Amino Acid Disorders 105

Home , Alkaptonuria, Episodic ataxia, Proline oxidase, Tyrosinemia type I, Tyrosinemia type II, Urocanase

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). Açaõ 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 transmissaõ da mole´stia de chagas por transfusaõ 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). Doençade acid transport are more easily recognized through the Chagas. In Doenças Infecciosas e Parasita´rias (R. Veroesi, Ed.), analysis of urine amino acids. Therefore, screening 7th ed., pp. 674–712. Guanabara Koogan, Saõ Paulo, Brazil. Spina-França, A., and Mattosinho-França, 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 Recently, the medical treatment of tyrosinemia type I have citrullinemia type II, a secondary disturbance of has been revolutionized by the use of 2-(2-nitro-4- the urea cycle that is caused by mutations in the gene trifluoromethylbenzoyl)-1,3-cyclohexane dione, also for citrin, a mitochondrial aspartate/glutamate trans- known as NTBC or nitisinone. This compound porter. prevents the accumulation of the toxic tyrosine The acute treatment of hyperammonemic crises metabolites fumarylacetoacetate, maleylacetoace- may require hemodialysis. The long-term treatment tate, and succinylacetone by blocking the catabolism of urea cycle defects generally requires a protein- of tyrosine at an earlier step. NTBC is also being restricted diet, often including replacement of natural tried as a treatment for alkaptonuria. In the future, protein with preparations of essential amino acids. other metabolic disorders may be treated using the Treatment with extra arginine and citrulline to same general strategy of inhibiting an earlier step in replace depleted urea cycle intermediates is bene- the affected pathway. ficial. Administration of benzoate, phenylacetate, or phenylbutyrate increases the excretion of nitrogen by alternative routes. Treatment of seizures with val- DISORDERS OF AMINO ACID SYNTHESIS proic acid should be avoided because this drug may worsen hyperammonemia. Despite careful dietary Serine Deficiency and pharmacological treatment, the long-term prog- Very few disorders of amino acid biosynthesis are nosis for cognitive function in patients with severe known. One such disorder, which is of significant urea cycle defects is poor. Liver transplantation is an neurological interest, is serine deficiency due to option that is being used more frequently. reduced activity of 3-phosphoglycerate dehydrogen- 108 AMINO ACID DISORDERS

Table 2 SELECTED DISORDERS OF THE CATABOLISM OF ESSENTIAL AMINO ACIDSa

Amino acid Disorder Enzyme defect Selected clinical features

Phenylalanine Phenylketonuria (PKU) Phenylalanine hydroxylase MR, hypopigmentation, eczema, seizures, ‘‘mousy’’ odor

Tetrahydrobiopterin (BH4) GTP cyclohydrolase, 6- MR, microcephaly, infantile Parkinsonism, deﬁcienciesb,d pyruvoyltetrahydropterin seizures, hyperphenylalaninemia, synthase, tetrahydropterin deﬁciencies of serotonin and dopamine;

carinolamine dehydratase, treated with BH4, precursors of serotonin dihydropteridine reductase and dopamine, low phenylalanine diet Leucine, isoleucine, Maple syrup urine disease Branched-chain ketoacid MR, PI, ketoacidosis, cerebral edema, ‘‘maple and valine dehydrogenase syrup’’ odor (urine, sweat, and cerumen) Multiple carboxylase deﬁciencyc Holocarboxylase synthetase, MR, ketoacidosis, lethargy, hypotonia, biotinidase seizures, other neurological abnormalities, skin rash, alopecia Isoleucine and valine Propionic aciduriac Propionyl-CoA carboxylase MR, PI, ketoacidosis, hyperammonemia, hypoglycemia, neutropenia Methylmalonic aciduriac Methylmalonyl-CoA mutase, MR, PI, ketoacidosis, hyperammonemia, Cbl reductase, Cbl hypoglycemia, neutropenia adenosyltransferase Leucine Isovaleric aciduriac Isovaleryl-CoA dehydrogenase MR, PI, ketoacidosis, hyperammonemia, neutropenia, ‘‘sweaty feet’’ odor 3-Methylcrotonyl glycinuriac 3-Methylcrotonyl-CoA MR, PI, ketoacidosis, hyperammonemia, carboxylase ‘‘cat’s urine’’ odor 3-Methylglutaconic aciduria type 3-Methylglutaconyl-CoA Reported in eight patients; mild to severe Ic hydratase neurological impairments 3-Hydroxy-3-methylglutaric 3-Hydroxy-3-methylglutaryl- MR, latic acidosis, hypoglycemia, aciduriac CoA lyase hyperammonemia Isoleucine 2-Methylacetoacetic aciduriac Mitochondrial acetoacetyl- MR, ketoacidosis, hyper- or hypoglycemia CoA thiolase Histidine Histidinemia Histidase Probably a benign abnormalitye Urocanic aciduriad Urocanase MR reported (probably coincidental) Lysine Glutaric aciduria type Ic Glutaryl-CoA dehydrogenase Macrocephaly, progressive dystonia and dyskinesia, acute episodes of ketoacidosis 7hyperammonemia

