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 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 metabolism, lipid changed markedly during this century. disease, , 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 . Pathological states such as chronic liver The dietary precursors of propionyl disease, ingestion of toxins, or dietary de­ CoA and propionic acid are , ficiency states have not been considered , , , 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 , and thrombocyto­ propionic acidemia Neutropenia, thrombo- penia with neutropenia. The neutropenia cytopenia Neutropenia, thrombo­ responds to diet therapy with an increase cytopenia in absolute polymorphonuclear neu­ Leukopenia, anemia, thrombocytopenia trophil count. If diet therapy is discon­ (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 , anemia In one patient the addition of large Anemia, thrombocytopenia purpura doses of 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 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 , 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 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 * In collaboration with Dr. Owen Rennert. HEMATOLOGIC ABERRATIONS IN METABOLIC DISEASES 503

C ystathionuria six separate carriers, and specific groups of amino acids are absorbed by each car­ Absence of cystathionase, the next en­ rier. The carrier of monoamino-mono- zyme in the homocystine pathway, causes carboxylic acids is greatly reduced in cystathionuria. This disease has a very in­ Hartnup’s disease; therefore, renal loss consistent clinical picture, and there is of these compounds occurs along with controversy as to whether or not it causes poor jejunal absorption. Owing to de­ any significant clinical disease. One case creased intestinal absorption, mono- of thrombocytopenia has been associated amino-monocarboxylic acids remain with an absence of cystathionase in the gut and bacterial conversion of activity.11 these amino acids occurs. provides the majority of abnormal G l u t a t h i o n e D e f i c i e n c y compounds,—specifically, indican, in- dolylacetic acid, and indolylacryloylgly- Two patients have been described with cine. With the decrease in tryptophan ab­ hemolytic anemia secondary to glu­ sorption, there is a lack of substrate for tathione deficiency. The anemia was production of ().18 associated with , spino­ Clinical symptoms of Hartnup’s disease cerebellar degeneration, peripheral include cerebellar ataxia and pellagra neuropathy, and myopathy. Enzyme (niacin deficiency) with secondary analysis of red blood cells revealed less and anemia. The neurological than 3 percent activity of y glutamylcys- symptoms improve with antibiotic gut teine synthetase.7 It has been postulated sterilization, probably limiting toxic that the y glutamyl cycle is involved in products from bacterial conversion of un­ amino acid transport, and this blockade absorbed amino acids. Pellagra and may be the cause of the hemolytic anemia diarrhea improve with the addition of as well as the aminoaciduria. large quantities of oral nicotinamide. The Another group of patients has been de­ hypochromic anemia improves when the scribed with glutathione synthetase ab­ pellagra symptoms are treated, but a mild sence and decreased glutathione produc­ suppression of production tion. The patients have had acidosis and continues even after long term therapy. hemolytic anemia with 5-oxoprolinuria. Owing to poor monoamino-mono- Erythrocytes and fibroblasts from these carboxylic acid absorption, serum levels patients had deficient enzyme activity of these amino acids are low and may ac­ and very low glutathione concentrations. count for the chronic anemia. General Finally, a third group of patients has been prognosis is good, although some patients investigated because of hemolytic anemia show residual neurological symptoms. in the absence of any other symptoms. These patients had deficient glutathione synthetase only in the erythrocyte, the H istidinemia rest of their tissues had normal levels.14 The erythrocyte deficiency of glutathione The clinical findings of histidinemia are is postulated to cause the hemolytic variable, but speech defects and mental anem ia. retardation have occurred in over 50 per­ cent of patients found. Some patients are totally asymptomatic in spite of high H a r t n u p ’s D is e a s e levels of serum . Several Amino acids are absorbed from the jeju­ hematologic aberrations have occurred, num and reabsorbed from the kidney by but it is difficult to ascertain if these specific carriers. It appears that there are findings are random or associated. Throm­ 504 BUEHLER

