20.04.09 Lysosomal storage disorders Flashcards
What are lysosomal storage disorders
Class of inherited metabolic diseases characterised by an abnormal build up of various toxic materials in cells as a result of enzyme deficiencies that inhibit the ability of the lysosomes to perform their normal function.
What are lysosomes
- Cellular membrane-bound organelles.
- Acidic content (pH 4.5-5.5) due to ATP=driven proton (H+) pump in lysosomal membrane
- Contain enzymes capable of breaking down various biological polymers (proteins, lipids, carbohydrates)
Collective incidence of lysosomal disorders
1:5,000 to 1:10,000 (individually very rare, 1:100,000)
Disease pathogenesis in lysosomal disorders
Defects in lysosome function often results in storage of partially degraded substances within the lysosomes, disturbing cell homeostasis. Leads to early cell death.
How are lysosomal diseases detected
- Biochemical testing of urine.
- Storage material leaks into tissues and is excreted in large quantities in the urine.
- Glycosaminoglycan cellulose acetate electrophoresis
- Results confirmed by enzyme analysis of plasma, skin fibroblasts, mutation analysis.
What are sphingolipidoses
- Lipid storage disorders caused by mutations in genes encoding enzymes that break down Sphingiolipids
- 1 in 10,000 (more common in certain ethnic groups such as Ashkenazi Jews)
What are sphingolipids
- Class of lipids with a sphingoid backbone
- Important in nervous system, form part of myelin sheath
Examples of sphingolipidoses
- Fabrys
- Gaucher
- Niemann-Pick disease
Review of Gaucher disease
- 1 in 1000 in Ashkenazi Jewish population
- AR, mutations in GBA gene.
- beta-glucosidase (GBA) catalyzes the breakdown of glucosylceramide to ceramide and glucose
- Defects cause intracellular accumulation of glucosylceramide
- Type 1 has no neurological involvement. Hepatosplenomegaly, anaemia, thrombocytopenia.
- Type 2 and 3, have neurological involvement and very severe.
Review of Niemann Pick type A and B
- 1 in 250,000 (1 in 40,000 in Ashkenazi Jews)
- AR, mutations in SMPD1 (Sphingomyelin phosphodiesterase 1)
- Defects lead to build up of sphingomyelin, leads to cell death.
- Jaundice, failure to thrive, enlarge liver. Type A also has deterioration of nervous system.
Review of Niemann pick type C
- 1 in 150,000
- AR, mutations in NPC1 (90%) or NPC2 (4%)
- Involved in transport of lipids from endosomes/ER and plasma membrane.
- Zavesca (glycosphingolipid inhibitor) used to treat neurological manifestations
Review of Fabry disease
- 1 in 50,000 males
- X linked, mutations in GLA.
- Defects in alpha galactosidase
- neuropathy, kidney failure, HCM,
- Females can be symptomatic due to random X-inactivation
- Treatment: enzyme/ gene replacement therapy.
What are mucopolysaccharidoses
Group of metabolic disorders caused by a defect in lysosomal enzymes needed to break down glycosaminoglycans (GAGs).
What are glycosaminoglycans
- Long chains of sugar carbohydrates.
- Used to build bone, cartilage, tendons, corneas, skin, connective tissue
Methods to diagnose mucopolysaccharidoses
- Measure GAGs in urine
- Enzyme activity (not accurate for carriers)
Examples of mucopolysaccharidoses
-Sanfilippo syndrome. AR, mutations in NAGLU, SGSH, HGSNAT, GNS etc genes. Dev delay and seizures. 1:50,000 to 1 in 280,000. Accumulation of Heparan sulfate.
What are oligo-saccharidoses
-Disorders caused by defects in enzymes responsible for degradation of oligosaccharide chains in glycoproteins and glycolipids. Results in an accumulation in oligosaccharides.
Examples of oligos-saccharidoses
- Mannosidosis. AR, mutations in MAN2B1 gene.
- Galactosialidosis. AR, mutations in CTSA gene.
Review of Pompe disease
- Glycogen storage disease (type 2)
- AR. GAA mutations.
- Alpha glucosidase defects lead to an accumulation in glycogen in lysosomes.
- Cardiomyopathy, hypotonia, failure to thrive, elevated serum creatine kinase, oligosaccharides in urine.
- Residual enzyme activity leads to a milder phenotype (e.g. adults have a leaky splice variant c.336-13T>G in trans with another variant)
What are neuronal ceroid lipofuscinoses
- Disorders with accumulation of autofluorescent lipopigments resembling ceroid and lipofuscin (undegradable material in lysosomes) in nerve cells.
- Also known as Batten disease
- 1 in 12,500 in some populations
- Usually AR. 14 genes
- progressive dementia, seizures, and progressive visual failure
- Treatment: replacement of deficient enzyme. Bone marrow transplantation.
Pros and cons of bone marrow transplant
- Pro: replaces deficient enzyme activity, can migrate to brain improving neurological function
- Cons: early transplantation, need a suitable donor, complications (graft vs host)
Pros and cons of enzyme replacement therapy
- Pros: Safe and effective for peripheral manifestations.
- Cons: expensive, regular infusions needed, patients may produce antibodies, unable to reach therapeutic concentrations in some tissues (CNS), low bioavailability for recombinant enzymes
What is substrate reduction therapy
- Reduction of lysosomal substance formation to a point at which residual enzyme activity can catabolise
- Cons: can only be used in the presence of residual enzyme activity
What is chemical chaperone therapy
- Binding and stabilizing of misfolded enzymes to improve their trafficking and residual activity.
- Cons: Relies on endogenous enzyme activity. Cannot be used for genotypes that don’t produce a protein product.
- Pros: Can diffuse across membrane barriers to reach CNS.
What is gene therapy
- Direct transfer of normal gene into the defective cells to supply therapeutic levels of defective enzyme.
- Only applicable to monogenic disorders.
