Aldolase A, deficiency

Inherited aldolase A deficiency and pyruvate kinase deficiency in erythrocytes cause hemolytic anemia. The exercise capacity of patients with muscle phos-phofiaictokinase deficiency is low, particularly on high-carbohydrate diets. By providing an alternative lipid fuel, eg, during starvation, when blood free fatty acids and ketone bodies are increased, work capacity is improved. 

On the other hand, a deficiency of aldolase A is a rare cause of hereditary hemolytic anemia. Only three families with aldolase A deficiency have been reported. In the first case, hereditary nonspherocytic hemolytic anemia, many dysmorphic features and mental and growth retardation were observed (B13). The second family had only hemolysis but no signs of myopathy (M24). The third case had both hemolytic anemia and predominantly myopathic symptoms (K25). 

K19. Kashi, H Mukai, T., Hirono, A., Fujii, H., Miwa, S and Hori, K Human aldolase A deficiency associated with a hemolytic anemia Thermolabile aldolase due to a single base mutation. Proc. Natl. Acad. Sci. U.S.A. 84,8623-8627 (1987). 

Only three cases of aldolase deficiency have been described. Beutler et aF have described a boy with an unstable enzyme with mental retardation and hemolytic anemia and dysmorphic features. Kishi et al described a patient with severe hemolytic anemia, exacerbated by infection, but none of the features described by Beutler et al. Kishi identified the mutation, leading to a conversion of aspartic acid at position 128 to glycine. Kreuder et ai reported on a boy with hemolytic anemia and myopathy caused by aldolase A deficiency. They identified a mutation, causative of an amino acid substitution at position 206 (Glu to Lys). 

Hereditary fructose intolerance is due to aldolase B deficiency and is often diagnosed when babies are switched from formula or mother s milk to a diet containing fructose-based sweetening, such as sucrose or honey. 

Cause and treatment of hereditary fructose intolerance A deficiency of fructokinase causes a benign condition, but a deficiency of aldolase B causes hereditary fructose intolerance, in which severe hypoglycemia and liver damage can lead to death if the amount of fructose (and, therefore, sucrose) in the diet are not severely limited. 

DHAP is a glycolysis intermediate, whereas glyceraldehyde must be reduced by a mitochondrial enzyme, glyceraldehyde dehydrogenase, to glycerol, which is then subject to action by glycerol kinase in the liver. The aldolase seems to be the principal pathway of metabolizing fructose and depends on the initial phosphorylation step catalyzed by fructokinase, which produces fructose-l-phosphate. Fructokinase is defective in an inherited disorder, essential fructosuria. Fructose-l-phosphate aldolase is deficient in the hereditary disorder fructose intolerance. 

A deficiency of fructose-1-phosphate aldolase produces this rare disorder with hypoglycemia and liver failure. Fructose ingestion inhibits glycogenolysis and giuconeogenesis, producing hypoglycemia. Early detection is important because this condition responds to a diet devoid of sucrose and fructose. 

Individuals with a deficiency in aldolase B have the condition known as fructose intolerance. As with most enzyme deficiencies, this is an autosomal recessive disease it does not cause difficulty as long as the patient does not consume any foods with fructose or sucrose. Frequently, children with fructose intolerance avoid candy and fruit, which should raise some eyebrows Likewise, they usually do not have many dental caries. However, if chronically exposed to fractose-containing foods, infants and small children may have poor weight gain and abdominal cramping or vomiting. 

In the liver, kidney, and intestine, fructose can be converted to glycolytic/ gluconeogenic intermediates by the actions of three enzymes—fructokinase, aldolase B, and triokinase (also called triose kinase)—as shovra in Figure 24-1. In these tissues, fructose is rapidly phosphorylated to fructose 1-phosphate (FIP) by fructokinase at the expense of a molecule of adenosine triphosphate (ATP). This has the effect of trapping fructose inside the cell. A deficiency in this enzyme leads to the rare but benign condition known as essential fmcto-suria. In other tissues such as muscle, adipose, and red blood cells, hexokinase can phosphorylate fructose to the glycolytic intermediate fmctose 6-phosphate (F6P). 

