Inborn of metabolism: energy and carbohydrate metabolism

Question 1

What is Galactosemia?

Answer 1

• A recessive genetic disorder; characterized by body’s inability to tolerate galactose due to galactose-1-phosphate uridyl transferase deficiency.
• Unable to tolerate milk, poor weight gain, liver damage & jaundice, irritability, convulsions.

Question 2

What is Fructosuria?

Answer 2

• Essential: Fructokinase deficiency. No symptoms. Mild, no need for tx.
• Hereditary fructosuria: Aldolase b deficiency. Hypoglycaemia, hepatomegaly, jaundice, vomiting. Avoid sucrose and fructose.

Question 3

List the disorders associated with hypoglycaemia.

Answer 3

1. Pyruvate carboxylase deficiency
2. Fructose-1,6-bisphosphatase deficiency
3. PEP carboxykinase deficiency (extremely rare)

Question 4

What is Pyruvate carboxylase deficiency?

Answer 4

• Severe neonatal- seizures, coma, lactic acidosis, mild hypoglycaemia
• Mild infantile- psychomotor retardation, mild lactic acidosis
• Diagnosis: increased lactate, ketosis

Question 5

What is Fructose 1,6 bisphosphatase deficiency?

Answer 5

• Acute onset with hepatomegaly, hypoglycaemia, seizures, coma.
• Diagnosis: increased lactate and ketosis

Question 6

What is Mitochondrial disease pattern of inheritance?

Answer 6

• Maternal.

Question 7

What is homoplasmy?

Answer 7

• Homoplasmy: all copies of mtDNA identical.
• IEM displaying homoplasmy: presence of a mutation affecting all mtDNA copies

Question 8

What is heteroplasmy?

Answer 8

• A mixture of more than one type of mtDNA
• Most mtDNA mutations heteroplasmic: Mutations only occurring in some copies of mtDNA
• Symptoms of severe HtM disorders frequently do not appear until adulthood as many cell divisions required for cell to receive enough mitochondria containing mutant alleles to cause symptoms.

Question 9

How does plasmy affect phenotype of IEM’s?

Answer 9

• Variation in number of mutated mtDNA molecules inherited by offspring, amount of mutant DNA present determines clinical presentation/severity.

Question 10

Mitochondrial disorders are involved in?

Answer 10

• The generation of chemical energy by Oxidative Phosphorylation:
  1. Pyruvate dehydrogenase (PDH) complex
  2. TCA cycle
  3. Electron transport chain (ETC)
  4. ATP synthase
• Blockage of ETC due to O2 deficiency, genetic defects or inhibitors causes rise in NADH+/NAD ratio and inhibits PDH and TCA

Question 11

What is the diagnostic criteria for mitochondrial disease?

Answer 11

• Type of inheritance.
• Clinical symptoms: encephalopathies, myopathies, cardiomyopathies.
• Biochemical features: Lactic acidosis.
• Respiratory chain deficiency diagnosis: Enzyme activity of specific ETC complex decreased. Morphological features = ragged red fibers
  (RRF) in muscle biopsy. DNA analysis.

Question 12

What is Pyruvate dehydrogenase complex deficiency?

Answer 12

• Progressive encephalopathy, brain malformation, psychomotor retardation, muscular hypotonia, epilepsy.
• Diagnosis: increased plasma lactate and enzyme analysis. Fibroblasts and muscle.

Question 13

What are storage disorders?

Answer 13

• Genetic diseases characterised by abnormal
  accumulation of lipids or carbohydrates.

Question 14

What are Glycogen storage disorders?

Answer 14

• An abnormal synthesis or degradation of glycogen, due to defect in genes coding for enzymes involved in glycogen metabolism.
• Affects liver and muscle.
• Signs: hypoglycaemia, muscle pain, cramps, weakness.
• 15 different types.

Question 15

What is glycogen?

Answer 15

• A branched polymer made of glucose.
• A rapidly accessible storage form of glucose.