a Abbreviations used: MR, mental retardation; PI, protein intolerance; CoA, coenzyme A; Cbl, cobalamin. b Tetrahydrobiopterin is a cofactor required by the phenylalanine, tyrosine, and tryptophan hydroxylases. c Diagnosis requires analysis of urine organic acids. d Diagnosis requires specialized assay. e Initial reports of neurological impairment appear to have been coincidental; many asymptomatic patients are known. ase. These patients have congenital microcephaly D1-Pyrroline-5-Carboxylate and develop spastic quadriplegia, psychomotor Synthase Deficiency retardation, and intractable seizures. The pathogen- esis of these symptoms most likely involves not D1-Pyrroline-5-carboxylate (P5C) synthase catalyzes only a deficiency of serine in the brain but also the reduction of glutamate to P5C, a critical step in deficiencies of various serine derivatives, such as the biosynthesis of proline, ornithine, citrulline, and glycine, serine phospholipids, sphingomyelins, or arginine. Baumgartner et al. reported homozygous cerebrosides. In the proper clinical setting, this mutations in P5C synthase in two siblings who suffer diagnosis is suggested by low levels of serine and from progressive neurodegeneration, joint laxity, glycine in the CSF and fasting plasma. Oral treat- skin hyperelasticity, and bilateral subcapsular catar- ment with supplemental serine usually stops the acts. Metabolic studies have shown these patients to seizures and ameliorates some of the other features of have paradoxical preprandial episodes of hyperam- the disorder. monemia and low plasma levels of proline, ornithine, AMINO ACID DISORDERS 109

Table 3 SELECTED DISORDERS OF THE CATABOLISM OF NONESSENTIAL AMINO ACIDSa

Amino acid Disorder Enzyme defect Selected clinical features

Tyrosine Tyrosinemia type I Fumarylacetoacetate hydrolase Liver failure, renal dysfunction, rickets, episodic polyneuropathy, liver cancer Tyrosinemia type II Tyrosine transaminase MR, palmar keratosis, corneal ulcers Tyrosinemia type III 4-Hydroxyphenylpyruvate MR possible; some patients asymptomatic dioxygenase (1st component) Hawkinsinuria 4-Hydroxyphenylpyruvate Asymptomatic in adults; metabolic acidosis, dioxygenase (2nd component) FTT, or liver dysfunction in some infants Alcaptonuriab Homogentisic acid oxidase Osteoarthritis, ochronosis Glycine Nonketotic Glycine cleavage system MR, hypotonia, seizures, lethargy, coma; often hyperglycinemia fatal in early infancy Proline Hyperprolinemia type I Proline oxidase Asymptomatic, incidental finding Hyperprolinemia type IIc Pyrroline-5-carboxylate Relatively benign disorder; some patients have dehydrogenase seizures Iminopeptiduria Prolidase MR, dermatitis, skin ulcers, recurrent infections, risk of lupus suggested Cysteine Sulfite oxidase deficiencyc Molybdenum cofactor, sulfite Seizures, MR, dislocated optic lenses, death in oxidase childhood frequent N-acetyl- Canavan diseaseb Aspartoacylase Macrocephaly, leukodystrophy, hypotonia, early aspartate death

