251 Review Article Ana Maria Martins Inborn errors of metabolism: a clinical overview Department of Pediatrics, Universidade Federal de São Paulo/ Escola Paulista de Medicina, São Paulo, Brazil ABSTRACT INTRODUCTION CONTEXT: Inborn errors of metabolism cause hereditary metabolic diseases (HMD) and classically they result from the In 1904 the doctor Archibald E. Garrod lack of activity of one or more specific enzymes or defects in the described alkaptonuria, a disease he classified transportation of proteins. as a lifelong congenital chemical alteration. OBJECTIVES: A clinical review of inborn errors of metabolism (IEM) to give a practical approach to the Later on, in 1909, he described other diseases: physician with figures and tables to help in understanding albinism, cystinuria, porphyria and pentosuria, the more common groups of these disorders. which he named “Inborn Errors of Metabolism”. DATA SOURCE: A systematic review of the clinical and biochemical basis of IEM in the literature, especially Garrod’s conclusions were completely correct considering the last ten years and a classic textbook in relation to the genetic basis of metabolic 1 (Scriver CR et al, 1995). disorders and the gene–enzyme concept. SELECTION OF STUDIES: A selection of 108 references about IEM by experts in the subject was made. Clinical cases According to Scriver, in the foreword of are presented with the peculiar symptoms of various diseases. “Physician’s Guide to the Laboratory Diagnosis 2 DATA SYNTHESIS: IEM are frequently misdiagnosed of Metabolic Diseases”, the importance of because the general practitioner, or pediatrician in the neonatal or intensive care units, does not think about this Garrod’s observation that inborn errors of diagnosis until the more common cause have been ruled out. metabolism (IEM) are manifestations of This review includes inheritance patterns and clinical and biochemical individuality was never recognized laboratory findings of the more common IEM diseases within a clinical classification that give a general idea about these during his lifetime, nor has it been in our days, disorders. A summary of treatment types for metabolic because many doctors still think of IEM as inherited diseases is given. situations of extreme rarity that will never be CONCLUSIONS: IEM are not rare diseases, unlike previous thinking about them, and IEM patients form part of seen in the typical medical practice. IEM the clientele in emergency rooms at general hospitals and produces manifestations in every organ, from in intensive care units. They are also to be found in the fetus to geriatric life and they are neurological, pediatric, obstetrics, surgical and psychiatric clinics seeking diagnoses, prognoses and therapeutic or omnipresent in appearance, not respecting the supportive treatment. doctor’s qualifications as a generalist or KEY WORDS: Inborn errors of metabolism. Metabolic specialist. inherited disease. Diagnosis. Inborn errors of metabolism cause hereditary metabolic diseases (HMD) and Sao Paulo Med J/Rev Paul Med 1999; 117(6):251-65. 252 classically they result from the lack of activity of IEM disorders have been found to be: 1 in 12,13 one or more specific enzymes or defects in the 11,818 to 1 in 15,000 for phenylketonuria; 12 transportation of proteins. The consequences 1 in 43,000 for maple syrup urine disease; 14 can usually be the accumulation of substances and 1 in 125,000 for biotin deficiency. present in small amounts, the deficiency of critical intermediary products, the deficiency of Inheritance Patterns specific final products or furthermore the The majority of HMD are inherited noxious excess of products of alternative autosomal recessive traits, i.e. they have a 3 metabolic pathways. recurrence risk of 25% for each gestation of The molecular basis of biochemical heterozygous parents. Some diseases are X- disorders in HMD are genetic mutations in linked, that is, the mother is carrier of the enzymatic loci that affect activator proteins or mutation, with the risk of recurrence for each co-factors for enzymes, protein transportation, gestation in these cases being 50% for males 3,4 carrier systems or recognition markers. and 50% for females to be carriers of the mutation who can pass it on to their children. Incidence There are in addition mitochondrial diseases, More than three hundred human diseases determined by mutations in mitochondrial DNA, are known today that are caused by inborn in which the risk of recurrence is virtually 100% 3 errors of metabolism and this number is of the children of both sexes. constantly growing because of new identification techniques for the various CLINICAL CLASSIFICATION OF INBORN biochemical phenotypes. However, the ERRORS OF METABOLISM detection of HMD incidence has not