Disorders of lysosome metabolism/Treatment

Lysosome

 * lysosomes are vesicles with a single membrane with a diameter of 0.8 μm, containing acid hydrolases (phosphatases, nucleases, prostheses, enzymes hydrolyzing polysaccharides, mucopolysaccharides, lipids)
 * lysosomal enzymes are synthesized in GER → vesicles - primary lysosomes, they fuse with the membrane vacuoles containing degraded material (= phagosomes) → phagolysosomes = secondary lysosomes - center of intracellular digestion of macromolecules + removal of damaged organelles
 * the enzymes act at pH 5.0 and are inactivated by the neutral pHof the cytosol (protection against damage in case the lysosome membrane ruptures)

Hereditary deficiency of some lysosomal hydrolases - diseases from storage in lysosomes

 * = Lyzosomal storage disorders
 * group of more than 40 inherited conditions, the cause is a deficiency of some lysosomal enzyme / cofactor / transporter / protein needed for lysosome function, the result is the accumulation of substrate, which is usually degraded in lysosomes, which can enlarge entire organs - mainly 3 systems are affected: connective tissue, nervous tissue, parenchymal organs, not all lysosomal storage disorders cause enlargement of organs, most disorders mainly affect the CNS nd cause chronic progressive disorders of neurological and mental functions
 * diagnosis of these disorders begins with the detection of partially degraded GAG / oligosaccharides in urine and is confirmed by a special examination of enzymes in serum / leukocytes / skin fibroblasts
 * for most disorders, treatment is palliative, but for some disorders great advances have been made in enzyme replacement therapy strategies, in addition, hematopoietic stem cell transplantation may improve prognosis in carefully selected patients, gene transfer using various vectors has been successful in cultured cells and animal models., but has not yet been successfully performed in human patients
 * prenatal diagnosis is possible for all disorders
 * clinical picture: very varied, mostly mental retardation, skeletal disorders, organomegaly, corneal opacity, rough facial appearance

Cell disease

 * ysosomal enzymes are synthesized but do not reach the right destination, lysosomal enzyme activity in plasma samples increases extremely, cells lack almost all lysosomal enzymes - many different types of undecomposed molecules forming inclusion bodies accumulate in lysosomes
 * cells contain normal receptor for lysosomal enzyme uptake, addressing of enzymes to lysosomes is wrong (this is normally done by mannose-6-P, there is no mannose phosphorylating enzyme
 * neurological disorders, bone deformities, most patients die in the first decade of life

Tay-Sachson disease

 * β-N-acetyl-hexoaminidase deficiency - cleaves ganglioside Gm2 to Gm3 in brain cells → accumulation of Gm2 with subsequent severe neurological disorders
 * higher incidence in Ashkenzai Jews
 * treatment: clinical study NB - DNJ (miglustat)

Cystinosis

 * free cystine accumulates in lysosomes of whole body cells, especially in RES, bones, kidneys, retina → tubular atrophy of kidneys, bone disease
 * terapie: podávání cysteaminu, který účinně snižuje hromadění cystinu

Gaucher's disease

 * accumulation of glucosylceramide for β-glucosidase deficiency
 * treatment: enzyme replacement therapy (early diagnosis is important - possibility of neonatal screening of lysosomal membrane protein-1 - positive in 72% of lysosomal storage disorders, the rest are sphingolipid storage diseases - saponins can be examined here - they support the activity of lysosomal hydrolases)

