Lecture 8: Inherited Errors of Metabolism Flashcards
What are four diseases of Inborn Errors of Metabolism (IEMs) we have learned about?
1) Phenylketonuria (PKU)
2) Galactosemia
3) Medium-Chain Acyl Dehydrogenase (MCAD) Deficiency
4) Hurler’s Syndrome
The diseases that are screened for on a Newborn Screening Card depends on your …. and should meet the …. & … Criteria
The diseases that are screened for on a Newborn Screening Card depends on your LOCATION and should meet the WILSON & YOUNGER Criteria
Inborn Errors of Metabolism are individually relatively …. , but collectively pretty ….
Inborn Errors of Metabolism are individually relatively RARE, but collectively pretty COMMON
PKU occurs due to a deficiency in the enzyme …. …. which converts Phenylalanine to ….
PKU occurs due to a deficiency in the enzyme PHENYLALANINE HYDROXYLASE which converts Phenylalanine to TYROSINE
True or False: Individuals with PKU can lead a normal life with a low protein diet?
TRUE
What are three possible treatments for PKU?
a) Low Phenylalanine/ High Tyrosine Diet
b) Enzyme Substitution Therapy
- Tetrahydrobioptrim (BH4) is Phenylalanine Hydroxylase’s co-factor
- “Kuvan” is BH4 enzyme therapy licensed in Ireland
c) Gene/Editing Therapy: CRISPR
- Future implications
Why do Irish Travellers have a higher prevalence of rare autosomal recessive diseases such as Galactosemia or Hurlers Disease?
Consanguinity
Who discovered Inborn Errors of Metabolism? What were the key findings?
Sir Archibald Garrod (1908)
- Found that Inborn Errors of Metabolism (IEMs) were:
a) Inherited at birth
b) Persisted through life
c) Relatively benign
d) Transmitted recessively
What are the three main characteristics of Alkaptonuria?
1) Black urine
2) Bluish/Black Connective Tissue
3) Severe Renal Stones
Alkaptonuria due to a defect in the … gene and is treated by the drug ….
Alkaptonuria due to a defect in the NFD gene and is treated by the drug Nitisone
True or False: We now know of over 1000 IEMs
TRUE
What is the classification of Group 1 IEMs?
Group 1= Intoxication or “Small Molecule Disease” IEMs
(Ex.) PKU, Maple Syrup Urine
- Decompensation
What is the classification of Group 2 IEMs?
Group 2= Energy Insufficiency
(Ex.) Beta Oxidation, Glycogen Storage, Ketogenic and/or Mitochondrial Diseases
- Decompensation
What is the classification of Group 3 IEMs?
Group 3= Production/Breakdown of Complex Molecules
(Ex.) Lysosomal/Peroxisomal Deficiencies like Hurlers or Zelweggers
- Progression
Group … IEMs are also known as …. …. …. and due to an enzyme deficiency leading to accumulation of a toxic substrate
Group 1 IEMs are also known as Small Molecule Intoxications and due to an enzyme deficiency leading to accumulation of a toxic substrate
True or False: Group 3 IEMs are associated with substrate buildup affecting/blocking secondary metabolic pathways?
FALSE: Group 1 IEMs are associated with substrate buildup affecting/blocking secondary metabolic pathways
Blockages in energy producing pathways in Group 2 IEMs causes …..
Blockages in energy producing pathways in Group 2 IEMs causes LOW ETC FUNCTIONING
What tissues does Mitochondrial Disorders typically affect?
Mitochondrial Disorders typically affect HIGH-ENERGY UTILIZING tissues such as the Heart, Liver, Kidneys and/or Eyes
True or False: Mitochondria disorders only occur due to mutations in one of the 37 genes in the Mitochondrial Genome?
FALSE: Mitochondrial Disorders can arise in a mutation of 1) Mitochondrial genes 2) Nuclear genes that encode for proteins/molecules important for proper Mitochondrial function
What is the main difference of pathogenicity between Lysosomal Storage Diseases and Peroxisomal Diseases?
Lysosomal Storage Diseases occur due to toxic SUBSTRATE buildup, while Peroxisomal Diseases occur due to a decrease in PRODUCT
Group 3 IEMs symptoms are …. in nature, are not liable to decompensation. They are investigated for when the patient demonstrates
a) ……. (ex. Zelwegger’s Diseases)
b) …./…. Imbalance
c) (HYPO/HYPER)glycaemia
Group 3 IEMs symptoms are PROGRESSIVE in nature, are not liable to decompensation. They are investigated for when the patient demonstrates:
a) ENCEPHALOPATHY (ex. Zelwegger’s Disease)
b) ACID/BASE Imbalance
c) HYPOglycaemia
Hurlers Syndrome due to a defect in the …… enzyme causing excessive accumulation of …. in the Lysosome
Hurlers Syndrome due to a defect in the ALPHA-1 IDURONIDASE enzyme causing excessive accumulation of GAGs in the Lysosome
True or False: IEMs are only important in the patient’s generation
FALSE: As IEMs are inherited, they are extremely important for pregnancies
- Thus, they are tested for on Newborn Screening Cards
Describe the “Unwell Regime” for IEM patients?
- Patients works closely with metabolic dieticians/physcians
- Patient provided Synthetic Drinks and reductions in dietary component that is not tolerated by body (Ex. restrict protein intake for PKU patient)
- If patient passes certain unwell criteria levels they come into Hospital to see their physicians/dieticians