a Abbreviations used: MR, mental retardation. b Diagnosis requires analysis of urine organic acids. c Diagnosis requires specialized assay. citrulline, and arginine. The hyperammonemia ap- Laboratory abnormalities include the presence of parently results from the decreased availability of homocystine in the urine and elevations of plasma ornithine, a urea cycle intermediate that is synthe- methionine and homocysteine. Cystathionine-b- sized from P5C (Fig. 2). The connective tissue synthase uses pyridoxal 50-phosphate (a derivative abnormalities might reasonably be attributed to the of pyridoxine) as a cofactor, and approximately 40% deficiency of proline, which is a major constituent of of patients with homocystinuria type I respond to collagens. Confirmation and further delineation of treatment with high doses of pyridoxine (vitamin B6). this fascinating syndrome await the identification of Treatment should also include folate, cysteine, a low additional patients. methionine diet, and, in some cases, betaine. Homocystinuria type II may be caused by any of Homocystinuria several recessive defects in vitamin B12 metabolism The biochemical pathway that humans use to that interfere with production of methylcobalamin, a synthesize cysteine (Fig. 3) serves simultaneously as cofactor required by methionine synthase. Cell the catabolic pathway for methionine and as a source complementation studies have revealed the existence of the important methyl donor S-adenosylmethio- of at least five such defects, designated cblC–cblG. In nine. Homocysteine, an intermediate in this pathway, addition to homocystinuria, these patients have accumulates in each of the several forms of homo- megaloblastic anemia, poor growth, developmental cystinuria. The most common form, homocystinuria delay, seizures, and other neurological abnormalities. type I (inherited as an autosomal recessive trait), is Their plasma homocysteine levels are elevated; due to deficiency of cystathionine-b-synthase. Clin- however, in contrast to homocystinuria type I, their ical features may include subluxations of the lenses methionine levels are decreased. Patients with cblC, of the eyes, mental retardation, psychiatric disorders, cblD, and cblF also suffer from methylmalonic a tall and thin body habitus with long fingers and aciduria due to defective formation of adenosylco- other skeletal abnormalities reminiscent of Marfan balamin (a cofactor for methylmalonyl-CoA mu- syndrome, a fair complexion, and a predisposition to tase). Treatment should include both vitamin B12 and thromboembolic events, especially in the brain. betaine. 110 AMINO ACID DISORDERS

Figure 3 Homocystinuria: abnormalities of methionine, homocysteine, and cysteine metabolism. 1, Cystathionine-b-synthase; 2, methionine synthase;

3, methylene tetrahydrofolate reductase; Vit B12, vitamin B12; MeCbl, methylcobalamin; AdoCbl, adenosylcobalamin; THF, tetrahydrofolate. The letters A-G indicate the metabolic blocks observed in complementation groups cblA–cblG, respectively. Note that cblG defects result from mutations in methionine synthase.

Homocystinuria type III, inherited as an autoso- renal tubular reabsorption of lysine, arginine, and mal recessive trait, is caused by deficiency of ornithine are impaired. Therefore, urinary excretion methylene tetrahydrofolate reductase. Patients with of these amino acids is high, and their plasma levels a complete absence of enzyme activity present with are low. Patients with this disorder suffer from neonatal apneic episodes and myoclonic seizures, protein intolerance and episodes of hyperammone- progressing to coma and death. Incomplete enzyme mia that result from having insufficient arginine and deficiencies can produce a range of phenotypes, ornithine for proper functioning of the urea cycle. including mental retardation, seizures, microcephaly, Other clinical features may include poor growth, spasticity, psychiatric symptoms, peripheral neuro- osteoporosis, immune deficiencies, alveolar protei- pathy, and/or premature vascular disease. Megalo- nosis, pulmonary fibrosis, or mental retardation. The blastic anemia does not occur. Laboratory findings occurrence of mental retardation is most likely typically show moderate elevations of plasma homo- related to the severity of the episodes of hyperam- cysteine and low or low-normal levels of methionine. monemia. Treatment involves a moderate dietary Treatment is difficult, and various combinations of protein restriction and replacement of urea cycle agents have been recommended. Regimens that intermediates through oral citrulline administration. include betaine appear to be the most successful. Amino acid transport mechanisms may also be specific to certain subcellular organelles. For example, cystinosis is a lysosomal storage disease caused DISORDERS OF AMINO ACID TRANSPORT by mutations in a lysosomal membrane protein. A variety of specific transport mechanisms catalyze These mutations result in decreased efflux of cystine the movement of amino acids across biological from lysosomes. The major clinical manifestation of membranes. Some such transporters operate on cystinosis is renal failure. The diagnosis of cystinosis groups of structurally related amino acids, whereas can be made by demonstrating an increased cystine others serve only one specific amino acid. Table 4 content in lymphocytes. Treatment with cysteamine lists most of the known disorders of amino acid helps remove cystine from lysosomes through the transport. These transport mechanisms may be formation of mixed disulfides and slows progression specific to certain cell types and may even be of the disease, but kidney transplantation is often localized to specific portions of the plasma mem- necessary. Later, extrarenal manifestations may brane. For example, lysinuric protein intolerance is occur, including ocular problems, hypothyroidism, caused by deficiency of a dibasic amino acid diabetes, myopathy, or encephalopathy. transporter that in renal and intestinal epithelial Hartnup’s disorder is inherited as an autosomal cells is localized to the basolateral membrane. When recessive trait with a prevalence of approximately 1 this transporter is defective, intestinal absorption and in 30,000 people. These patients have decreased AMINO ACID DISORDERS 111