Disorders of sphingolipid metabolism

 * sphingolipids - physiologically, during degradation after transport via endosomes into the lysosome, they are gradually hydrolyzed by specific sphingolhydrolases, some of which need cofactors called sphingolipid activating proteins for their activity
 * sfingolipidózy jsou podskupinou lyzosomálních střádavých poruch, kdy se hromadí sfingolipidy v jednom nebo více orgánech jako důsledek primárního deficitu enzymu nebo jeho kofaktoru
 * Gaucher's disease
 * block of lysosomal degradation of glucosylceramide (glucocerebroside) (massively accumulates in the liver and spleen) and glucosylsphingosine - acid β-glucosidase deficiency
 * therapy
 * enzyme replacement therapy by slow infusions of recombinant enzyme with the addition of mannose residues to optimize entry into macrophages
 * substrate restriction
 * Niemann-Pick disease type A,B
 * acid sphingomyelinase deficiency - accumulation of sphingomyelin (massively in the liver, spleen, accumulation in all organs in all types of disease and accumulation in the brain in neuropathic forms)
 * specific treatment not available
 * Niemann-Pick disease type C
 * complex disorder of cellular lipid transport - accumulation of non-esterified cholesterol in the lysosomal apparatus
 * therapy
 * no specific treatment is available yet
 * experiments with NB-DNJ (miglustat) - inhibitor of glycosphingolipid synthesis leads to delayed onset of neurological symptoms and prolonged life expectancy
 * GM1-Gangliosidosis
 * acid lysosomal β-glucosidase deficiency, which catabolizes the cleavage of glycoconjugates containing a terminal β-galactoside bond, and is required not only for the degradation of GM1 ganglioside and other glycosphingolipids, but also oligosaccharides containing galactose and keratan sulphates
 * there is no effective treatment yet
 * Crab disease
 * demyelination of the central and peripheral nervous system
 * deficiency of galactosylceramidase or galactocerebrosidase, cerebroside-β-galactosidase - a lysosomal enzyme that catabolizes galactosylceramide - hl. myelin lipid)
 * deficiency leads to accumulation of galactosylceramide in pathognomic "globoid cells" (multinuclear macrophages), which are present in demyelinated white matter lesions, and the toxic metabolite galactosylsphingosine (psychsin) in oligodendrocytes and Schwann cells
 * therapy
 * in advanced disease - supportive analgesic treatment, due to frequent pain
 * allogeneic bone marrow transplantation / umbilical cord blood transplantation - effective in preventing the onset / stopping of disease progression in cases of late onset
 * Metachromatic leukodystrophy
 * block in lysosomal degradation of sulfatide (or galactosylceramide sulfate or other sulfate glycolipids)
 * treatment: symptomatic treatment of spasticity and pain from radiculopathy
 * Fabry disease
 * X-linked multiorgan dysfunction - involvement of the main kidneys and heart, significantly reduces life expectancy
 * α-galactosidase A deficiency
 * treatment: enzyme replacement therapy with recombinant & glactosidase A - reduces pain, stabilizes renal function
 * Farber's disease – Farber's lipogranulomatosis
 * acid ceramidase deficiency - accumulation of ceramide in various organs
 * no specific treatment, symptomatic treatment: analgesics

Mukopolysaccharidoses, oligosaccharidoses

 * AR hereditary (except Hunter's disease - X bound)
 * mucopolysaccharides - glycosaminoglycans - GAG - basic connective tissue components, including cartilage and blood vessel walls, consist of long carbohydrate chains that contain alternating uronic acid and hexosamine residues linked into repeating units and are highly sulfated, polysaccharide chains are bound to specific proteins through complex macromolecules - proteoglycans, their degradation takes place in lysosomes and requires a number of acid hydrolases - deficit leads to storage disorders - mucopolysaccharidoses - general symptoms may be: facial dysmorphia, bone dysplasia, hepatosplenomegaly, neurological abnormalities, regression and shortening of life expectancy
 * Hurle Syndrome (MPS IH) and Scheiev Syndrome (MPS IS) – MPS I
 * iduronidase deficiency - dermatan sulfate and heparate sulfate are stored
 * Hunter's disease – MPS II
 * iduronate-2-sulfatase deficiency - dermatan sulfate and heparate sulfate are accumulated
 * Sanfilip's syndrome – MPS III
 * heparan sulfate catabolism disorder
 * Morquio's syndrome – MPS IV
 * keratan sulfate degradation disorder
 * Maroteaux-Lamy syndrome – MPS VI
 * N-acetylgalactosamine-4-sulfatase disorder
 * Sly's syndrome – MPS VIII
 * β-glucuronidase deficiency
 * Natowitz syndrome – MPS IX
 * hyaluronidase deficiency - accumulation of hyaluronic acid