QUESTION: 309

Which of the following symptoms can occur frequently in infants suffering from mediumchain acyl- CoA dehydrogenase (MCAD) deficiency if periods between meals are protracted?

bone and joint pain and thrombocytopenia
hyperammonemia with decreased ketones
hyperuricemia and darkening of the urine
hypoglycemia and metabolic acidosis with normal levels of ketones
metabolic alkalosis with decreased bicarbonate

Answer(s): D

Explanation:

In infants, the supply of glycogen lasts less than 6 hours and gluconeogenesis is not sufficient to maintain adequate blood glucose levels. Normally, during periods of fasting (in particular during the night) the oxidation of fatty acids provides the necessary ATP to fuel hepatic gluconeogenesis as well as ketone bodies for nonhepatic tissue energy production. In patients with MCAD deficiency there is a drastically reduced capacity to oxidize fatty acids. This leads to an increase in glucose usage with concomitant hypoglycemia. The deficit in the energy production from fatty acid oxidation, necessary for the liver to use other carbon sources, such as glycerol and amino acids, for gluconeogenesis further exacerbates the hypoglycemia. Normally, hypoglycemia is accompanied by an increase in ketone formation from the increased oxidation of fatty acids. In MCAD deficiency there is a reduced level of fatty acid oxidation, hence near normal levels of ketones are detected in the serum. None of the other choices (A, B, C, and E) reflect symptoms related in any way to MCAD deficiency and are not in themselves indicative of any specific disorder per se.

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QUESTION: 310

Reticulocytes control the rate of globin synthesis as a consequence of the level of heme in the cell. This prevents globin protein from being made when there are insufficient amounts of heme. Which of the following best explains the effects of heme on protein synthesis in these cells?

A heme-controlled phosphatase dephosphorylates cap-binding factor, which prevents recognition of globin mRNA by the ribosomes.
A tRNA-degrading enzyme is active in the absence of heme.
Heme normally activates peptidyltransfersase in reticulocytes.
RNA polymerase activity is decreased in reticulocytes by low heme.
The initiation factor eIF-2 becomes phosphorylated, reducing its level of activity.

Answer(s): E

Explanation:

One mechanism by which initiation of translation in eukaryotes is effected is by phosphorylation of a ser(S) residue in the alphasubunit of eIF-2. The factor eIF-2 requires activation by interaction with GTP. The energy of GTP hydrolysis is used during translational initiation, thereby allowing eIF-2 to have GDP bound instead of GTP. In order to reactivate eIF-2, the GDP must be exchanged for GTP. This requires an additional protein of the GEF family known as eIF-2B. The phosphorylated form of eIF-2, in the absence of the eIF-2B, is just as active an initiator of translation as the nonphosphorylated form. However, when eIF-2 is phosphorylated, the GDP-bound complex is stabilized and exchange for GTP is inhibited. When eIF-2 is phosphorylated, it binds eIF-2B more tightly thus slowing the rate of exchange. It is this inhibited exchange that affects the rate of initiation. Within reticulocytes the phosphorylation of eIF-2 is the result of an activity called heme-controlled inhibitor, HCI (see below figure).

The presence of HCI was first seen in an in vitro translation system derived from lysates of reticulocytes.
When heme is limiting it would be a waste of energy for reticulocytes to make globin protein, since active hemoglobin could not be generated. Therefore, when the level of heme falls, HCI becomes activated, leading to the phosphorylation of eIF-2 and reduced globin synthesis. Removal of phosphate is catalyzed by a specific eIF-2 phosphatase which is unaffected by heme. There is no heme- controlled phosphatase activity (choice A) in any cell. No tRNA-specific degrading enzymes (choice B) are present in cells. There is no effect of heme levels on peptidyltransferase activity (choice C) or RNA polymerase activity (choice D).

