Metabolic disorders Flashcards
Question
F. Valine
Organic Acidemia
Catabolism of several essential amino acids (valine, isoleucine, methionine, and threonine) along with odd-chain fatty acids results in the generation of propionyl-CoA. Propionyl-CoA is subsequently converted to methylmalonyl-CoA in a reaction catalyzed by biotin-dependent propionyl-CoA carboxylase. Isomerization of methylmalonyl-CoA then generates succinyl-CoA, which enters the TCA cycle.
This patient’s presentation is consistent with propionic acidemia, an autosomal recessive organic acidemia caused by congenital deficiency of propionyl-CoA carboxylase. This enzyme catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA. In its absence, excess propionic acid accumulates in the bloodstream, causing severe metabolic acidosis. Hypoglycemia and ketosis frequently develop secondary to the acidosis. Affected patients present 1-2 weeks after birth with lethargy, poor feeding, vomiting, and hypotonia. Treatment involves starting a low-protein diet containing minimal amounts of valine, isoleucine, methionine, and threonine.
(Choice A) Alanine transaminase catalyzes the transfer of an amino group from alanine to α-ketoglutarate, generating pyruvate that can be used for gluconeogenesis.
(Choice B) Aspartate is a nonessential amino acid; it can be converted into oxaloacetate for use in the TCA cycle by aspartate transaminase.
(Choice C) Glutamate is deaminated by glutamate dehydrogenase to form the TCA cycle intermediate α-ketoglutarate.
(Choice D) Lysine and leucine are essential amino acids that are strictly ketogenic. They are metabolized into acetyl-CoA, which is a precursor for ketone bodies.
(Choice E) Phenylalanine is converted to tyrosine by the enzyme phenylalanine hydroxylase. Tyrosine is further converted into fumarate (TCA cycle intermediate) and acetoacetate (ketone body).
Educational objective:
Propionyl-CoA is derived from the metabolism of valine, isoleucine, methionine, threonine, and odd-chain fatty acids. Congenital deficiency of propionyl-CoA carboxylase, the enzyme responsible for the conversion of propionyl-CoA to methylmalonyl-CoA, leads to the development of propionic acidemia. The condition presents with lethargy, poor feeding, vomiting, and hypotonia 1-2 weeks after birth.
Priopionyl-CoA build-up caused by
Propionic acidemia (an organic acidemia)
deficiency of propionyl-CoA carboxylase
inability to form methamalonyl-CoA
Methylmalonyl-CoA build up caused by
Methylmalonic acidemia (an organic acidemia)
deficiency in methylmalonyl-CoA isomerase
cannot form succinyl-CoA
Organic Acidemia amino acids
Valine
Isoleucine
Methionine
Threonine
Question
E. Pleiotropy
This patient presenting with skeletal abnormalities, lens dislocation, intellectual deficits, vascular thromboses, and a genetic defect in the cystathionine beta-synthase enzyme likely has homocystinuria. The occurrence of multiple, seemingly unrelated phenotypic manifestations, often in different organ systems, as a result of a single genetic defect is termed pleiotropy. Most syndromic genetic illnesses including homocystinuria exhibit pleiotropy.
(Choice A) Dominant negative mutations occur when an abnormal gene negatively affects the product of the wild-type gene in the same cell. For example, certain oncogene p53 mutations can lead to translation of a protein product that prevents wild-type p53 from binding to the promoter of its target genes.
(Choice B) Genetic linkage describes the tendency of alleles located near one another on the same chromosome to be inherited jointly.
(Choice C) Penetrance refers to the proportion of individuals with a given genotype that express the associated phenotype. In incomplete penetrance, less than 100% of individuals with a given genotype express its associated phenotype.
(Choice D) Locus heterogeneity refers to the ability of one disease or trait to be caused by mutations in multiple different genes. An example is familial hypercholesteremia, which can be caused by different mutations affecting cholesterol metabolism genes (eg, LDL receptor, apo B-100).
(Choice F) Polyploidy occurs when more than 2 complete sets of homologous chromosomes exist within an organism or cell. In a partial hydatidiform mole, for example, there are cells of nonstandard ploidy (typically 69,XXX; 69,XXY; or 69,XYY). The chromosomes in this case are derived from 1 haploid maternal set and 2 haploid paternal sets of chromosomes.
(Choice G) The law of segregation (Mendel’s first law) describes the phenomenon whereby gametogenesis within the parent organism results in the separation of paired alleles so that each offspring inherits only half of each parent’s genetic composition.
Educational objective:
Pleiotropy describes instances where multiple phenotypic manifestations result from a single genetic mutation. Most syndromic genetic illnesses exhibit pleiotropy.
