AMINO ACID DISORDERS 105 Massaro, A. S. (1995). Trypanosomiasis. In Guide to Clinical tions in biological fluids relatively easy. These Neurology (J. P. Mohrand and J. C. Gautier, Eds.), pp. 663– analyzers separate amino acids either by ion-ex- 667. Churchill Livingstone, New York. Nussenzweig, V., Sonntag, R., Biancalana, A., et al. (1953). Ac¸a˜o change chromatography or by high-pressure liquid de corantes tri-fenil-metaˆnicos sobre o Trypanosoma cruzi in chromatography. The results are plotted as a graph vitro: Emprego da violeta de genciana na profilaxia da (Fig. 1). The concentration of each amino acid can transmissa˜o da mole´stia de chagas por transfusa˜o de sangue. then be calculated from the size of the corresponding O Hospital (Rio de Janeiro) 44, 731–744. peak on the graph. Pagano, M. A., Segura, M. J., DiLorenzo, G. A., et al. (1999). Cerebral tumor-like American trypanosomiasis in Most amino acid disorders can be diagnosed by acquired immunodeficiency syndrome. Ann. Neurol. 45, measuring the concentrations of amino acids in 403–406. blood plasma; however, some disorders of amino Rassi, A., Trancesi, J., and Tranchesi, B. (1982). Doenc¸ade acid transport are more easily recognized through the Chagas. In Doenc¸as Infecciosas e Parasita´rias (R. Veroesi, Ed.), analysis of urine amino acids. Therefore, screening 7th ed., pp. 674–712. Guanabara Koogan, Sa˜o Paulo, Brazil. Spina-Franc¸a, A., and Mattosinho-Franc¸a, L. C. (1988). for amino acid disorders is best done using both South American trypanosomiasis (Chagas’ disease). In blood and urine specimens. Occasionally, analysis of Handbook of Clinical Neurology (P. J. Vinken, G. W. Bruyn, cerebrospinal fluid (CSF) amino acids will provide a and H. Klawans, Eds.), Vol. 52, pp. 45–349. Elsevier, diagnostic finding. For example, patients with non- Amsterdam. ketotic hyperglycinemia typically have an elevation of CSF glycine that exceeds the corresponding increase in plasma glycine. Amino Acid Disorders Encyclopedia of the Neurological Sciences DISORDERS OF AMINO ACID CATABOLISM Copyright 2003, Elsevier Science (USA). All rights reserved. Most of the known disorders of amino acid MORE THAN 70 inherited disorders of amino acid metabolism are disorders of amino acid catabolism. metabolism are known, including many that cause When an enzyme deficiency interferes with one of neurological impairment. The diagnosis and manage- these pathways, a specific amino acid or amino acid ment of these disorders often requires measurement by-product may accumulate to toxic levels. Of of amino acid concentrations in body fluids. course, a deficiency of downstream products may also be detrimental. Reflecting important differences in treatment strategies, the disorders of amino acid catabolism may be divided into three categories: urea CLINICAL AMINO ACID ANALYSIS cycle disorders, defects in the catabolism of specific The development of automated amino acid analyzers essential amino acids, and defects in the catabolism has made measurements of amino acid concentra- of specific nonessential amino acids. Figure 1 A normal plasma amino acid profile. The labeled peaks include the 20 amino acids commonly found in proteins. Instead of free cysteine, the disulfide cystine is seen. Peaks corresponding to citrulline, a-aminobutyric acid, ornithine, ammonium, and an internal standard are also noted. 106 AMINO ACID DISORDERS However, human beings and other terrestrial verte- brates are unable to eliminate sufficient ammonia by this route. Instead, we have evolved a series of biochemical reactions, known as the urea cycle, that serve to convert ammonia to urea, which is then excreted in urine (Fig. 2). The complete urea cycle is functional only in the liver. Eight inherited disorders of the urea cycle are known (Table 1). Their collective incidence is approximately 1 in 8000 live births. Except for ornithine aminotransferase (OAT) deficiency, all these disorders cause hyperammonemia and may result in mental retardation. OAT deficiency, also known as gyrate atrophy of the choroid and retina, causes visual loss due to retinal degeneration. Overall, the clinical presentations of the hyper- Figure 2 ammonemic syndromes are similar. Severe enzyme The urea cycle. 