From bedside to cell biology: a century of history on lysosomal dysfunction.

Lysosomal storage disorders (LSDs) are a group of rare genetic diseases, generally caused by a deficiency of specific lysosomal enzymes, which results in abnormal accumulation of undegraded substrates. The first clinical reports describing what were later shown to be LSDs were published more than a hundred years ago. In general, the history and pathophysiology of LSDs has impacted on our current knowledge of lysosomal biology. Classically, depending on the nature of the substrates, LSDs can be divided into different subgroups. The mucopolysaccharidoses (MPSs) are those caused by impaired degradation of glycosaminoglycans (GAGs). Amongst LSDs, the MPSs are a major group of pathologies with crucial historical relevance, since their study has revealed important biological pathways and highlighted interconnecting pathological cascades which are still being unveiled nowadays. Here we review the major historical discoveries in the field of LSDs and their impact on basic cellular knowledge and practical applications. Attention will be focused on the MPSs, with occasional references to other LSDs. We will show as studies on the metabolic basis of this group of diseases have increased our knowledge of the complex degradative pathways associated with the lysosome and established the basis to the development of specific therapeutic approaches aiming at correcting or, at least ameliorating their associated phenotypes.

Lysosomal storage diseases: natural history and ethical and economic aspects.

Potential treatment for lysosomal diseases now includes enzyme replacement therapy, substrate reduction therapy, and chaperone therapy. The first two of these have been implemented commercially, and the spectrum of diseases that are now treatable has expanded from Gaucher disease to include several other disorders. Treatment of these diseases is extremely costly. We explore some of the reasons for the high cost and discuss how, by proper selection of patients and appropriate dosing, the economic burden on society of treating these disease may be ameliorated, at least in part. However, the cost of treating rare diseases is a growing problem that society needs to address.

A historical perspective of the glycosphingolipids and sphingolipidoses.

Glycosphingolipids are a polysaccharide chain between 1 and 40 carbohydrate residues long glycosidically linked to ceramide (a long-chain aliphatic amino-alcohol or sphingoid) that is embedded in the cell plasma membrane with the carbohydrate moiety on the outside. The sphingoid imparts rigidity to the membrane and the carbohydrate tails protect the cell surface and have functions in relation to cell adhesion, growth, regulation, differentiation, cell interaction, recognition and signalling. They provide adhesion sites for pathogens and change during oncogenic transformation. Ceramide is also a component of sphingomyelin. Glycosphingolipids are degraded by lysosomal hydrolysis. The sphingolipidoses are a series of diseases in which mutations affecting the enzymes catalysing the last 11 steps of this process causing abnormal compounds proximal to the metabolic block to accumulate intralysosomally. Thus, they are a sub-group of the lysosomal storage diseases. The degradation of sphingolipids containing three or less carbohydrate residues requires a sphingolipid activator protein and mutations affecting these proteins also cause abnormal glycosphingolipid storage. With one exception (Fabry disease, which is X linked) the sphingolipidoses are inherited autosomally. The phenotypic manifestations of the individual sphingolipidoses are variable although the more severe variants are usually the better known. They have generally been regarded as untreatable but notable therapeutic advances are being made by enzyme replacement therapy and regulating the rate of glycosphingolipid synthesis by inhibiting UDP-glucose-N-acylsphingosine D-glucosyl transferase (CerGlcT), which is the first reaction on the pathway of glycosphingolipid synthesis. The compounds used are N-alkylated iminosugars whose glucose and galactose stereochemistries inhibit CerGlcT. Prenatal and carrier state diagnosis, genetic counselling and the abortion of affected foetuses are reducing the incidence of some of the most severe sphingolipidoses in certain high-incidence populations.