ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 10, No. 6 Copyright © 1980, Institute for Clinical Science, Inc. Hematologic Aberrations in Metabolic Diseases BRUCE A. BUEHLER, M.D. Department of Pediatric Metabolism University of Utah College of Medicine Salt Lake City, UT 84132 ABSTRACT This study of enzyme deficiencies and hematologic aberrations in meta­ bolic diseases includes disorders of amino acidopathies, lipid disease, al­ binism, carbohydrates, and mucopolysaccharidosis. Introduction clinical evidence of marked hematologi­ cal aberrations. This list is divided into The definition of metabolic disease has problems of amino acid metabolism, lipid changed markedly during this century. disease, albinism, carbohydrate disorders When Sir Archibald Garrod gave the orig­ and, finally, the mucopolysaccharidoses. inal Croonian lectures in 1902, metabolic disease was synonomous with the term Amino Acidopathies “inborn errors of metabolism,” but pres­ ent concepts have expanded to include all A c id e m i a s diseases that affect availability of biologi­ In 1971, Hsia6 described the enzyme cal substrates or energy production. It deficiency that accounted for ketotic would be impossible to summarize all the hyperglycinemia. Fibroblasts from pa­ metabolic diseases that may have a pri­ tients with this disease were found to be mary or secondary effect on hemato- deficient in propionyl CoA carboxylase poiesis; therefore, this study has been ar­ activity, and the toxic product responsible bitrarily limited to diseases which have a for the clinical symptoms was propionic known or postulated genetic enzyme de­ acid. Since this discovery, the disease is ficiency as the primary aberration. now referred to as propionic acidemia. Pathological states such as chronic liver The dietary precursors of propionyl disease, ingestion of toxins, or dietary de­ CoA and propionic acid are valine, ficiency states have not been considered leucine, isoleucine, methionine, within the scope of this text. threonine, cholesterol, and odd chain fatty In table I are indicated the categories of acids. If these substances are drastically enzyme deficiencies that present with reduced in the diet, there is clinical and 500 0091-7370/80/1100-0500 $01.20 © Institute for Clinical Science, Inc. HEMATOLOGIC ABERRATIONS IN METABOLIC DISEASES 501 biochemical improvement; unfortunately, T A B L E I exacerbations occur even when the pa­ Enzyme Deficiency and Hematologic tient strictly follows the diet. Manifestations in Metabolic Disease Most patients with propionic acidemia present in the newborn period with se­ Diseases Hematologic Aberration vere metabolic acidosis, lethargy, Amino Acidopathies hyperammonemia, and thrombocyto­ propionic acidemia Neutropenia, thrombo- penia with neutropenia. The neutropenia cytopenia Methylmalonic acidemia Neutropenia, thrombo­ responds to diet therapy with an increase cytopenia in absolute polymorphonuclear neu­ Isovaleric acidemia Leukopenia, anemia, thrombocytopenia trophil count. If diet therapy is discon­ Homocystinuria (cysta­ Platelet aggregation, thionine synthetase thromboembolism tinued, the neutropenia will recur, deficiency) suggesting a toxicity of the metabolite Gluthathione deficiency Hemolytic anemia Cystathionuria Thrombocytopenia (1 case) propionic acid.13 Hartnup's disease Pellagra, anemia In one patient the addition of large Histidinemia Anemia, thrombocytopenia purpura doses of biotin corrected the propionic PKU (during therapy) Anemia, megaloblastic acidemia with a concommitant normaliza­ Orotic aciduria Megaloblastosis, hypo­ chromic anemia, tion of the neutropenia.1 leukopenia Lipid Diseases If propionyl CoA carboxylase is present, Niemann-Pick Sea-blue histiocytes, propionyl CoA is converted to methyl- microcytic anemia, thrombocytopenia malonyl CoA and methylmalonic acid. Gaucher's Thrombocytopenia, 1euko- The next step, conversion of methyl- penia, microcytic anemia, Gaucher's cells malonyl CoA to sueeinyl CoA, requires a F a b r y 's Anemia mutase enzyme to convert the initial com­ Cholesterol ester Microcytic anemia, lipid storage and Wolman1s laden macrophages pound from the D-isomer to the L-isomer. Familial lecithin: Normochromic anemia cholesterol acyl trans­ Two abnormalities of this conversion ferase deficiency have been described: one form is sec­ Bassen-Kornzweig Acanthocytosis, anemia ondary to a racemase deficiency, and the Albinism other is secondary to a mutase apoenzyme Chediak-Higashi Neutropenia, anemia, syndrome thrombocytopenia, abnormality. Adenosylcobalamin, from abnormal leukocyte vitamin B12, is a cofactor for the mutase function, leukemia Hermansky-Pudlak Platelet dysfunction apoenzyme; two abnormalities of vitamin syndrome B12 conversion have caused clinically and