1, N-acetylglutamate synthetase; 2, carbamoyl phosphate synthetase; 3, ornithine transcarbamoylase; 4, defects tend to present in neonates with life- argininosuccinate synthetase; 5, argininosuccinate lyase; 6, threatening episodes of hyperammonemia and cere- arginase; 7, mitochondrial ornithine transporter; 8, ornithine bral edema. Typically, an affected child is well at aminotransferase; NAG, N-acetylglutamate, an allosteric activator 1 birth but then develops lethargy, irritability, and/or of carbamoyl phosphate synthetase; P5C, D -pyrroline-5- vomiting at 1 or 2 days of age. Tachypnea and a carboxylate; UMP, uridine monophosphate. transient respiratory alkalosis are frequent. Sepsis is usually considered a likely diagnosis. If the hyper- Urea Cycle Disorders ammonemia is not detected and appropriate treat- The catabolism of amino acids liberates unneeded ment is not begun promptly, the child’s disease is nitrogen in the form of ammonia (NH3). If ammonia likely to progress to seizures, coma, and death. Less accumulates to higher than normal levels, it becomes severe enzyme defects may present later in infancy toxic, especially to the brain. In most lower organ- with poor growth, hepatomegaly, developmental isms and marine creatures, excess NH3 is eliminated delay, spasticity, and/or other neurological symp- by diffusion into the surrounding environment. toms. Older children or adults may present with Table 1 UREA CYCLE DISORDERSa Suggestive plasma Urine Enzyme defect Disorder amino acid findings orotate Other distinguishing features N-acetylglutamate synthetase NAGS deficiency N/ + citrulline N (NAGS) Carbamoyl phosphate synthetase CPS deficiency + citrulline N (CPS) Ornithine transcarbamoylase OTC deficiency + citrulline ** X-linked; random X-inactivation (OTC) affects phenotype in females Argininosuccinate synthetase Citrullinemia **citrulline * Argininosuccinate lyase Argininosuccinic aciduria * citrulline * Hepatomegaly, cirrhosis, brittle * argininosuccinate hair Arginase Argininemia * arginine * Commonly presents with spastic diplegia Mitochondrial ornithine HHH syndrome * ornithine * Homocitrullinuria transporter Ornithine aminotransferase (OAT) OAT deficiency * ornithine N Normal ammonia levels; gyrate atrophy of choroid and retina a Abbreviations used: N, normal; * , increased; + , decreased; HHH, hyperammonemia, hyperornithinemia, homocitrullinuria. AMINO ACID DISORDERS 107 acute episodes of metabolic encephalopathy brought Defects in the Catabolism of Essential on by a physical stress or they may present with Amino Acids chronic symptoms, such as learning disorders, mental Table 2 lists selected disorders of the catabolism of retardation, or seizures. Some have presented with specific essential amino acids. Because these parti- stroke-like episodes. A dietary history may reveal an cular amino acids are not synthesized by human aversion to high-protein foods. Magnetic resonance beings, many of these disorders may be effectively imaging of the brain is often abnormal in both acute treated by reducing the dietary intake of the relevant and chronic presentations. amino acid(s). However, early treatment may be The pathophysiology of urea cycle defects is essential to prevent irreversible consequences, such incompletely understood. As with most metabolic as brain damage. Some patients may also benefit defects, substrates upstream of the enzymatic block from treatment with specific enzyme cofactors. For accumulate, and downstream products may become example, thiamine, a cofactor required for the depleted. Glutamine and alanine levels generally function of the branched-chain ketoacid dehydro- increase together with the ammonia level. Evidence genase, helps some patients with maple syrup urine suggests that at least some of the cerebral edema is disease. Biotin can be used to treat multiple due to the osmotic force of accumulated intracellular carboxylase deficiency due to either biotinidase glutamine. deficiency or a partial loss of holocarboxylase When a urea cycle defect is present, the plasma synthetase activity. amino acid pattern and urine orotic acid level often suggest the specific diagnosis (Table 1). Low citrul- Defects in the Catabolism of Nonessential line levels characterize N-acetylglutamate synthetase Amino Acids deficiency, carbamoyl phosphate synthetase defi- Table 3 lists selected disorders of the catabolism of ciency, and ornithine transcarbamoylase (OTC) nonessential amino acids. Because these amino acids deficiency. Among these, the urine orotic acid level are synthesized within the human body, restricting is elevated only in OTC deficiency. Citrullinemia, the dietary intake of the offending amino acid is argininosuccinic aciduria, argininemia, and the usually not sufficient to prevent disease progression. HHH syndrome can be distinguished by specific Thus, these disorders tend to be more difficult to amino acid patterns. Enzyme assays or gene sequen- treat than those involving essential amino acids. cing may be useful to confirm a suspected diagnosis Disorders of tyrosine catabolism may be amelio- or to provide a prenatal diagnosis in an at-risk rated to some extent by restricting the dietary intake pregnancy. A small fraction of patients with hyper- of both tyrosine and its precursor phenylalanine. ammonemia and elevated plasma citrulline levels will