Autosomal Recessive Disorders Flashcards
What are the 3 general consequences of enzyme deficiency?
- Substrate accumulation
- Product deficiency
- Upregulation of minor alternate pathway
What is the clinical course of Tay-Sachs?
- Normal development for 3-5 months
- Slowing of progress -> plateau -> loss of milestones
- By 8-10 months: decrease in purposeful activity and lack of awareness of surroundings
- Death by age 5
Symptoms of Tay-Sachs
- Hyperacusis and easily startled
- Progressive weakness and hypotonia
- Decreased visual attentiveness and abnormal eye movements
- Eventual deafness and blindness
- Seizures
- Vegetative state
What enzyme deficiency disorders are caused by accumulation of substrate?
- Tay-Sachs
- mucopolysaccharidoses
- I-cell
- glycogen storage diseases
- urea cycle defects
What enzyme deficiency disorders are caused by product deficiency?
- glycogen storage diseases
- biotinidase deficiency
What enzyme deficiency disorders are caused by toxic effects of abnormal metabolites?
- Galactosemia
What is the incidence of Tay-Sachs disease and carriers?
Disease: 1/3500 Ashkenazi Jews and 1/300,000 non-Jews
Carrier: 1/25 Ashkenazi Jews and 1/300 non-Jews
What enzyme deficiency causes Tay-Sachs?
Hexosaminidase A (alpha subunit)
What is the function of hexosaminidase A?
Degradation of ganglioside GM2 in neuronal lysozymes
GM2 -> GM3 + galNAc
Allelic heteogeneity
Different alleles leading to very similar phenotypes
What mutation causes Tay-Sachs?
Multiple different mutations to HEXA:
- insertion => frameshift
- missense => defective splicing
- deletion => no transcription
- missense => defective processing
Tay-sachs brain histology
Neurons distended due to accumulation of fatty GM2 in lysosomes
What are the basic structural elements of GM2
cerebroside (3 carbon backbone) - glu - gal - NANA and galNAc
What elements are removed in the catabolism of GM1 -> GM2 -> GM3
- terminal galactose removed
2. N-acetylglucosamine removed
How does hexosaminidase activity compare in people +/- Tay-Sachs?
No difference
Compare the gene dosage of hexosaminidase A in normal, parents, and Tay-Sachs patients
- normal
- 1/2 (obligate heterozygotes)
- negligable
What genes are involved in hexosaminidase A synthesis and how are the subunits assembled?
1 alpha chain (HEXA) + 1 beta chain (HEXB) + activation by activator (GM2A)
What is the function of activator?
Used to bring fatty, hydrophobic GM2 to the water soluble proteins it needs to interact with in vivo
What are symptoms of mucopolysaccharidosis I?
- Joint contractures
- Joint stiffness
- Dysostosis multiplex = radiographic abnormalities (Gibbus abnormality, rounded hand x-ray, thicker ribs, thinner pelvis)
- Visceromegaly = enlarged liver and spleen
- Coarse facies
- Corneal clouding
- Metachromasia test of urine
Which mucopolysaccharidosis is NOT autosomal recessive?
Hunter is X-linked
Where do GAGs accumulate in patients with mucopolysaccharidoses?
Tissues and urine
How were cross-corrective studies used in the study of mucopolysaccharidoses?
- Cells from patients with different mucopolysaccharidoses cultured together with radioactive sulfate
- Healthy cells should reach a steady state where incorporation and breakdown are constant
- Diseased cells continue to accumulate sulfate as they can’t break down GAGs
- If diseased cells cross-correct, must impact different enzymes
- If diseased cells DON’t cross-correct, they must impact different enzymes
Locus heterogeneity
Different genes (loci) => same phenotype
Allelic heterogeneity
different mutations at the same locus => same phenotype
What class of diseases do Tay-Sachs and mucopolysaccharidoses belong to and why?
Storage diseases because the buildup of the involved molecules is visible
Why is there toxicity associated with defective urea cycle enzymes?
Ammonia buildup
How are urea cycle enzyme defects treated?
- Give product of defective enzyme reaction so cycle can continue
- Any accumulated intermediate from before defective enzyme will be excreted in urine
What is the clinical consequence of propionyl carboxylase deficiency?
Acidosis
What products are generated from alternative pathways for propionyl CoA when propionyl CoA carboxylase is deficient?
- propionic acid
- 3-hydroxypropionante
- methylcitrate
- propionyl glycine
- lactate
What are the biotin dependent carboxylases?
- Propionyl CoA carboxylase
- Acetyl CoA carboxylase
- Methylcrotonal carboxylase
- Pyruvate carboxylase
What is the function of holocarboxylase synthase?
Adds biotin to biotin-dependent carboxylase apoenzymes
Apoenzyme
Inactive enzyme without cofactor
Holoenzyme
Active enzyme with cofactor
What enzyme is defective in early onset multiple carboxylase deficiency?
holocarboxylase deficiency
What enzyme is defective in late onset multiple carboxylase deficiency? Why are the symptoms late onset?
- Biotinidase
- Apoenzymes can be biotinilated, but biotin cannot be recycled from degraded enzyme so eventually biotin will be depleted such that the biotin cycle cannot proceed
What is the purpose of the biotin cycle?
- Add biotin to biotin-dependent carboxylase apoenzymes
- Recycle biotin after proteolytic degradation of biotinilated proteins
What is the function of biotinidase?
Removes biotin from lys residues after proteolytic degradation of a biotin-dependent carboxylase
What intermediate causes the toxicity associated with galactosemia?
gal-1-p
What alternative pathway for galactose is upregulated in galactosemia?
Reduction of galactose to galactitol via the polyol pathway
What issue does galactitol cause in the lens?
Cataracts: galactitol is osmotically active, pulling water into the lens