bocytopenia purpura occurred in one thrive, retarded motor development, crys- patient and the platelet abnormalities im­ talluria with ureteral obstruction, hypo­ proved with institution of diet therapy. chromic anemia, leukopenia, and a Anemia has occurred on occasions.4 megaloblastic bone marrow which does The absence of histidase activity in not respond adequately to large doses of fibroblasts and liver biopsy is consistent folate. In the absence of enzyme studies of with the elevation of serum and urine his­ the leukocyte pyrimidine pathway, the tidine levels in these patients. diagnosis can be confirmed by the pres­ ence of large amounts of orotic acid in the PKU urine, and a clinical remission of the megaloblastosis following oral uridine is due to total or partial therapy. The presence of orotic acid in the loss of the enzyme hydrox­ urine is not diagnositic since ylase. Diet therapy lessens the severity of enzyme deficiencies and allopurinol mentation defects, decreases the severe therapy can produce orotic aciduria. skin rash, and improves the general nu­ The explanation of a single gene pro­ tritional state of the patient. Dietary ducing a deficiency of two re­ therapy requires continual monitoring of mains obscure, but suggests a of serum phenylalanine levels to keep the the operant control locus in this disease. value below 10 mgm per dl, but greater than 4 to 5 mgm per dl, whereas normal levels in unaffected individuals are 2 to 3 Lipid Diseases mgm per dl. If therapy is not monitored S phingolipodystrophies closely, phenylalanine deficiency may occur. The sequelae of phenylalanine de­ Sphingolipids are found in membran­ ficiency includes aminoaciduria, hypo­ ous tissues throughout the body. They glycemia, and megalablastic anemia. The share a common base structure of the anemia responds to replacement of amino alcohol sphingosine, with a long phenylalanine in levels greater than 3 chain fatty acid bond at carbon 2; this mgm per dl.15 structure is called ceramide. The hallmark of these diseases is the lack of a hydrolytic O r o t i c A c i d u r i a enzyme necessary for catabolism of a specific sphingolipid. Niemann-Pick, The presence of severe megaloblastosis Gaucher’s, and Fabry’s disease are in this and hypochromic anemia, which is resis­ category, and they cause similar hema­ tant to standard iron plus folate therapy, tologic aberrations. are the hallmarks of orotic aciduria. This probable autosomal recessive disease ap­ N i e m a n n -P i c k D is e a s e pears to involve deficiencies of the two sequential pyrimidine enzymes, oroti- Niemann-Pick disease is caused by a dine-5-phosphate decarboxylase and oro- deficiency of sphingomyelinase with a tate phosphoribosyltransferase. In the ab­ build up of tissue sphingomyelin. Clinical sence of these enzymes, large quantities findings include hepatosplenomegaly, of orotic acid are formed and excreted in pulmonary infiltrates, and varying de­ the urine. grees of nervous system involvement. Presently, there are only nine described Hematologic abnormalities are consistent patients with orotic aciduria, but their with hypersplenism, specifically, mic­ clinical presentations have been similar. rocytic anemia, and thrombocytopenia. The patients have been diagnosed in the The bone marrow contains characteristic first year of life because of failure to “sea-blue histiocytes,” but the blood- HEMATOLOGIC ABERRATIONS IN METABOLIC DISEASES 505 forming cells of the marrow appear to be not appear to affect the erythropoietic normal. The “sea-blue histiocytes” in this system. disease contain lipid inclusions which appear laminated with electron C h o l e s t e r o l E s t e r S t o r a g e microscopy.3 D i s e a s e

There are two distinct phenotypic ex­ pressions of deficient acid lipase activity: G a u c h e r ’s D is e a s e cholesterol ester storage and Wolman’s Gaucher’s disease is characterized by disease. Wolman’s occurs in infancy with absence of the enzyme glucocere- hepatosplenomegaly, steatorrhea, adrenal brosidase and the elevation of gluco- calcifications, anemia, and death; cerebroside in various organs and tissues. whereas, cholesterol ester storage is de­ Clinical symptoms include hepato- tected in adults with widespread lipid des- splenomegaly, bone pain, pathologic frac­ position, elevated triglycerides and tures of the femur, hip joint collapse, CNS cholesterol esters, hepatomegaly, and involvement in the infantile and juvenile premature atherosclerosis. Microcytic, forms, elevated acid phosphatase, and hypochromic anemia is common, but the often severe hematologic emergencies. mechanism is obscure. The bone marrow Hypersplenism occurs in nearly 100 can contain foam cells, but the blood- percent of the patients causing throm­ forming tissues appear normal. bocytopenia, epistaxis, purpura, hemor­ rhagic infarcts, and gastrointestinal bleed­ F a m i l i a l L e c i t h i n -C h o l e s t e r o l ing. These problems are corrected by A c y l T r a n s f e r a s e D e f i c i e n c y splenectomy, but this may hasten liver and bone involvement.10 The bone mar­ This rare disease is characterized by row contains characteristic lipid laden renal failure, corneal opacity, hyper- histiocytes which stain for carbohydrate lipidemia, and hemolytic anemia. The en­ with periodic acid Schiff reagent. Micro­ zyme deficiency is the acyl transferase scopic appearance is different from “sea- causing the increased serum and tissue blue histiocytes” owing to the appearance lipids. The anemia is due to hemolysis, of “crinkled tissue paper” or “crumpled presumably secondary to accumulation of silk” in the cytoplasm. These cells do not cholesterol and phospholipids on the red appear to cause loss of the normal blood- cell membrane. The lipid content of the forming cells in the marrow. red blood cell causes the appearance of “target cells” which clear in normal

F a b r y ’s D i s e a s e plasma.2 The bone marrow contains nonspecific “foam cells.” Dietary therapy Fabry’s disease demonstrates deficient has not yet been successful in preventing activity of galactosidase with systemic these sequelae. deposition of globotriaosylceramide.

