Lecture 8: Inherited Errors of Metabolism

Question 1

What are four diseases of Inborn Errors of Metabolism (IEMs) we have learned about?

Answer 1

1) Phenylketonuria (PKU)
2) Galactosemia
3) Medium-Chain Acyl Dehydrogenase (MCAD) Deficiency
4) Hurler’s Syndrome

Question 2

The diseases that are screened for on a Newborn Screening Card depends on your …. and should meet the …. & … Criteria

Answer 2

The diseases that are screened for on a Newborn Screening Card depends on your LOCATION and should meet the WILSON & YOUNGER Criteria

Question 3

Inborn Errors of Metabolism are individually relatively …. , but collectively pretty ….

Answer 3

Inborn Errors of Metabolism are individually relatively RARE, but collectively pretty COMMON

Question 4

PKU occurs due to a deficiency in the enzyme …. …. which converts Phenylalanine to ….

Answer 4

PKU occurs due to a deficiency in the enzyme PHENYLALANINE HYDROXYLASE which converts Phenylalanine to TYROSINE

Question 5

True or False: Individuals with PKU can lead a normal life with a low protein diet?

Answer 5

TRUE

Question 6

What are three possible treatments for PKU?

Answer 6

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

Question 7

Why do Irish Travellers have a higher prevalence of rare autosomal recessive diseases such as Galactosemia or Hurlers Disease?

Answer 7

Consanguinity

Question 8

Who discovered Inborn Errors of Metabolism? What were the key findings?

Answer 8

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

Question 9

What are the three main characteristics of Alkaptonuria?

Answer 9

1) Black urine
2) Bluish/Black Connective Tissue
3) Severe Renal Stones

Question 10

Alkaptonuria due to a defect in the … gene and is treated by the drug ….

Answer 10

Alkaptonuria due to a defect in the NFD gene and is treated by the drug Nitisone

Question 11

True or False: We now know of over 1000 IEMs

Answer 11

TRUE

Question 12

What is the classification of Group 1 IEMs?

Answer 12

Group 1= Intoxication or “Small Molecule Disease” IEMs
(Ex.) PKU, Maple Syrup Urine
- Decompensation

Question 13

What is the classification of Group 2 IEMs?

Answer 13

Group 2= Energy Insufficiency
(Ex.) Beta Oxidation, Glycogen Storage, Ketogenic and/or Mitochondrial Diseases
- Decompensation

Question 14

What is the classification of Group 3 IEMs?

Answer 14

Group 3= Production/Breakdown of Complex Molecules
(Ex.) Lysosomal/Peroxisomal Deficiencies like Hurlers or Zelweggers
- Progression

Question 15

Group … IEMs are also known as …. …. …. and due to an enzyme deficiency leading to accumulation of a toxic substrate

Answer 15

Group 1 IEMs are also known as Small Molecule Intoxications and due to an enzyme deficiency leading to accumulation of a toxic substrate

Question 16

True or False: Group 3 IEMs are associated with substrate buildup affecting/blocking secondary metabolic pathways?

Answer 16

FALSE: Group 1 IEMs are associated with substrate buildup affecting/blocking secondary metabolic pathways

Question 17

Blockages in energy producing pathways in Group 2 IEMs causes …..

Answer 17

Blockages in energy producing pathways in Group 2 IEMs causes LOW ETC FUNCTIONING

Question 18

What tissues does Mitochondrial Disorders typically affect?

Answer 18

Mitochondrial Disorders typically affect HIGH-ENERGY UTILIZING tissues such as the Heart, Liver, Kidneys and/or Eyes

Question 19

True or False: Mitochondria disorders only occur due to mutations in one of the 37 genes in the Mitochondrial Genome?

Answer 19

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

Question 20

What is the main difference of pathogenicity between Lysosomal Storage Diseases and Peroxisomal Diseases?

Answer 20

Lysosomal Storage Diseases occur due to toxic SUBSTRATE buildup, while Peroxisomal Diseases occur due to a decrease in PRODUCT

Question 21

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

Answer 21

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

Question 22

Hurlers Syndrome due to a defect in the …… enzyme causing excessive accumulation of …. in the Lysosome

Answer 22

Hurlers Syndrome due to a defect in the ALPHA-1 IDURONIDASE enzyme causing excessive accumulation of GAGs in the Lysosome

Question 23

True or False: IEMs are only important in the patient’s generation

Answer 23

FALSE: As IEMs are inherited, they are extremely important for pregnancies
- Thus, they are tested for on Newborn Screening Cards

Question 24

Describe the “Unwell Regime” for IEM patients?

Answer 24

• 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