20.04.09 Lysosomal storage disorders

Question 1

What are lysosomal storage disorders

Answer 1

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.

Question 2

What are lysosomes

Answer 2

• 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)

Question 3

Collective incidence of lysosomal disorders

Answer 3

1:5,000 to 1:10,000 (individually very rare, 1:100,000)

Question 4

Disease pathogenesis in lysosomal disorders

Answer 4

Defects in lysosome function often results in storage of partially degraded substances within the lysosomes, disturbing cell homeostasis. Leads to early cell death.

Question 5

How are lysosomal diseases detected

Answer 5

• 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.

Question 6

What are sphingolipidoses

Answer 6

• 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)

Question 7

What are sphingolipids

Answer 7

• Class of lipids with a sphingoid backbone

- Important in nervous system, form part of myelin sheath

Question 8

Examples of sphingolipidoses

Answer 8

• Fabrys
• Gaucher
• Niemann-Pick disease

Question 9

Review of Gaucher disease

Answer 9

• 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.

Question 10

Review of Niemann Pick type A and B

Answer 10

• 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.

Question 11

Review of Niemann pick type C

Answer 11

• 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

Question 12

Review of Fabry disease

Answer 12

• 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.

Question 13

What are mucopolysaccharidoses

Answer 13

Group of metabolic disorders caused by a defect in lysosomal enzymes needed to break down glycosaminoglycans (GAGs).

Question 14

What are glycosaminoglycans

Answer 14

• Long chains of sugar carbohydrates.

- Used to build bone, cartilage, tendons, corneas, skin, connective tissue

Question 15

Methods to diagnose mucopolysaccharidoses

Answer 15

• Measure GAGs in urine

- Enzyme activity (not accurate for carriers)

Question 16

Examples of mucopolysaccharidoses

Answer 16

-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.

Question 17

What are oligo-saccharidoses

Answer 17

-Disorders caused by defects in enzymes responsible for degradation of oligosaccharide chains in glycoproteins and glycolipids. Results in an accumulation in oligosaccharides.

Question 18

Examples of oligos-saccharidoses

Answer 18

• Mannosidosis. AR, mutations in MAN2B1 gene.

- Galactosialidosis. AR, mutations in CTSA gene.

Question 19

Review of Pompe disease

Answer 19

• 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)

Question 20

What are neuronal ceroid lipofuscinoses

Answer 20

• 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.

Question 21

Pros and cons of bone marrow transplant

Answer 21

• Pro: replaces deficient enzyme activity, can migrate to brain improving neurological function
• Cons: early transplantation, need a suitable donor, complications (graft vs host)

Question 22

Pros and cons of enzyme replacement therapy

Answer 22

• 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

Question 23

What is substrate reduction therapy

Answer 23

• 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

Question 24

What is chemical chaperone therapy

Answer 24

• 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.

Question 25

What is gene therapy

Answer 25

• Direct transfer of normal gene into the defective cells to supply therapeutic levels of defective enzyme.
• Only applicable to monogenic disorders.