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Lysosomal disease 

Lysosomal disease

Lysosomal disease

P.B. Deegan

and T.M. Cox



Lysosomal function – new understanding of the central signaling complex that controls tissue and cell growth

Treatment – extensive discussion of many new agents for many lysosomal diseases, particularly enzyme replacement therapies, molecular chaperone therapies and substrate reduction therapies.

Updated on 30 Jul 2015. The previous version of this content can be found here.
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date: 24 March 2017

Lysosomal function and classification of diseases

The lysosome is an intracellular organelle that recycles biological macromolecules derived either endogenously, from digestion of cellular components (autophagy), or from the breakdown of material that has been incorporated from outside the cell by, for example, phagocytosis. The lysosome is now known to be involved in nutrient sensing and central to the regulation of the metabolic economy of the cell.

Lysosomal diseases may be classified according to the nature of the primary storage molecules (biochemical classification) or according to the defective molecular cell physiology (functional classification). Biochemical classification readily identifies: (1) sphingolipidoses, (2) mucopolysaccharidoses, (3) glycoproteinoses, (4) glycogenosis -with or without lysosomal debris derived from subcellular organelles-due to impaired autophagy and (5) others or miscellaneous conditions with multiple classes of storage material. Functional classification describes (1) deficiency of a specific acid hydrolase activity, (2) deficiency of an activator protein, (3) deficiency of a lysosomal membrane protein or transporter, (4) abnormal post-translational modification of lysosomal proteins, and (5) abnormal biogenesis of lysosomes. A combination of two classification systems may allow the best description of the pathological basis of particular conditions.

General aspects of lysosomal diseases

More than 70 single-gene defects are responsible for inborn errors affecting the function of lysosomes and lysosome-related organelles, such as melanosomes, and various intracellular bodies such as lytic granules in natural killer T lymphocytes and platelet dense granules. The diseases are most often caused by deficiency of specific acid hydrolases, but mutations occur in protein activators necessary for their action, or in membrane proteins that transport the substrates for, or products of, lysosomal digestion. About one in 5000 live-born infants have a lysosomal disorder, with Gaucher disease and Fabry disease (both glycosphingolipidoses) probably the most frequent.

Lysosomal diseases occur at all ages and are clinically diverse; they differ greatly in their rate of progression and represent a large burden of illness in the population. The range of manifestations includes organomegaly, disturbed function of visceral organs, skeletal effects and neurological features.

A detailed family history, including careful analysis of the extended pedigree, is of critical importance. Simple histochemical stains of existing biopsy material and examination of urine metabolites, including lipids and oligosaccharides, may point to the diagnosis. Specific enzymatic assays on leucocytes or cultured fibroblasts are often definitive but may be supported by molecular analysis of genes encoding proteins destined for the lysosome.

There is no specific or curative treatment for most lysosomal disorders: supportive and palliative measures are nonetheless of great benefit. However, proteins can be delivered directly to lysosomes from the extracellular fluid phase by means of specific glycoprotein receptors, hence recombinant DNA technology which with protein engineering allows large-scale manufacture and post-translational modification of human proteins for targeting to this intracellular compartment. This technology has led to the development of enzyme-replacement therapy for several lysosomal diseases. The success of such treatment is predicated on characterization of single-gene defects responsible for lysosomal disorders and the discovery of lectin-like ligands and their receptors, by which nascent lysosomal proteins are specifically delivered to the organelle during biogenesis. Orally active agents are in development for at least one important class of lysosomal disorders, the sphingolipidoses; these treatments, based on small molecules, may allow access to the brain -which is often affected.

Particular lysosomal diseases

Gaucher disease—one of the most common lysosomal diseases; autosomal recessive; usually caused by catalytic deficiency of acid glucocerebrosidase. Characteristic manifestations of the most frequent form—‘adult non-neuronopathic’ (type I)—include (1) pancytopenia, with bleeding due to thrombocytopenia; (2) splenic enlargement; and (3) bone pain with osteoporosis and episodic avascular necrosis. Diagnosis is based on acid β‎-glucosidase activity in freshly prepared leukocytes; biopsy material may show characteristic multinucleate storage cells with striated cytoplasm on Leishmann staining. Enzyme replacement therapy (with imiglucerase, Cerezyme™, or velaglucerase, VPRIV™) is extremely expensive but corrects cytopenia, reduces hepatosplenomegaly and the frequency of episodic bone infarction, and improves quality of life.

Fabry disease is an X-linked disorder caused by deficiency of α‎-galactosidase A that leads to the accumulation of globotriaosyl-ceramide (Gb3). Typically manifest in early childhood with lancinating pain and background burning sensations in the extremities, Fabry disease rivals Gaucher disease in frequency. Other features include diarrhoea, lack of peripheral sweating, impotence, high-tone deafness, angiokeratomas (small, raised, red, vascular lesions, particularly around the buttocks and genital region), chronic kidney disease (progressing to renal failure), cardiac hypertrophy and stroke. Affected male hemizygotes are diagnosed by finding excess glycolipid in urine or plasma supported by finding deficient α‎-galactosidase A activity in white cells or cultured skin fibroblasts; molecular analysis of the α‎-galactosidase A gene is usually needed for identifying heterozygote females. Enzyme replacement with recombinant human α‎-galactosidase A is very costly but improves neuropathic pain and cardiac hypertrophy and may stabilize renal function particularly if given before proteinuria becomes florid.

Cystinosis, is an important genetic disorder of lysosomal transport which impairs effux of cystine derived from breakdown of protein in the lysosome—the condition can be ameliorated by early treatment with the reactive thiol agent, cysteamine. In nephropathic cystinosis, the build-up of cystine crystals in the lysosomal compartment leads to progressive injury of the proximal renal tubule and a Fanconi-like syndrome with full blown metabolic acidosis. This is followed by diverse manifestations in the cornea, thyroid, renal failure, skeletal and cardiac muscle as well as the smooth muscle of the oesophagus. Cysteamine complexes with cystine, thus allowing efflux of the thiol adducts via a lysosomal carrier mechanism which effects clearance of the intracellular crystal deposits.

Other diseases discussed in this chapter include (1) the mucopoly-saccharidoses, (2) Pompe disease (glycogen storage disease type II), (3) Niemann-Pick disease, (4) cholesteryl ester storage disease, (5) Danon disease, and (6) diseases more recently attributed to primary defects in lysosomes and related organelles.

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