Inborn errors of metabolism

Question 1

Cause of suxamethonium sensitivity?

Answer 1

Plasma cholinesterase defective.

Suxamethonium (muscle relaxant) not rapidly broken down.

Question 2

What is von Gierke’s disease? (type 1 GSD)

Answer 2

Glucose-6-phosphatase deficiency. Terminal reaction in gluconeogenesis and glycogenolysis slowed –> reduced blood glucose between meals. (Glucose –> Glucose + Pi)

Hepatorenomegaly (from glycogen build up)

Increased glycolysis (stimulated by high [G-6-P]) leads to lactic acidosis

Body responds to hypoglycaemia by releasing more glucagon and adrenaline which increases fatty acid release from adipose tissue, and return to liver (which causes fatty liver and increased VLDL synthesis) (hypertriglyceridaemia)

[increased G6P –> hyperuricaemia from increased G6P down PPP)

Question 3

What 2 enzyme deficiencies cause galactosaemia?

and what is the pathophysiology and symptoms of galactosaemia?

Answer 3

Galactokinase (Galactose + ATP –> Gal-1-P + ADP)

Or GALT: Gal-1-P uridylyltransferase (causes toxic Gal-1-P build up! which negative-feedback inhibits Galactokinase anyway too)

Aldose reductase reduces excess galactose to toxic Galactitol [using NADPH] which causes cataracts.

Gal-1-P toxic accumulation from GALT deficiency only –> hepatomegaly and cirrhosis, seizures and brain damage.

Galactouria (draws water) leads to dehydration.

Question 4

What is Phenylketonuria caused by? (+symptoms)

Answer 4

Deficiency of Phenylalanine hydroxylase (that makes tyrosine) leads to mental retardation if not put on low phenylalanine diet. (+tyrosine supplements for precursors to dopamine/noradrenaline)

Build up of phenylalanine [and phenylketones] inhibits pyruvate kinase [and pyruvate transport in mitochondria] which reduces energy supply needed for myelin formation in brain development

High phenylalanine also reduces tyrosine transport across BBB by competing for LNAA transporter –> reduced dopamine and NE synthesis.

[Can screen blood for phenylalanine or urine for phenylpyruvate]

Question 5

What is alkaptonuria??

Answer 5

Defect in homogentisic acid oxidase (tyrosine metabolism) leads to build-up of homogentisic acid (which polymerises and gets oxidised) to form alkaptons (black pigments that can be seen in urine left standing)

Silent alkapton deposition in connective tissue can lead to arthritis! (alkaptonuric arthritis)

Question 6

Glucose-6-Phosphate Dehydrogenase deficiency effects? (hint RBCs)

Answer 6

Glucose-6-Phosphate dehydrogenase oxidises G-6-P to 6-phosphogluconolactone (using NADP+) in red blood cells to supply the reducing power of NADPH to produce reduced Glutathione (GSH) [from GS-SG.] (via glutathione reductase)

Reduced glutathione itself acts to keep Haemoglobin and other RBC proteins in reduced state. [can also reduce dangerous peroxides]

[prevents oxidation of Haemoglobin to MetHb, which accumulates as Heinz bodies in RBCs causing them to be destroyed in spleen [haemolytic anaemia]]

[in response to certain environmental factors like Primaquine, Pamaquine antimalarials needing reducing in Type-A, and fava beans in Type-B [mediterranean]]

Question 7

Differences between type-A and B G6PDH deficiency?

Answer 7

Type A in black americans (sensitive to antimalarials Primaquine and Pamaquine, which need reduction in RBCs)

Type B [‘mediterranean type’] in Kurdish Jews and Sardinians! May be protective against malaria as P.falciparum requires effective GSH in RBCs for growth!

Sensitive to compounds in Fava beans that cause increased MetHb formation. [hence favism]

Question 8

Basics of Congenital Porphyria?

Answer 8

Werewolves…

Inability to make haemoglobin cause by UROD‘uroporphyrinogen decarboxylase’ gene mutations, leading to build up of uroporphyrin in skin and tissues.

(porphyria cutanea tarda) (almost always asymptomatic)