Propose three hypotheses that are biochemical in nature. Genetic mutation, WITH

Question

Propose three hypotheses that are biochemical in nature.

Genetic mutation, WITH specific biochemistry affected • Dietary alteration, WITH specific molecule involved • Environmental exposure, WITH specific biochemistry affected • Altered tissue-level process (i.e., signaling, autoimmunity, transport, etc.), WITH specific molecule or biochemistry involved

Scenario:

A 4-year old girl is brought into the emergency room by her dad after she had fainted on the playground. At the ER, she was still very pale fatigued and confused.

The Dad reports that the girl was always ‘the quiet one’ of his daughters., but recently he has been noticing that she is increasingly lacking energy and does not like to run around with other kids in her day care group. She says she is uncomfortable doing so and it makes her feel ‘weak’. You are an awesome physician, skilled in thinking about biochemistry in context, and you notice signs of jaundice around her eyes. You suspect that the girl has anemia caused by a metabolic enzyme deficiency in the glycolytic pathway [insert your favorite enzyme]. The fraternal twin sister of the girl does not exhibit any of these symptoms. You want to test this hypothesis related to glycolytic enzymes. This cannot be one of your three hypotheses above.

Explanation / Answer

Haemolytic anaemia, due to PK (pyruvate kinase) deficiency is an autosomal recessive disorder. Many individuals are compound heterozygotes. PKR enzyme is a homotetramer composed of four chains derived from the products of the two alleles, enzyme kinetic variations are many and genotype/phenotype correlates are not predictable. Within families, the severity of the haemolysis tends to be similar in affected individuals. PK catalyses the ultimate step in the glycolytic pathway. The deficient activity leads to accumulation of substrates further up the pathway, including 2,3-DPG. The increased concentration of 2,3-DPG in PK-deficient red cells shifts the oxygen dissociation curve to the right, which indicates the low oxygen affinity. Patients with PK deficiency tolerate apparent anaemia well because the lower Hb content will deliver the same amount of oxygen to tissues as the normal Hb, at least under normal conditions.

Faternal twin sisters do not exhibit the problems related enzymes in the glycolytic pathways as:

(1) the glucose fatty acid cycle plays a major role in the secondary--but not the primary--abnormalities of glucose metabolism; (2) insulin resistance in non-diabetic identical co-twins patients is restricted exclusively to the pathway of exogenous glucose storage; (3) however, the decreased glucose storage is not by an impairment of insulin stimulated skeletal muscle glycogen synthase activity; and finally (4) the impairment of skeletal muscle glycogen synthase activity in patients has an apparent non-genetic component and can be escaped (or postponed) in individuals (twins) with a 100% genetic predisposition to non identical patients..

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