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QUESTION: 311

Infants exhibiting profound metabolic ketoacidosis, muscular hypotonia, developmental retardation, and who have very large accumulations of methylmalonic acid in their blood and urine suffer from a disorder known as methylmalonic acidemia. This disorder results from a defect in which of the following enzymes?

alpha-keto acid dehydrogenase
homogentisic acid oxidase
methylmalonyl-CoA mutase
phenylalanine hydroxylase
tyrosine aminotransferase

Answer(s): C

Explanation:

Defects in methylmalonyl-CoA mutase activity comprise four distinct genotypes whose clinical symptoms are remarkably similar. Characteristic findings in methylmalonyl-CoA mutase deficiency include failure to thrive leading to developmental abnormalities, recurrent vomiting, respiratory distress, hepatomegaly, and muscular hypotonia. In addition, patients have severely elevated levels of methylmalonic acid in the blood and urine. Unaffected individuals have near undetectable levels of methylmalonate in their plasma, whereas, affected individuals have been found to have levels ranging from 3 to 40 mg/dL in their blood.
Deficiency in alpha-ketoacid dehydrogenase (choice A) results in MSUD, so named because of the characteristic odor of the urine in afflicted individuals. Mental retardation in the MSUD is extensive.
Deficiency in homogentisic acid oxidase (choice B) results in alkaptonuria. Alkaptonuria results from the accumulation of homogentisic acid, a byproduct of tyrosine catabolism, in the urine and tissues. Oxidation of homogentisate in the urine causes it to turn dark and in the tissues results in ochronosis, which refers to the ochre color of the deposits in connective tissue, bones, and other organs. Deficiency in phenylalanine hydroxylase (choice D) results in PKU which results in severe mental retardation if not detected and treated properly. Deficiency in tyrosine aminotransferase (choice E) results in eye, skin, and neurologic symptomology. The neurologic symptoms are similar to those seen in PKU.

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QUESTION: 312

Following a minor respiratory illness, a seemingly healthy, developmentally normal 15-month-old boy exhibited repeated episodes of severe lethargy and vomiting following periods of fasting, such as during the middle of the night. The parents brought the infant to the emergency room following a seizure. The child was hypoglycemic and was administered 10% dextrose, but remained lethargic. Blood ammonia was high, liver function tests were slightly elevated, and his serum contained an accumulation of dicarboxylic acids. Only low levels of ketones were detecteable in the urine. This infant suffers from which of the following disorders?

glutaric acidemia type II
Lesch-Nyhan syndrome
MCAD deficiency
pyruvate dehydrogenase (PDH) deficiency
type III (Cori) glycogen storage disease

Answer(s): C

Explanation:

Deficiency in MCAD is the most common inherited defect in the pathways of mitochondrial fatty acid oxidation. The most common presentation of infants with this disorder is episodic hypoketotic hypoglycemia following periods of fasting. Although the first episode may be fatal, and incorrectly ascribed to sudden infant death syndrome, patients with MCAD deficiency are normal between episodes and are treated by avoidance of fasting and treatment of acute episodes with intravenous glucose. Accumulation of acylcarnitines (dicarboxylic acids) is diagnostic, in particular octanoylcarnitine. Glutaric acidemia type II (choice A) results from a defect in electron transfer flavoproteinubiquinone oxidoreductase and presents with symptoms of hypoketotic hypoglycemia as in the case of MCAD deficiency. However, this disorder manifests within the first 2448 h after birth and is frequently associated with congenital anomalies. Lesch- Nyhan syndrome (choice B) results from a defect in HGPRT--an enzyme involved in nucleotide metabolism. Symptoms of Lesch-Nyhan syndrome include hyperuricemia, bizarre neurobehavioral manifestations, growth retardation, and anemia. Deficiency in PDH (choice D) results in lactic acidemia, which can be quite severe at birth leading to neonatal fatality. Milder deficiency results in lactic acidemia associated with profound psychmotor retardation. Cori disease (choice E) results from a defect in the glycogen debranching enzymes. Clinical features include hepatomegaly, hypoglycemia, skeletal myopathy and short stature, and cardiomyopathy.

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