Table 4 SELECTED DISORDERS OF AMINO ACID TRANSPORTa

Disorder Amino acid(s) Transporter Major sites involved Clinical features

Cystinosis Cystine Cystine transporter Lysosomal Renal failure; late endocrine, ocular, membranes and neuromuscular manifestations Cystinuria Cystine, arginine, Shared cystine and Renal tubules, Cystine renal stones lysine, ornithine dibasic amino acid intestinal mucosa transporter Lysinuric protein intolerance Arginine, lysine, Dibasic amino acid Renal tubules, PI, hyperammonemia, MR, poor ornithine transporter intestinal mucosa growth, osteoporosis, hepatosplenomegaly Dicarboxylic aminoaciduria Aspartate, Dicarboxylic amino Renal tubules, Asymptomatic glutamate acid transporter intestinal mucosa Hartnup disorder Most neutral Neutral amino acid Renal tubules, Most asymptomatic, intermittent amino acids transporter intestinal mucosa ataxia and rash possible Histidinuria Histidine Histidine transporter Renal tubules, Possible MR, possible seizures intestinal mucosa Iminoglycinuria Glycine, Shared glycine and Renal tubules, Asymptomatic hydroxyproline, amino acid intestinal mucosa proline transporter Methionine malabsorption Methionine Methionine Intestinal mucosa MR, seizures, hyperpnea, white hair, transporter a-hydroxy butyricaciduria

a Abbreviations used: PI, protein intolerance; MR, mental retardation. intestinal absorption and decreased renal tubular and the clinical variability of these disorders have not reabsorption of many neutral amino acids, including yet been determined. However, each of these defects tryptophan. Symptoms of episodic ataxia and a has been associated with severe neurological symp- ‘‘pellagra-like’’ rash are seen in some patients. toms in at least a few patients. Two of the three Mental retardation has been reported in a few. disorders appear to be treatable with oral creatine. However, population screening suggests that the vast Creatine is formed from glycine, arginine, and S- majority of patients with Hartnup’s disorder remain adenosylmethionine (Fig. 4). Creatine synthesis oc- asymptomatic. Human cells require nicotinamide, curs primarily in the liver, pancreas, and kidneys. which may be synthesized from either tryptophan or Other organs, especially the brain and muscles, take niacin. Niacin deficiency produces pellagra. Treat- up creatine from the blood. Inside cells, creatine is ment with niacin has been reported to improve the phosphorylated and serves as a reservoir of high- symptoms of Hartnup’s disorder in some patients, energy phosphate groups, allowing more rapid and it is likely that sufficient dietary niacin intake is regeneration of adenosine triphosphate and thus one of the factors that accounts for the lack of supporting many energy-requiring reactions. symptoms in most Hartnup patients. A deficiency of either arginine:glycine amidinotransferase or guanidinoacetate methyltransferase impairs the production of creatine. Patients with DISORDERS OF AMINO ACID DERIVATIVES these autosomal recessive disorders have shown Neurotransmitter Disorders variable neurological symptoms, including mental retardation, seizures, hypotonia, and/or dystonia. Many neurotransmitters, including serotonin, g- Cerebral magnetic resonance spectroscopy (MRS) in aminobutyric acid, dopamine, epinephrine, and affected individuals shows absence of the usual peaks norepinephrine, are derived from amino acids. corresponding to creatine and phosphocreatine. Defects in the metabolism of these compounds are Treatment with oral creatine gradually restores brain discussed elsewhere in this encyclopedia. creatine concentrations to nearly normal levels and results in some clinical improvement. Similar symp- Creatine-Deficiency Syndromes toms and MRS findings have also been described in Recently, three interesting disorders of the metabo- patients with mutations in the X-linked gene encod- lism of creatine have been described. The incidence ing the transporter that allows creatine to enter brain 112 AMINO ACIDS

