Aldolase myopathies

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). 

Since the work of Sibley and Fleisher (S22) made it plain that elevation of serum aldolase activity occurred quite characteristically in other diseases besides myopathy, such as in hemolytic anemia and in acute hepatitis, it would be most useful to know that in muscular dystrophy the increased serum aldolase was indeed derived from the diseased muscle. Direct demonstration of this origin has been provided (D14) by showing that in 5 of 10 patients with muscular dystrophy the femoral venous return had a higher serum aldolase activity than the femoral arterial supply to the diseased muscles of the lower limb. Further strong support is given by the discovery that serum contains two aldolases (S8) with different substrate requirements (H5) whereby colorimetric methods have been devised for the separate assay of each (S5). These are 1,6-diphosphofructoaldolase ( muscle aldolase) and 1-phosphofruc-toaldolase ( liver aldolase). The ratio in mammalian tissues of muscle to liver aldolase activity is 40 in skeletal and cardiac muscle, 12-25 in spleen, lung, and red cells, and only unity in liver and kidney (S6, S7). The serum activities of both are equally elevated in hepatitis, but in muscular dystrophy and in muscle crush injury only that of muscle aldolase is raised (S4, S6) indeed, the ratio of serum activity of muscle to liver aldolase has been reported as about unity in healthy individuals and in patients with virus hepatitis, but as about 26 in a series of 14... 

Thus in muscular dystrophy it is apparent that both the mean elevations of the serum enzyme values and the magnitudes of their variations upon physical activity are proportional to the mass of dystrophic muscle remaining and to the severity of the disease in it. Both are thus greater in early than in evident Duchenne-type dystrophy, less in limb-girdle dystrophy, and least in myotonia congenita. Further, though serum creatine kinase has been found to be an exceedingly delicate index of myopathy (A2, S14), for present purposes serum aldolase is suflBciently... 

D14. Dreyfus, J.-C., Schapira, G., and D mos, J., Etudes des differences art6rio-veineuses au cours des myopathies. I. Oxygtee, glucose at acide lactique. II. Aldolase plasmatique. Clin. Chim. Acta 3, 571 (1958). 

The majority of patients also had an elevated leukocyte count with modestly elevated levels of aldolase, a marker of muscle injury however, creatine phosphokinase, another indicator of muscle injury, was normal in most patients. This inconsistency between the levels of these two muscle-associated enzymes, previously described in some patients with systemic sclerosis and the toxic oil syndrome (TOS) (see below), is helpful in differentiating EMS from other myopathies (muscle diseases) and from eosinophilic fasciitis (EE) (see below). Approximately one-half of patients had abnormal liver function tests, although the changes were mild. The erythrocyte sedimentation rate, rheumatoid factor, and levels of IgE, complement, and cryoglobulin (all markers of immune dysfunction) were normal in most patients tested. 

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). 

Kreuder J, Borkhardt A, Repp R, Pekrun A, Gottsche B, Gottschalk U, et al. Brief report inherited metabolic myopathy and hemolysis due to a mutation in aldolase A. N Engl J Med 1996 334 1100-4. 

Some enzymopathies of erythrocytes may be associated with multisystem disease (e.g., aldolase deficiency with mental and growth retardation). Individuals with 6-phosphofructokinase deficiency exhibit hemolysis and myopathy and have increased deposition of muscle glycogen (a glycogen storage disease see Chapter 15). The myopathy is usually characterized by muscle weakness and exercise intolerance. (See also Chapters 10, 15, and 28.)... 

Aldolase is also changed in myopathies. The gastrocnemius muscle of chickens with hereditary dystrophy shows the A3C and A2C2 isoenzymes in addition to aldolase A4 (Schapira, 1970). To explain changes in aldolase isoenzyme patterns one can put forward arguments similar to those proposed above for CPK. 

---