Question 16

What is GSD V?

Answer 16

• McArdle disease: muscle glycogen phosphorylase deficiency (linear glycogen not converted to glucose 1 phosphate).
• Doesn’t cause hypoglycaemia.

Question 17

What is GSD I?

Answer 17

• Von Gierke’s Disease: glucose 6 phosphatase deficiency (prevents conversion of G6P to glucose)
• Hypoglycaemia, lactic acidosis, ketosis, hepatomegaly

Question 18

What is GSD II?

Answer 18

• Pompe: lysosomal a1,4 Glucosidase Deficiency, also a lysosomal disorder.
• Cardiomegaly, muscle weakness, death 2yrs.
• Glycogen deposits inside lysosomes within the muscular tissue.
• Doesn’t cause hypoglycaemia.

Question 19

Discuss disorders involving complex molecules.

Answer 19

• Symptoms: permanent, progressive, independent of intercurrent events, unrelated to food intake.
• Limited enzyme replacement, bone marrow transplant.

Question 20

List then disorders involving complex molecules.

Answer 20

• Lysosomal storage disorders: Sphingolipidoses and Mucopolysaccharidosis (glycosaminoglycans) .
• Peroxisomal disorders: Zellweger Syndrome, X linked adrenoleucodystrophy.
• Congenital disorders of glycosylation.

Question 21

What are Lysosomes?

Answer 21

• Cellular organelles containing acid hydrolases that break down macromolecules into small molecules, highly acidic

Question 22

What are peroxisomes?

Answer 22

• Cellular organelles involved in the breakdown of very long and branched chain fatty acids, also involved in the biosynthesis of molecules critical for normal brain function, hydrogen peroxide generated from FA oxidation.

Question 23

What is Precursor of sphingolipids?

Answer 23

• Ceramide.

Question 24

What are glycosphingolipids?

Answer 24

• Synthesis in Golgi.
• Ceremide precursor.
• Addition of glucosyl monomers
  from UDP- sugar donors

Question 25

What is Sphingolipidoses?

Answer 25

• Lysosomal storage disease, defect in degradation of sphingolipids causing accumulation.

Question 26

What is Mucopolysaccharidoses (Hurler’s and Hunter Syndromes)?

Answer 26

• MPS
• A deficiency in lysosomal enzymes involved in breakdown of GAGs (constituents of cartliage, tendons, connective tissue, and skin).
• Accumulation of partially degraded carbohydrates in lysosomes causes cell and tissue damage.
• Progressive: leading to marked dysmorphology, severe bone disorders, learning difficulties, behavioural problems, and mental retardation.

Question 27

How is MPS diagnosed and treated?

Answer 27

• Diagnosis: Clinical suspicion, urinary glycosaminoglycan analysis, enzyme assay and genetic analysis.
• Treatment: Enzyme replacement therapy available for Hurler’s (MPS I) and Hunter (MPS II) syndromes.

Question 28

What are peroxisomal disorders?

Answer 28

• A defect in peroxisome assembly.
• Results in peroxisome biogenesis disorders (PBD).
• Single enzyme defects:
  1. X-linked adrenoleukodystropy: progressive disorder affecting adrenal gland and white
  matter in nervous system
  2. Refsum’s disease: prevents breakdown of phytanate

Question 29

What is the function of Golgi apparatus?

Answer 29

• Modifies N-linked oligosaccharides & adds O-linked oligosaccharides.
• Sorts proteins delivering them to correct destination.

Question 30

What happens in protein glycosylation by Golgi Apparatus?

Answer 30

• Aids protein folding.
• Provides protection against proteases (e.g. lysosomal membrane proteins).
• Employed for signalling and trafficking.

Question 31

What are congenital disorders of glycosylation?

Answer 31

• Abnormal glycosylation
• Usually begins in infancy, severe developmental delay, hypotonia, multiple organ system involvement, hypoglycaemia and protein losing enteropathy.
• May have normal development
• CDG-Ia= most common