a. Diagram A

b. Diagram B

c. Diagram C

d. Diagram D

e. Diagram E

f. Diagram F

g. Diagram G

h. Diagram H

383. A couple present for genetic counseling because three of their first four children have had pyloric stenosis, a narrowing of the valve between stomach and duodenum that presents with severe vomiting and loss of gastric hydrochloric acid (hypochloremic alkalosis). When parents with three affected children have a higher recurrence risk than parents with one affected child, the disease in question is likely to exhibit which of the following modes of inheritance?

a. Autosomal dominant inheritance

b. Autosomal recessive inheritance

c. X-linked recessive inheritance

d. X-linked dominant inheritance

e. Multifactorial determination

384. A newborn Caucasian girl presents with poor feeding, vomiting, jaundice, and an enlarged liver. The urine tests positive for reducing substances, indicating the presence of sugars with aldehyde groups. Which of the following processes is most likely to be abnormal?

a. Conversion of glucose to galactose

b. Conversion of lactose to galactose

c. Conversion of activated galactose to activated glucose

d. Excretion of glucose by the kidney

e. Excretion of galactose by the kidney

385. The frequency of galactosemia is approximately 1 in 40,000 live births. The frequency of the carrier state can be calculated as which of the following?

a. 1 in 50 live births

b. 1 in 100 live births

c. 1 in 200 live births

d. 1 in 500 live births

e. 1 in 1000 live births

Digestive System—Gastroenterology and Nutrition

Answers

363. The answer is d. (Murray, pp 11-14. Scriver, pp 3-45.) The normal aeration eliminates answers b and c positing respiratory acidosis, and the lack of urine glucose eliminates diabetes mellitus (incorrect answer a). The sum of measured cations (Na 140 + K 4.5 = 144.5) is greater than the sum of measured anions (Cl 110 + bicarbonate 8 = 118) by 26.5, creating an anion gap greater than the normal of 12 to 14 mEq/L due to unmeasured phosphates or sulfates in serum. Ammonium ion is positively charged and would not increase a negative ion gap (incorrect answer e). Fatty or organic acids that build up due to missing enzymes in inborn errors of metabolism are hidden anions in serum and cause the kidney to excrete bicarbonate in an effort to balance the serum pH. Anion gaps over 20 and lowering of the pH to cause acidosis (7.1 in this case) indicate the kidney can no longer compensate. Such changes can occur in neonates with inborn errors of organic acid metabolism, or in older children with disorders of fatty acid oxidation who have a routine illness, stop eating, and accumulate a fatty acid anion when they attempt to switch from glucose to fat metabolism.

Separate enzyme pathways exist for breakdown of long-, medium-, or short-chain fatty acids, so deficiency in one (like medium chain fatty acyl-CoA dehydrogenase or MCAD) may not compromise the child until there are severe demands for fat breakdown and energy once carbohydrates and glycogen are depleted (3-4 hours after feeds on average). Depletion of glycogen and inability to maintain glucose through gluconeogenesis may lead to low serum glucose (hypoglycemia), and ineffective fatty acid/organic acid breakdown will not yield the ketones seen in hypoglycemia from other causes or in diabetes mellitus where glucose cannot enter cells. Fatty acids that build up due to the enzyme block manifest as hidden anions. If the disorder is suspected, feeding or infusion of glucose is curative by preventing the need for fat oxidation to provide energy. A child similar to this was not recognized in time, leading the politically connected parents to advocate for expanded newborn screening that is becoming the standard in most states.

364. The answer is e. (Murray, pp 11-14. Scriver, pp 3-45.) It is important to realize that any type of prolonged vomiting will remove stomach hydrochloric acid with increasing pH and low chloride ion concentration (hypochloremic alkalosis). Pure metabolic acidosis (incorrect answer c) or pure metabolic alkalosis (incorrect answer e) exhibits abnormal bicarbonate and normal lung function. Pure respiratory acidosis (incorrect answer d) or alkalosis (incorrect answer a) is associated with normal renal function (and normal blood acids) with a normal bicarbonate and abnormal Pco₂. Incorrect answer b must involve compensation, since both the Pco₂ and bicarbonate are abnormal. The infant is affected with pyloric stenosis (MIM*179010), blocking the exit of stomach contents into the duodenum and causing vomiting. The blockage is caused by failure of pyloric tissue to regress by cell death during development, leaving a ball of muscular tissue surrounding the pyloric valve (gastro-duodenal junction). The preferred treatment is surgical, slicing the excess tissue (pyloromyotomy) to relieve the blockage. When diagnosis is delayed, infants can die because of severe metabolic alkalosis caused by expulsion of hydrochloric acid in stomach fluid.

365. The answer is b. (Murray, pp 35-47. Scriver, pp 3-45. Lewis, pp 194-199.) The activity of tissue enzymes must be compared based on equivalent amounts of tissue protein, expressed as units (micromoles substrate converted or product produced per minute of reaction) over milligram of tissue protein added (enzyme specific activity). This avoids error arising from different yields of protein in a patient and controls (incorrect answer a) and compares enzyme activity, not the degree of purity (incorrect answer c). The specific activity does not give information about enzyme structure (incorrect answer d) or activation (incorrect answer e) unless it is correlated with other measures (eg, migration by electrophoresis, increased/decreased by the presence of phosphorylation, etc). Glycogen phosphorylase deficiency (MIM*232700) causes type VI glycogen storage disease (Hers disease), which, like most other inborn errors, exhibits autosomal recessive inheritance (or X-linked recessive inheritance if the locus is on the X chromosome).

366. The answer is a. (Murray, pp 70-83. Scriver, pp 4571-4636.) Phosphorylase kinase is a cyclic AMP-regulated enzyme that converts inactive phosphorylase b to active phosphorylase a. (incorrect answers c-e). Phosphorylase kinase is an allosteric enzyme regulated by cAMP, but phosphorylase is activated or deactivated by kinases that add (phosphorylase kinase) or remove (phosphoprotein phosphatase) a phosphate from the enzyme. Glycogen phosphorylase is thus directly regulated by phosphorylation through allosteric modulation of phosphorylase kinase activity (incorrect answer b). In liver, glucagon triggered by low glucose levels increases cAMP and phosphorylase kinase activity; in muscle, norepinephrine released by stress (flight or fright) stimulates phosphorylase kinase to activate phosphorylase and release glucose for muscle activity. Several types of mutations alter activity of glycogen phosphorylase or its kinase including those of glycogen storage disease type IV (MIM*232700).

367. The answer is e. (Murray, pp 84-93.) These digestive enzymes are proteases and are secreted as inactive zymogens; the active site of the enzyme is masked by a small region of its peptide chain, which is removed by hydrolysis of a specific peptide bond. Synthesis of proteases as zymogens is a mechanism that ensures that proteases will only be active when and where they are needed as inappropriate protease activity would be expected to have a very deleterious effect on the cell.

368. The answer is d. (Murray, pp 132-139, 548-567. Scriver, pp 1521-1551.) The infant had been previously normal, excluding severe diseases such as galactosemia (answer b) or early diabetes (answer e) that should have elevated glucose in addition to times of hypoglycemia. The ability to digest breast milk lactose with absorption and conversion to glucose makes malabsorption unlikely (answer a) and sucrose is a disaccharide of glucose-fructose (answer c). Low glucose during fasting and liver enlargement implies altered regulation of glycogen synthesis/release due to one of the enzyme deficiencies within the category of glycogen storage disease.

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