Carbohydrate Disorders biochemically similar pictures to the Glycogen storage Hypersplenism, vascular disease Type I fragility mutase deficiency. The dietary precursors (Von Gierkes) of methylmalonic acid are the same as for Galactosemia Severe hemolysis propionic acidemia. Mucopolysaccharidosis Hypersplenism (very The lack of conversion of methyl- late complication) malonyl CoA to succinyl CoA causes methylmalonic acidemia. This disease causes a clinical picture identical to pro­ rations are secondary to the severe acido­ pionic acidemia with severe neutropenia sis and not to direct product toxicity, as and thrombocytopenia in early infancy. seen in propionic acidemia. The major hematologic difference is the Metabolism of leucine can occur by the fact that correction of the acidosis returns pathway described for the two previous the white blood cell count and platelet diseases, but there is an alternate pathway count to normal in spite of continuing ele­ which converts leucine to ketoisocaproic vation of methylmalonic acid.17 This acid. The next step is decarboxylation of would suggest that the hematologic aber- ketoisocaproic acid to isovaleryl CoA, and 5 0 2 BUEHLER then oxidation to methylcrotonyl CoA by individuals. Extensive research efforts isovaleryl CoA dehydrogenase. The ab­ attempting to identify the cause of throm­ sence of this enzyme causes isovaleric boembolism haye failed to identify the acidemia. This disease is characterized by offending metabolite and there is conflict­ vomiting, acidosis, severe neurologic ing evidence that platelet adhesiveness is symptoms, a smell of “sweaty feet,” and increased in affected individuals. severe leukopenia with anemia and Unpublished work,* attempted to in­ thrombocytopenia.9 The hematologic ab­ duce platelet aggregation with methio­ normalities improve with therapy but re­ nine and homocystine in vitro. I f turn during periods of relapse with the sample were acidotic, aggregation acidosis. would occur with either metabolite; The consistent finding of acidosis and otherwise, platelet abnormalities did not leukopenia with thrombocytopenia in appear. Our laboratory was unable to find isovaleric acidemia, propionic acidemia, any primary defect in platelets from pa­ and methylmalonic acidemia raises the tients with homocystinuria. Recently, question of cause and effect. The evi­ Harker5 demonstrated decreased platelet dence against acidosis as the sole cause of survival time in patients with homocys­ leukopenia is the finding of normal tinuria. These findings were then dupli­ hemograms during severe episodes of cated in baboons by creating vascular wall maple syrup urine disease, hyperam­ desquamation with homocystine infu­ monemia, and lactic acidosis. These dis­ sions. At the present time, this finding eases create similar systemic acidosis to strongly points to a vascular abnormality the former diseases, but no effects on causing thromboembolism instead of hematopoiesis are noted. primary platelet abnormalities. Dietary therapy limiting methionine Sulfur Compound Abnormalities reduces the incidence of thromboem­ bolism but does not eliminate it. In 50 Cystathionine synthetase deficiency percent of the patients, pyridoxine (vita­ causes classical homocystinuria. The sul­ m in B6) reduces or elim inates the n eed for fur containing methyl donor compound diet therapy. The exact mechanism of S-adenosylmethionine is the precursor for pyridoxine effect is not yet understood. S-adenosylhomocysteine which is con­ In 1969, Mudd12 described a patient verted to homocysteine and then to cys­ with homocystinuria who excreted large tathionine by cystathionine synthetase. quantities of methylmalonic acid. Inves­ The initial compound in the sulfur path­ tigations revealed that this patient had an way is derived from ATP and the essential inability to metabolize B12 intracellularly. amino acid methionine. The clinical constellation was similar to classic homocystinuria, but the patient H omocystinuria had normal cystathionine activity. The Classical homocystinuria is charac­ hematologic aberrations in this disease terized by ectopia lentis (dislocated were different because there was no evi­ lenses), osteoporosis, biconcavity of the dence of thromboembolism but there was vertebrae, tall stature, thin habitus, men­ marked megaloblastic anemia which did tal retardation in 80 percent of the pa­ not correct with large doses of vitamin B12. tients, and recurrent thromboembolism. It There are two other forms of homocys­ is generally accepted that the vascular tinuria that have been described, but complications of this disease are the cause there is no evidence of thromboembolism of mental retardation as evidenced by or anemia in these diseases. the multiple brain infarcts in affected *