ALTHOUGH it has been proposed that the first living things on Earth may have been self-replicating polymers of ribonucleic acids, amino acids are now equally indispensable to all known forms of life. The genetic code carried in nucleic acids is translated into proteins composed of linear polymers of amino acids. It is largely these proteins that carry out the Figure 4 work of the living cell. Thus, amino acids play a Creatine and creatinine metabolism. 1, Arginine:glycine critical role in nature as the building blocks of amidinotransferase; 2, guanidinoacetate methyltransferase; 3, proteins. In addition, amino acids serve living things creatine phosphokinase; S-AdoMet, S-adenosylmethionine; S- as sources of metabolic energy, as neurotransmitters, AdoHcy, S-adenosylhomocysteine. and as required substrates for the biosyntheses of a variety of other important molecules. and muscle cells. As might be predicted, patients STRUCTURE OF AMINO ACIDS with such transporter defects have not responded to treatment with oral creatine. The term amino acid usually refers to an a- —Edward G. Neilan and Vivian E. Shih aminocarboxylic acid in which the a carbon atom adjacent to a carboxylic acid moiety (-COOH) carries three other substituents: an amino group (-NH2), a hydrogen atom (-H), and a variable side See also–Amino Acids chain conventionally symbolized as ‘‘-R’’ (Fig. 1). These four substituents are arranged around the a carbon in a tetrahedral fashion. Two nonoverlapping Further Reading arrangements are possible. By convention, these Baumgartner, M. R., Hu, C. A., Almashanu, S., et al. (2000). optically active, mirror-image stereoisomers are Hyperammonemia with reduced ornithine, citrulline, arginine designated the l and d forms. Except in the case of and proline: A new inborn error caused by a mutation in the gene encoding D1-pyrroline-5-carboxylate synthase. Hum. Mol. glycine, in which R is a second hydrogen atom, the Genet. 9, 2853–2858. four substituents are different, making the a carbon Fernandes, J., Saudubray, J.-M., van den Berghe, G. (Eds.) (2000). atom a center of chirality. Inborn Metabolic Diseases: Diagnosis and Treatment, pp. 171– Only the l-isomers of amino acids are commonly 291, 439–444. Springer, Berlin. found in proteins. The biosynthetic pathways that Item, C. B., Stockler-Ipsiroglu, S., Stromberger, C., et al. (2001). Arginine:glycine amidinotransferase deficiency: The third inborn error of creatine metabolism in humans. Am. J. Hum. Genet. 69, 1127–1133. Palmieri, L., Pardo, B., Lasorsa, F. M., et al. (2001). Citrin and aralar1 are Ca2 þ -stimulated aspartate glutamate transporters in mitochondria. EMBO J. 20, 5060–5069. Salomons, G. S., van Dooren, S. J., Verhoeven, N. M., et al. (2001). X-linked creatine-transporter gene (SLC6A8) defect: A new creatine-deficiency syndrome. Am. J. Hum. Genet. 68, 1497–1500. Scriver, C. R., Sly, W., Childs, B., et al. (Eds.) (2001). The Metabolic and Molecular Bases of Inherited Disease, 8th ed., pp. 1667–2163, 4909–4981, 5085–5108. McGraw-Hill, New York. Sto¨ ckler, S., Isbrandt, D., Hanefeld, F., et al. (1996). Guanidinoa- Figure 1 cetate methyltransferase deficiency: The first inborn error of The structure of amino acids. Most are optically active and exist as creatine metabolism in man. Am. J. Hum. Genet. 58, 914–922. mirror-image l-ord-isomers.