Lysosomal Diseases

Lysosomal diseases ("storage diseases“) are rare, heritable conditions leading to substrate accumulation in lysosomes as a result of insufficient activity of some of the lysosomal enzymes or associated transport proteins. These are multisystemic condition with permanent progressionthat can manifest at any age. Most affected are metabolically active organs and tissues (bone marrow, bones, sceletal musles, myocardium and CNS). More than 60 different lysosomal defects have been described. Early-onset forms typically have more serious presentation with rapid progression and unfavourable prognosis. The incidence is estimated as 1 affected per 8200 live births. The inheritance is most often autosomal recessive, but there are also rare X-linked recessive forms (Fabry disease and mucopolysaccharidosis type II). Lysosomal enzymes, so called acidic hydroxylases, allow for gradual breakdown of large complex molecules (sphingolipids, glycoproteins či mucopolysaccharides) from cell membranes of senescent cells. Insufficient level or insufficient enzymatic activity leads to accumulation of substrate in lysosomes of various cells. Some diseases can me treated by substituting missing enzyme - enzyme replacement therapy (in Gaucher, Fabry and Pompe disease and in mucopolysaccharidosis type I, II and VI) or by reducing amount of accumulated substrate - substrate reduction therapy (in Gaucher disease, Niemann-Pick disease type C). In rare cases, bone marrow transplant can be also indicated (mucopolysaccharidosis type I).

Division

 * Lysosomal diseases from defects in lysosomal transport proteins
 * Lysosomal diseases from deficiency of lysosomal membrane proteins
 * Lysosomal diseases from deficiency of lysosomal hydrolases
 * Lysosomal diseases from deficiency of enzyme activators of lysosomal hydrolases

Pathophysiological mechanisms of lysosomal diseases and their examples

 * Accumulation of secondary products
 * Cholesterol (NPC C)
 * Sphingomyelin (NPC A, NPC B)
 * Mucopolysaccharides
 * Neuroinflammation
 * as induced through microglia which work as phagocytes in CNS. These become swollen (just like foam cells in atheroma) as result of material building up in their lysosomes. Eventually they „burst“ (undergo lysis) releasing lytic enzymes into the surroundings.
 * The defect in calcium metabolism
 * includes Gaucher disease which is a defect in enzyme  glucosylcerebrosidase  which modulates function of ryanodine receptors in endoplasmic reliculum. These regulate the calcium balance inside the cell. When their function is compromised, there is a calcium eflux from ER leading to activation of lytic enzymes and caspases (apoptosis).
 * Oxygen radicals
 * arise probably as a result of mitochondrial and ER damage, especially in brain
 * Increased autophagy
 * increased autophagy for multiple reasons ultimately leads to apoptosis. . One of them is defective circulation of plasma membrane components which leads to damage of cell and its chemical and electrical gradients, opening path for apoptosis.

I-cell disease (mucolipidosis II)

 * Deficiency in GlcNAc-1-phosphotransferase.
 * Man-6-P serve as a chemical marker tagging enzymes which are to be transported into lysosomes.
 * Inclussion cell disease is caused by defect in lysosomal transport of proteins tagged by Man-6-P. This is caused by mutation in N-acetylglucosamin 1-phosphotransferase.
 * Receptor for Man-6-P is not affected; enzyme-bound Man-6-P doesn’t form at all.
 * This all leads to increased activity of lysosomal proteins in extracellular liquid and plasma, but decreased activity of many lysosomal enzymes in tissues.
 * Lysosomal are enlarged due to substrate accumulation.
 * As a result of accumulating lysosomes, lymphocyte became vacuolisated („inclusion cells“).
 * Pacients have: rough facial features, thickened gingiva, mild hepatomegaly and splenomegaly, bone disease – dysostosis multiplex, psychomotoric retardation, increased activity of lysosomal hydroxylases in plasma, but decreased activity in tissues.

Dannon's disease

 * Deficiency in LAMP2 (Lysosomal-associated membrane protein 2)

Cystinosis

 * Deficiency in cystinosin
 * Clinical presentation:
 * Kidney disease with Fanconi's syndrome
 * Renal failure requiring kidney transplant
 * Crystals in cornea, photophoby
 * Growth retardation
 * Normal intelligence

Sialuria

 * Deficiency in sialin

Lysosomal diseases from deficiency of enzyme activators of lysosomal hydrolases

 * Lysosomes contain diffent hydrolases depending on where the sustrate is degraded. Defect in funtion of these enzymes leads to accumulation of substrate in the lysosomal apparatus of the cell. They include:
 * Lipidoses a Sphingolipidoses
 * Mucopolysaccharidoses
 * Mucopolysaccharidoses and glycoproteinoses
 *  Glycogenoses (this includes only glykogenosis II - Morbus Pompe)
 * Proteinoses