The toxic effects of FIP can also be exhibited in patients that do not have a deficiency in aldolase B if they are parenterally fed with solutions containing fructose. Parenteral feeding with solutions containing fructose can result in blood fructose concentrations that are several times higher than can be achieved with an oral load. Since the rate of entry into the hepatocyte is dependent on the fructose gradient across the cell, intravenous loading results in increased entry into the liver and increased formation of FIP. Since the rate of formation of FIP is much faster than its further metabolism, this can lead to hyperuricemia and hyperuricosuria by the mechanisms described above. 

A deficiency in aldolase B leads to the condition known as fructose intolerance. 

Essential fructosuria is a rare and benign genetic disorder caused by a deficiency of the enzyme fructok-inase. Why is this disease benign, when a deficiency of aldolase B (hereditary fructose intolerance) can be fatal Could Candice Sucher have essential fructosuria ... 

The effect on 2,3-BPG metabolism varies (Fig. 18.2). If the disorder is proximal to the 2,3-BPG shunt (e.g. deficiencies of hexokinase, phosphoglucose isomerase and aldolase A), the flow of metabolites through glycolysis will be decreased and consequently the concentration of 2,3-BPG will fall. If the deficiency is distal to the 2,3-BPG shunt (e.g. pyruvate kinase deficiency), the concentration of 2,3-BPG will rise. 

It is now well established that great majority of cases of TSD occur in Jewish families. Exceptions were reported by Falkenheim (1901), Starck (1920), Catel (1943), Aronson et al. (1960). Probably, the incidence of TSD in races other than the Jewish would actually be even smaller than reported wdth more complete knowledge of the type of amaurotic family idiocy in some subjects and of the ancestry in others. 90% of 219 Tay-Sachs children of Aronson and Volk (1962) belonged to the Jewish race as jugded by their religion. TSD in Japanese families was reported by Cordes and Horner (1929) and Murakami (1957). From epidemiologic studies on the frequency of a deficiency of fructose-1-phosphate aldolase (Volk et al. 1964), the incidence of TSD in Jews is 100 times that of non-Jews. This is discussed in more detail in the chapter by Fuhrmann. 

Of great interest is the discovery of a deficiency or absence of fructose-1-phosphate aldolase in TSD serum (Volk et al. 1964). The enzyme, which normally catalyzes the splitting of fructose-1-phosphate into two three-carbon compounds which then gain access to the glycolytic pathway, was determined by a modi-... 

Hereditary fructose intolerance which is a more serious condition in which there are metabolic disturbances, e.g. hypoglycaemia, after fructose ingestion. It is due to a deficiency of the enzyme fructose-1-phosphate aldolase. 

B13. Beutler, E Scott, S., Bishop, A., Margolis, N Matsumoto, F., and Kuhl, W Red cell aldolase deficiency and hemolytic anemia A new syndrome. Trans. Assoc. Am. Physicians 76,154-166 (1973). 

M24. Miwa, S., Fujii, H., Tani, K Takahashi, K., Takegawa, S., Fujinami, N Sakurai, M., Kubo, M Tanimoto, Y., Kato, T., and Matsumoto, N., Two cases of red cell aldolase deficiency associated with hereditary hemolytic anemia in a Japanese family. Am. J. Hematol. II, 425-437 (1981). 

Muscle aldolase deficiency. The first patient with muscle aldolase deficiency was identified in 1996 this young boy suffered from a hemolytic trait but also... 

Genetic deficiency of fructokinase is benign and often detected incidentally when the urine is checked for glucose with a dipstick. Fructose 1-phosphate aldolase deficiency is a severe disease because of accumulation of fructose 1-phosphate in the liver and renal proximal tubules. Table 1-12-4 compares the two conditions. Symptoms are reversed after removing fructose and sucrose from the diet. 

D-4) Aldolase deficiency at this step. Associated with a hemolytic anemia and, sometimes, muscle weakness. 

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