Clinical symptoms include a raised scrotal B a s s e n -K o r n z w e i g D i s e a s e lesion (x-linked disease), pain in the ex­ tremities which improves with Dilantin, Abetalipoproteinemia demonstrates fat hypohidrosis, lymphedema, severe kid­ , ataxic neuropathy, di­ ney disease, and anemia. The anemia is arrhea, retinitis pigmentosa, and acan- due to decreased red blood cell survival,8 thocytosis with anemia. Very low density and late in the disease is secondary to the lipoprotein (VLDL) fractions, low density renal disease. There are lipid-laden mac­ lipoprotein (LDL) fractions, and chylo­ rophages in the bone marrow but these do microns are absent from the serum, 506 BUEHLER

presumably owing to absent triglyceride Whatever the defect is in HPS, the transport. The anemia is probably due to presence of white blood cell inclusions general malnutrition, and it is reversible and albinism should alert the clinician to with parenteral iron with folate therapy. the bleeding diathesis associated with The confusing phenomena is acan- platelet aggregation abnormalities. thocytosis; no explanation has been ac­ CHS is a rare form of albinism as­ cepted for their presence in this disease. sociated with early childhood infection, In defibrinated blood, autohemolysis oc­ progressive neuropathy, lymphoreticular curs in 40 percent of the acanthocytes; malignancy, anemia, neutropenia, throm­ autohemolysis can be reversed by addi­ bocytopenia and peroxidase-positive tion of LDL and high density lipoprotein lysosomal granules in the leukocytes. (HDL) lipid fractions.19 No clinical Death occurs prior to age 20. No etiology sequelae of this phenomena have been is known and few studies have been done noted. Vitamin E therapy improves the on these patients. neurologic symptoms.

Carbohydrate Disorders Albinism G lycogen Storage Disease Type I The term albinism encompases that (Von G ierke’s) group of disorders exhibiting ocular or oculocutaneous hypomelanosis. The This disease is included because clini­ metabolic defect is in the melanocyte of cians associate this disorder of - the eye and skin, which appear to be nor­ 6-phosphatase with skin bleeding and mally distributed in human albinos. The mild anemia. The studies indicate no ab­ site of enzymatic disturbance is the path­ normalities of hematologic function in way producing and occasionally spite of chronic acidosis. The skin bleed­ involves conversion steps. There ing is secondary to vascular fragility are three distinct ocular types and seven which appears to be a function of the sev­ oculocutaneous syndromes. erity of liver disease. The anemia also cor­ The two syndromes associated with relates with the liver disease. The vascu­ hematologic aberrations are Her- lar problems do not appear to be a primary mansky-Pudlak (HPS) and Chediak- consequence of altered glycogen release. Higaski (CHS) syndromes. HPS patients have with G alactosemia hemorrhagic episodes, bruisability, pro­ longed bleeding during tooth extraction, This abnormality of galactose-1- and hemoptysis. A great deal of investiga­ phosphate uridyl transferase is charac­ tion has been directed at the basic abnor­ terized by early onset vomiting, diarrhea, mality in HPS, but the exact etiology is jaundice, failure to thrive, mental retarda­ still undetermined. The presently popu­ tion, and severe hemolysis resembling lar theory is an aberration in prostaglandin erythroblastosis. The hemolysis can be a synthesis in the platelet.20 Platelets are terminal event in these patients. The definitely abnormal in function and no exact cause of hemolysis is unknown, but other hematologic defect can be found. red blood cells from patients with galac­ Pigment laden macrophages which tosem ia have im paired oxygen uptake and stain blue with azure dye are found in the possible decreased adenosine triphos­ bone marrow, while peripheral leuko­ phate availability.16 Diets free of galactose cytes contain ceroid-like inclusions or can reverse the process noted including membrane bound dense bodies. the hematological aberrations. HEMATOLOGIC ABERRATIONS IN METABOLIC DISEASES 5 0 7