What is Pleiotropy
The occurrence of multiple, seemingly unrelated phenotypic manifestations, often in different organ systems, as a result of a single genetic defect
Homocystinuria Pathogenesis
Most commonly due to an autosomal recessive mutation causing cystathionine synthase deficiency
Homocystinuria clinical findings
4 listed
- Optic lens dislocation
- Intellectual disability
- Marfanoid habitus (eg, elongated limbs & arachnodactyly)
- Thromboembolic complications
Homocystinuria Dx
↑ Plasma & urinary homocystine levels
Homocystinuria Tx
Pyridoxine (vitamin B6) administration
Dietary methionine restriction & cysteine supplementation
Question
A. gluconeogenesis
The metabolism of ethanol by alcohol dehydrogenase and aldehyde dehydrogenase reduces NAD+ to NADH and increases the NADH/NAD+ ratio. This inhibits all other pathways requiring NAD+, including reactions required for gluconeogenesis. In particular, lactate cannot be converted to pyruvate, and instead the reaction is driven from pyruvate toward lactate. In addition, excess NADH inhibits the conversion of malate to oxaloacetate. Pyruvate and oxaloacetate are intermediates in gluconeogenesis; therefore, conversion of these molecules to lactate and malate inhibits gluconeogenesis.
Alcohol does not inhibit glycogenolysis (Choice B), and so in the initial phase of binge drinking (heavy alcohol intake with reduced nutritional carbohydrate intake), hepatic glycogenolysis is able to maintain euglycemia. However, after a prolonged binge, hepatic glycogen is eventually depleted and blood glucose levels drop.
(Choices C and D) Ethanol has no direct effect on insulin sensitivity. Impaired clearance of insulin is a major contributor to hypoglycemia in patients with advanced renal insufficiency.
(Choice E) Excess NADH inhibits free fatty acid oxidation, thereby diverting free fatty acids away from lipolysis to the formation of triglycerides. This contributes to alcohol-induced hepatic steatosis but does not cause hypoglycemia.
Educational objective:
Ethanol inhibits gluconeogenesis and can cause hypoglycemia once hepatic glycogen stores are depleted.
Question
C. Infant botulism
This 5-month-old patient has consumed honey, a food notorious for contamination with Clostridium botulinum spores. When an infant consumes C botulinum spores, the bacteria can germinate in the gastrointestinal tract. Bacteriolysis releases botulinum toxin, which is absorbed systemically and blocks release of acetylcholine from cholinergic presynaptic terminals.
Constipation is usually the first manifestation of infant botulism, followed days to weeks later by mild weakness, lethargy, and reduced feeding. In rare, severe cases, infants can have weakened suckling and crying, diminished gag reflex, and symmetric, descending flaccid paralysis with loss of head control that can cause the infant to appear “floppy.” In contrast, adult botulism usually results from ingestion of preformed toxin (eg, contaminated canned foods) and is almost always very severe.
While infant botulism can be diagnosed based on the clinical presentation and food consumption history, the diagnosis is usually confirmed through identification of C botulinum spores or toxin in stool samples.
(Choice A) Measurement of blood liver enzyme levels can indicate damage to hepatic cells in hereditary fructose intolerance (genetic deficiency in aldolase B). Although patients with fructose intolerance can have poor feeding shortly after juice and honey are added to the diet, other classic manifestations include hypoglycemia, vomiting, and hepatomegaly rather than loss of extremity muscle tone.
(Choice B) Serum viral titers are frequently used in the evaluation of patients with viral hepatitis or suspected Epstein-Barr or cytomegalovirus infections. Poor feeding with loss of extremity muscle tone is more characteristic of infant botulism.
(Choice D) Allergic proctocolitis in infants can present after introduction of different food groups, and the diagnosis can be supported by stool studies that are positive for gross or occult blood. However, these infants usually appear well despite persistent diarrhea and/or rectal bleeding.
(Choice E) Patients with amino acids in their urine may have an inborn error of metabolism (eg, maple syrup urine disease) with symptoms usually manifesting in the neonatal period or early infancy.
(Choice F) High levels of urine glucose and ketones, together with hyperglycemia and metabolic acidosis, can support a diagnosis of diabetic ketoacidosis.
Educational objective:
Infant botulism can result from consumption of honey, which frequently contains C botulinum spores that can germinate and produce botulinum toxin. Symptoms of infant botulism include constipation, mild weakness, lethargy, poor feeding, and, in severe cases, flaccid paralysis. The diagnosis can be confirmed by identification of C botulinum spores or toxins in the stool.
