Errors of Metabolism

Sickle Cell Anemia and Other Hemoglobinopathies 145 Normal and Abnormal Hemoglobins 145 Pathology of Sickle Cell Anemia 

Protein Structure and Clinicomolecular Correlation in Hemoglobin Disease 

Inborn Errors of Plasma Proteins 158 Properties of Plasma Proteins Agammaglobulinemia Wilson s Disease Acatalasia 

Inborn Errors of Carbohydrate Metabolism 163 Glycogen Storage Disease Glycogen Metabolism Von Gierke s Disease 

Drug-Induced Hemolytic Anemia 170 Inborn Errors of Aromatic Amino Acid Metabolism 172 Phenylketonuria Tyrosinosis Alkaptonuria Albinism Histidinemia 

Formiminotransferase deBciency syndrome was first described in two patients by Arakawa (A7). It was characterized by mental retardation, a very high serum folate level, and excessive excretion of formiminoglutamic acid following a histidine load. A third patient with this syndrome was later 

A total of 10 patients have now been described with formiminotransferase deficiency. Some have had a variable degree of mental retardation and a severe anemia while others have been asymptomatic. Arakana and his colleagues described five patients (two of whom were brothers) and all were severely mentally retarded (A9, AlO). 

It is not possible to say if all of these patients are true examples of formiminotransferase deficiency. A degree of clinical variation could be expected and this would depend on how much of the active enzyme was available. The patients described by Perry excreted much more formimino- 

Another variant has been found affecting two sisters (N5, N6). This was characterized by the urinary excretion of large quantities of hydantoin-5-propionic acid and formiminoglutamic acid, and was unresponsive to treatment with folic acid. One had retarded speech, but this was the only defect, and the other child was normal. 

Impaired Folate Uptake by Bone Marrow Cells 

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Epilepsy may be defined as a permanent, recurrent seizure disorder. Examples of the known causes of epilepsy include brain injury at birth, head injuries, and inborn errors of metabolism, hi some patients, the cause of epilepsy is never determined. 

Garrod AE Inborn errors of metabolism. (Croonian Lectures.) Lancet 1908 2 1,73, 142,214. 

Hepatic urea synthesis takes place in part in the mitochondrial matrix and in part in the cytosol. Inborn errors of metabolism are associated with each reaction of the urea cycle. 

Understanding of the degradative pathways for GAGs, as in the case of glycoproteins (Chapter 47) and glycosphingohpids (Chapter 24), has been gready aided by elucidation of the specific enzyme deficiencies that occur in certain inborn errors of metabolism. When GAGs are involved, these inborn errors are called mucopolysaccharidoses (Table 48—7). 

Phenylketoniuia (PKU) is an inborn error of metabolism by which the body is unable to convert siuplus pherylalanine (PA) to tyrosine for use in the biosynthesis of, for... 

Other diseases Autoimmune diseases Amyloidosis Aplastic anemia Paroxysmal nocturnal hemoglobinuria Fanconi s anemia Thalassemia major Sickle cell anemia Severe combined immunodeficiency Inborn errors of metabolism... 

Sepsis syndrome Anorexia nervosa Complications during pregnancy Geriatric patients with multiple chronic disease Organ transplantation Inborn errors of metabolism Cystic fibrosis Extreme prematurity... 

MATSUMOTO, I., KAHURA, T., A new chemical diagnostic method for inborn errors of metabolism by mass spectrometry - rapid, practical, and simultaneous urinary metabolites analaysis, Mass Spec. Reviews, 1996,15,43-57. 

RASHED, M.S., BUCKNALL, M.P., LITTLE, D., AWAD, A., JACOB, M., ALAMOUDI, M., ALWATTAR, M., OZAND, P.T., Screening blood spots for inborn errors of metabolism by electrospray tandem mass spectrometry with a microplate batch process and a computer algorithm for automated flagging of abnormal profiles, Clin. Chem., 1997,43,1129-1141. 

The Editors have striven, as in previous years, to include in the present volume reviews on greatly diversified subjects, all of timely importance. The article on mellituria in Volume 4 has been supplemented by a survey of galactosemia, and we expect to follow in future volumes with reviews of other inborn errors of metabolism or, in modern parlance, of molecular diseases. Likewise, the article on peptiduria supplements that on aminoaciduria in Volume 2 and that on microbiological assay of vitamins extends previous summaries on the nucleogenic vitamins. The haptoglobins lie on the borderline of hematology. 