been increasing in parallel, probably because its One of the most educational and clinical diagnosis is being underestimated. Faulty classifications of IEM is to be found in The diagnosis of IEM is related to a series of factors: Metabolic and Molecular Bases of Inherited 15 (1) they are individually considered rare and Disease, 1995 edition, by Saudubray & 5 therefore many physicians do not consider IEM Charpentier, which classifies IEM in until most frequent conditions have been ruled accordance with the clinical phenotype and out, (2) blood and urine samples for presents tables of signs and symptoms and flow investigation of metabolic errors need to be charts that aid daily practice greatly. Table 1 collected at the right time in relation to the course shows a summary of the authors’ classification. of the disease, and (3) many metabolic diseases 3,5,6 only produce intermittent abnormalities. Category 1 IEM are not rare diseases when we observe Diseases that only affect a functional or 7 their cumulative incidence, which is about one anatomical system or an organ, such as the in every 5000 live births. Nevertheless, the endocrine system, immune system, coagulation prevalence of each disease has many variables, factors or lipoproteins. The symptoms are especially relating to race. Examples of frequency uniform and the correct diagnosis is usually for specific diseases include: 1 in 500 for familial easy, because the basis of the biochemical 8 hypercholesterolemia; 1 in 12,000 for defect incorporates the given consequence, for 4,9 phenylketonuria; 1 in 15,000 for organic example, the tendency to bleed seen in cases 10 acidurias; 1 in 60,000 for glycogen storage of coagulation defects. 4 8 diseases; 1 in 45,000 for galactosemia; 1 in 8 100,000 to homocystinuria and 1 in 290,000 Category 2 11 for maple syrup urine disease. Diseases in which the biochemical basis In Brazil the incidence of some specific affects one metabolic pathway common to a great Sao Paulo Med J/Rev Paul Med 1999; 117(6):251-65. 253 4 number of cells or organs, such as in storage Table 2 lists lysosomal disorders. diseases due to lysosomal disorders, or is restricted Peroxisomal Biogenesis Disorders. to one organ with humoral and systemic Involving many anabolic functions. These consequences, such as hyperammonemia in include the biosynthesis of plasmalogen, which defects of the urea cycle or hypoglycemia in is a major myelin component, cholesterol and hepatic glycogenesis. bile acids. Generalized peroxisomal β-oxidation Diseases in this category have great deficiency results in a variety of disturbances clinical diversity. The central nervous system that are still not well understood, partly because (CNS) is frequently attacked and in the evolution there is an overlap in function between the of the disease many secondary abnormalities peroxisomes and other organelles such as the can appear, making the diagnosis more difficult. mitochondria and the endoplasmic reticulum. This category includes many errors in These multiple and complex biochemical intermediary metabolism (carbohydrate defects; abnormalities result in specific defects of amino acid or organic acid metabolism with neuronal migration with malformations and primary or secondary disturbances of vitamin severe neurologic dysfunction, hypotonia, or metal homeostasis; purine and peroxisome mental retardation and developmental disorders), diseases of intracellular transport regression. In contrast to lysosomal disorders, (endoplasmic reticulum and Golgi apparatus there is no intracellular accumulation of defects) and lysosomal disorders. undigested polymers. A useful marker for their These diseases can be divided into three diagnosis is the accumulation of very long chain groups from a physiopathological perspective, fatty acids in plasma, such as X-linked greatly assisting in diagnostic reasoning. adrenoleukodystrophy (“Lorenzo’s oil disease”). 4 Table 2 lists the diseases in this group. Group I Defects In Intracellular Transport. Involving Disturbances in the synthesis or catabolism defects in intracellular transport and protein of complex molecules. The symptoms are processing. This group includes α1-antitrypsin permanent, progressive, independent of deficiency and carbohydrate-deficient incidental events and are not related to glycoprotein syndrome. alimentary ingestion. Lysosomal Disorders. Also called storage Group 2 diseases. These lead to the progressive Inborn errors of intermediary metabolism accumulation of undigested substrates, usually leading to acute and recurrent intoxication polymers, that cannot usually be hydrolyzed. (metabolic acidosis, vomiting, lethargy, The polymers accumulate in lysosomes, where dehydration, thromboembolic complications) or they can be seen using