Mucopolysaccharidosis physiology in Fabry’s disease. J. Lab. Clin. Med. 12:906, 1968. Finally, a brief statement to reiterate 9. L e v y , H. L ., E r ic k s o n , A. M., L o t t , I. T., and KlERTZ, D. J.: Isovaleric acidemia: results of the fact that in spite of severe storage de­ family study and dietary treatment. Pediatrics fects, hepatosplenomegaly, and bone 52:83, 1973. damage, these patients show no aberra­ 10. M a t h o t h , Y. and F r i e d , K .: C hronic Gaucher’s disease: Clinical observations on 34 tions of the hematological system until patients. Israel J. Med. Sci. 1:521, 1965. late in the disease. The only hematology 11. M o n g e a u , J. G., H il g a r t n e r , M ., W o r t h e n , problems in these patients is when the H . G., and F r im p t e r , G. W.: Cystathionuria: study of an infant with normal mentality, liver disease has reached terminal stages. thrombocytopenia, and renal caluli. J. Pediat. The patient then becomes anemic and has 69:1113-1120, 1969. decreased clotting factors. Hyper­ 12. M u d d , S. H., L e v y , H. L ., and A b e l e s , R. H.: A derangement in B12 metabolism leading to splenism is not seen in this disease homocystinuria, cystathioninemia, and complex. methylmalonicaciduria. Biochem. Biophys. Res. Commun. 35:121-126, 1969. 13. N y h a n , N. L.: Amino Acid Metabolism and Genetic Variation. New York, McGraw-Hill Book Co., 1967, p. 257. References 14. O r t , M., L o o s , J. A., and PRINS, H.: Hereditary absence of reduced glutathione in the 1. Ba r n e s , N. D ., H u l l , D ., Ba l g o l in , L., and erythrocytes—a new clinical and biochemical G o m p e r t z , D .: Biotin—responsive pro- entity? Vox Sang. 6:270-373, 1961. pionieacidemia. Lancet 2 :2 4 4 -2 4 5 , 1970. 15. R o y s d o n , N.J. and P e r r y , T. E.: Megaloblastic 2. B l o m h o f f , J. P ., H o l m e , R ., H o v ig , T ., anemia complicating dietary therapy of F l a t m a r k , A., a n d G j o n e , E.: Lipid deposition phenylketonuria in infancy. Arch. Dis. Child. in the kidneys in hepatorenal syndrome: A 37:430, 1962. pathogenetic factor? Digestion 12:250, 1975. 16. Sc h w a r t z , V., G o l d b e r g , L., Ko m r o w e r , G. 3. B r a d y , R. O.: The sphingolipidoses. New Eng. M., and H o l z e l , A.: Some disturbances of ery­ J. Med. 275:312, 1966. throcyte metabolism in galactosemia. Biochem. 4. C a r t o n , D ., D h o n d t , F ., d e Sh r ijv e r , F ., Sa - J. 62:34, 1956. MYN, W ., Ki n t , J., D e l b e k e , M. J., and HOOFT, 17. S t a n b u r y , J. B., W y n g a a r d e n , J. B., and C .: Histidinemia. Helv. Pediat. Acta 25:127, F r e d r ic k s o n , D. S.: The Metabolic Basis of 1970. Inherited Disease, 4th ed. New York, 5. H a r k e r , L. A., Sl i c h t e r , S. J., Sc o t t , C. R., McGraw-Hill Book Co., 1978, p. 422. and Ross, R.: Homocystinemia: vascular injury 18. T a r l o w ,M . J., Se a k in s , J. W., L l o y d , J. K., and arterial thrombosis. New Eng. J. Med. M a t t h e w s , D. M ., C h e n g , B., and T h o m a s , A. 291:537, 1974. J.: Intestinal absorbtion and biopsy transport of 6. H s ia , Y. E., Sc u l l y , K. J., and R o s e n b e r g , L. peptides and amino acids in Hartnup’s disease. E.: Inherited propionyl CoA carboxylase defi­ Clin. Sci. 39:18, 1970. ciency in “ketolic hyperglycinemia.” J. Clin. 19. W a y s , P. and Sim o n , E. R.: The role of serum in Invest. 50:127, 1971. acanthocyte autohemolysis and membrane 7. Ko n r a d , P. N., R ic h a r d , F ., II, V a l e n t in e , W. lipid composition. J. Clin. Invest. 43:1322, N., and Pa g l ia , D .: Glutamylcysteine synthe- 1964. lase deficiency. New Eng. J. Med. 286:557- 20. W h i t e , J. G ., W it k o p , C. J., and G e r r it s e n , S. 561, 1972. M.: The Hermanski-Pudlok syndrome: Inclu­ 8. K r i v i t , W., V a n c e , D . E., D e s n i c k , R., sions in circulating leukocytes. Brit. J. Haemat. W h it e c a r , J. P., and Sw e e l e y , C. C.: Red cell 24:761, 1973.