The One Gene One Enzyme Principle Garrod (G3, G4) suggested, over 50 years ago, that an inborn error of metabolism was caused by the inherited absence of an enzyme. This... 

G3. Garrod, A. E., The Croonian lectures on inborn errors of metabolism. II. Alkaptonuria. Lancet ii, 73-79 (1908). 

Pentosuria was classified as an inborn error of metabolism in 1908 by Garrod (Gl). The harmless metabolic condition has been described almost exclusively in individuals of Jewish origin. 

To date, cellular and gene therapy products submitted to FDA have included clinical studies indicated for bone marrow marking, cancer, cystic fibrosis, AIDS, and inborn errors of metabolism and infectious diseases. Of the current active INDs approximately 78% have been sponsored by individual investigators or academic institutions and 22% have also been industry sponsored. In addition to the variety of clinical indications the cell types have also been varied. Examples include tumor infiltrating lymphocytes (TIL) and lymphocyte activated killer (LAK) cells, selected cells from bone marrow and peripheral blood lymphocytes, for example, stem cells, myoblasts, tumor cells and encapsulated cells (e.g., islet cells and adrenal chromaffin cells). 

Fieser, L.F. Fieser, M. (1950) Organic Chemistry, 2nd ed. D.C. Heath Co., Boston. Galjaard, H. (1980). Genetic Metabolic Diseases. Elsevier North Holland, Amsterdam. Garrod, A.E. (Reprinted 1963, Harris, H. Ed.). Inborn Errors of Metabolism. Oxford University Press. 

Garrod. Inborn Errors of Metabolism. Concept of pH introduced by Sorensen. Tsvett used chromatography to separate chlorophylls. Vitamins isolated. B vitamins shown to be parts of co-... 

In order to function efficiently and to survive, a cell must adapt quickly to changing circumstances and to channel intermediates along pathways which are the most appropriate for the conditions at the time. The facility to increase or reduce the rate of an enzyme catalysed reaction is a crucial part of metabolic control and therefore the adaptability of metabolism as this allows optimal utilization of possibly scarce resources. In short, a cell must be able to control its metabolic activities in order to meet a challenge from the environment. Loss of biological or metabolic control is likely to be detrimental to the cell as is illustrated by certain abnormal conditions such as cancer, genetically determined inborn errors of metabolism or following the... 

If this is so, then the next question to be answered is What metabolic peculiarities are crucial with respect to susceptibility to alcoholism It is obvious that the answer to this question must be based upon some knowledge of metabolic peculiarities in general. What metabolic peculiarities exist from which one might choose the crucial ones Because of lack of attention to biochemical individuality, little indeed was known about metabolic peculiarities. When we began the study of alcoholism, the list of known peculiarities was pretty much limited to the relatively rare so-called "inborn errors of metabolism," alcaptonuria, phenyl ketonuria, cystinuria, and the like. The chance that any of these were involved was very minute. 

Since Williams and co-workers proposed the genetotrophic concept in 1950,20, 21 many genetotrophic diseases have been discovered. Stark examples include the so-called nutrient "dependencies" and other nutrition-responsive inborn errors of metabolism.22, 23 More subtle cases include all the complex diseases now being found to involve both nutrition and genetic predispositions. 

Familial LCAT deficiency, an inborn error of metabolism that affects the levels of plasma cholesteryl esters, was recently discovered in Scandinavia (G7, G8, G9, GIO, Gll, N4). Patients with this disease have... 

Norum, K. R., and Gjone, E, Familial plasma licithin cholesterol acyltransferase deficiency biochemical study of a new inborn error of metabolism. Scand. J. Clin. Lab. Invest. 20, 231-243 (1967). 

Cefditoren Cefditoren is contraindicated in patients with carnitine deficiency or inborn errors of metabolism that may result in clinically significant carnitine deficiency because use of cefditoren causes renal excretion of carnitine. 

Inherited absence or mutations in enzymes involved in critical metabolic pathways—eg, the urea cycle or glycogen metabolism—are referred to as inborn errors of metabolism. If not detected soon after birth, these conditions can lead to serious metabolic derangements in infants and even death. 

Most inborn errors of metabolism manifest after birth because the exchange of metabolites between mother and fetus provides for fetal metabolic needs in utero. 

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