Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 2 Comparative Medical Genetics
One proceeds from metabolite identification to the demonstration
of an enzyme or other gene product defect by
assaying the functions of candidate proteins chosen based
on the knowledge of metabolic pathways and the previous
descriptions of metabolic diseases in the same or other species.
Metabolic disorders are often named according to the
aberrant substrate associated with the pathological condition
rather than the truly defective (deficient) enzyme or cofactor
(e.g., cystinuria, lactic aciduria, methylmalonic aciduria, porphyria,
and mucopolysaccharidosis). Urine as a metabolic
screening specimen is preferred, because abnormal metabolites
in the blood will be filtered through the glomeruli but
then fail to be reabsorbed, as no specific renal transport
systems exist for most abnormal metabolites ( Fig. 2-10 ). In
those cases in which normal metabolites accumulate, their
quantities usually exceed the renal threshold. As a consequence
the amount of such compounds in a given volume
of urine is often several fold greater than in blood. The
renal tubules do not have the capacity to reabsorb abnormal
metabolites or excess normal metabolites, and they become
concentrated as water is conserved (Giger and Jezyk, 2000;
Sewell et al. , 2007 ).
(a)
(b)
i . Examples of Amino Acidurias The cyanide nitroprusside
reaction, which detects any compound containing a
sulfhydryl group, is used to screen for cystinuria (and
homocystinuria). Cystinuria and other aminoacidurias
can be detected by simple spot (nitroprusside) test, paper
chromatography using butanol/acetic acid/water as a
solvent and ninhydrin stain, and high-pressure liquid
chromatography. Cystinuria is caused by defects in
renal basic amino acid transporters, which also affect
the reabsorption of other amino acids, easily recalled as
COLAs: cystine, ornithine, lysine, and arginine. Because
cystine precipitates in acidic urine, cystine calculi are
formed in the kidney, ureters, bladder, and urethra, leading
to life-threatening urinary obstruction ( Figure 2-10 ). The
molecular defect has been defined in affected Newfoundland
and Labrador retriever dogs, but in the many other dog
breeds where the disease is milder and only appears to
affect males, the molecular basis still needs to be elucidated.
Cystinuria has been identified as a common renal transport
defect in a variety of canine breeds, domestic shorthair cats,
and also some wild carnivores ( Henthorn and Giger, 2006 ).
Interestingly in cats, which completely depend on arginine
intake from their diet, the urinary loss in arginine can result
in arginine deficiency and ensuing hyperammonemia and
neuropathy. In addition, the most severe renal tubular defect
involves glucosuria, lactic aciduria, and generalized amino
aciduria and is known as Fanconi syndrome. Originally
discovered and still common in Basenji dogs, it is now
recognized in many other canine breeds, but can also be
induced by dietary supplements.
(c)
FIGURE 2-10 Cystinuria caused by renal amino acid transport defects.
(a) Urinary nitroprusside screening test to detect cystine (magenta red discoloration
indicates a positive reaction. (b) Characteristic hexagonal cystine
crystals in urine sediment. (c) Cystine calculi removed from the urinary
bladder.
ii . Screening for Organic Acids Methylmalonic aciduria
is a prime example of an organic aciduria. Methylmalonic
acid is a metabolite of an alternative pathway that only
accumulates when there is a block in the catabolism
of various amino acids, fatty acids, and cholesterol in
the tricarboxic cycle. It may be caused by either an
intermediary enzyme deficiency or cobalamin (vitamin
B 12 ) deficiency, because cobalamin is a cofactor of the