage disorders, Pompe disease Each of the lysosomal storage disorders (LSDs) has unique features, including symptoms, clinical course, organ involvement, type of lysosomal pathology and underlying molecular defects. Our knowledge about the LSDs has gradually evolved from the time that the first case reports were published, presenting the clinical and pathological details, via the identification of the storage products and the lysosomal enzyme deficiencies, to the identification of the causative genetic defects. Using present-day technology, it is now possible to identify the genetic defect before the function of the encoded enzyme is known, as in the case of Batten disease. Figure 1 illustrates how the number of lysosomal diseases with a known gene or protein defect has increased over the past 40 years. If anything can be said about the common features of LSDs, it is that almost all of these diseases present with a spectrum of clinical phenotypes, with the onset of disease ranging from shortly after birth to late in adulthood. The early-onset forms usually progress more rapidly than the late-onset forms, and more organs are involved. When it comes to the pathogenic mechanism, the order of events is the same in all LSDs. Inherited mutations in genes coding for proteins that are in some way involved in lysosomal function, lead to lysosomal dysfunction, usually manifested as lysosomal storage. The clinical signs and symptoms are the ultimate expression of the molecular and biochemical changes that give rise to pathological changes in cells, tissues and organs. Examples of cell type-specific pathogenesis The unique features of each LSD arise from disease- specific gene mutations that lead to the loss of a specific lysosomal function. Within a given disease, subtype specificity may find its origin in genetic heterogeneity of the locus, that is, certain types of mutation may ha ve a particular effect on clinical presentation. Although all cells in the body ha ve the same genetic defect, lysosomal storage may be detri- mental in one cell type but not in another cell type that is shaped and equipped to perform a different function. For example, in the case of a lysosomal enzyme deficiency, the indigestible substrate will accumulate preferentially in the cell type with the highest turnover of that substrate. ISSN 0803-5326 print/ISSN 1651-2227 online # 2006 Taylor & Francis DOI: 10.1080/08035320600618957 Correspondence: A.J.J. Reuser, Department of Clinical Genetics, Erasmus MC, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. Tel: 0031 10 4087153; Fax: 0031 10 4089461; E-mail: a.reuser@erasmusmc.nl Acta Pædiatrica, 2006; Suppl 451: 77 Á /82