Inherited Metabolic Disease: Amino Acids, Organic Acids, and Galactose1



Inherited Metabolic Disease: Amino Acids, Organic Acids, and Galactose1


Louis J. Elsas II

Phyllis B. Acosta


Deceased.





GENETIC PERSPECTIVE

Geneticists approach the general subject of nutrition and the specific requirement for nutrients with the view that the recommended dietary allowance (RDA) (1) for an essential nutrient is not optimum for all individuals. Rather, individuals in a population have genetically determined variations in their nutrient requirements that extend over a wide range. This concept arose historically from two older scientific disciplines: human biochemical genetics and nutrition science. The former discipline originated with Sir Archibald Garrod’s Croonian lectures of 1908. Garrod defined four “inborn errors of metabolism” as inherited blocks in the normal flow of metabolic processes. Biochemical and clinical expression of these metabolic blocks demonstrated patterns of inheritance consistent with Mendel’s predictions for transmission
of single genes with a large effect on the phenotype. In alkaptonuria, Garrod observed that the amount of protein ingested was proportional to the darkness of urine and thus the amount of alkaptones excreted. Most individuals did not express this phenomenon, but asymptomatic carriers could be stressed with protein and excrete discernible amounts of alkaptones. Thus arose the “individualistic” concept that an individual’s genes controlled metabolism and that disease states were created by blocks in this metabolic flow that yielded accumulated precursors and deficient products.

Today, we recognize that “inborn errors” are discontinuous traits resulting from variations in the amount and function of enzymes and coenzymes (2, 3, 4). The amino acid sequences and the quantity of enzymes are dictated by genes and epigenetic regulation. The control of enzyme function is predicated by molecular regulation through gene transcription, posttranscriptional processing of RNA, translation, posttranslational modification, cofactor interaction, trafficking, and protein turnover. More than 20,000 monogenic human disorders are cataloged and available. Of these, approximately 400 have a defined biochemical basis (5). The extent of normal variation in genes controlling enzyme activity suggests that approximately 30% of our population is heterozygous for common alleles (6). Within this continuous diversity, mutations produce discontinuous, relatively rare traits that are expressed as disease under normal environmental conditions.

Mutant gene frequencies vary in populations; for example, mitochondrial branched-chain α-ketoacid dehydrogenase (BCKAD) deficiency (maple syrup urine disease [MSUD]) occurs in 1 of approximately every 185,000 newborns worldwide, but it occurs in 1 of 176 in an inbred Mennonite population (7). The Mennonite mutation is in the E1α gene and changes a tyrosine (TYR) at position 194 to asparagine (Y302N). In the homozygous state, it produces extreme toxicity caused by accumulated branchedchain α-ketoacids (BCKAs) if affected newborns are fed the RDA for branched-chain amino acids (BCAAs). Normal development is expected if dietary isoleucine (ILE), leucine (LEU), and valine (VAL) are restricted to 20% to 40% of the RDA during infancy, however (8). Considerable human variation occurs in the structure and activity of enzymes involved in the catabolism of essential amino acids, but only a few persons are so impaired that ingestion of the RDA creates severe disease. Populationbased newborn screening and dietary intervention are now applied through public health programs to more than 40 rare inborn errors for which newborn screening predicts genetic susceptibility given a normal diet (2, 3). By contrast to these relatively rare inborn errors, all humans lack the enzyme that converts L-gulono-α-lactone to ascorbic acid, but scurvy does not occur if sufficient vitamin C is ingested and absorbed (9). Thus, the frequency of genetic susceptibility given a “normal” diet ranges from rare to common and extends to the metabolism of amino acids, nitrogen, carbohydrates, lipids, fatty acids, organic acids, purines, pyrimidines, minerals, and vitamins.


GENETIC DISORDERS BENEFITED BY NUTRITION SUPPORT

More than 400 genetic disorders have been reported in which toxic manifestations relate to accumulation, deficiency, or overproduction of normally occurring substrates and products of metabolic flow (3). In many of these disorders, modification of the dietary supply alleviates the manifestations. In many others, however, irreversible damage has already occurred by the time symptoms appear. Optimum management of these disorders depends on identifying affected persons while they are presymptomatic or before irreversible disease has occurred. Because the disorders are heritable, genetic markers are present from the moment of conception, and thus the genetic power of prediction and prevention is applicable. In practice, certain disorders can be detected in the fetus in the tenth to sixteenth week of gestation by studies on chorionic villus or amniotic fluid cells. Prenatal diagnosis can be made in the ninth to twelfth week of gestation through the use of chorionic villus biopsy (10). Teratogenic sequelae of an inborn error in a pregnancy, such as birth defects in children of mothers with phenylketonuria (PKU), may be prevented by strict control of blood phenylalanine (PHE) before conception and throughout pregnancy. Other inherited metabolic alterations are detected postnatally in the presymptomatic infant by analysis of blood, urine, erythrocytes, leukocytes, or cultured skin fibroblasts for impaired enzymes, accumulated substrates, or products of alternate metabolic pathways.

A selective search for presymptomatic genetic disease is often undertaken when a family history of inherited disease is present. Selective screening for inherited disease is also initiated for relatively common symptoms such as failure to thrive in childhood. Early treatment has proven effective for many diseases such as PKU, galactosemia, isovaleric acidemia, homocystinuria, MSUD, argininosuccinic aciduria, and citrullinemia. Irreversible brain damage occurs if treatment is not initiated in PKU before the second week of life. In MSUD, galactosemia, isovaleric acidemia, and disorders of the urea cycle, irreversible damage to the brain may occur within the first week of life, whereas disorders of fatty acid oxidation may remain undetected for weeks until an intermittent infection produces hypoglycemia. To predict and prevent irreversible damage from inherited metabolic disorders, population-based, newborn screening of dried blood spots from a newborn’s heel stick has been performed since the 1960s. The screening technology has progressed from bioassay to tandem mass spectrometry (MS/MS), which has enabled expansion of detection of accumulated analytes from a few amino acids to include fatty acids and organic acids. These compounds are determined from their acylcarnitine profiles,
and amino acids are determined from their butylester derivatives. In 2006, the American College of Medical Genetics (11) recommended a uniform panel of 29 disorders with primary targets and 25 secondary disorders. Forty-two disorders are screened for by MS/MS of dried blood spots, and all these disorders require rapid retrieval of the screen-positive newborn and urgent confirmation or denial of the screening results with immediate dietary intervention for the confirmed diagnosis. These metabolic conditions were selected through an iterative process among clinicians, laboratorians, and nutritionists. Selection was based on sufficient knowledge and availability of screening and confirmatory technology, the possibility for preventive intervention, and the probability that a screenpositive infant for one of these disorders would have a good outcome from the early intervention. Some of the disorders screened for, their MS/MS profiles, and the acute interventions required for a screen-positive infant are outlined in Table 69.1 (11, 12, 13, 14, 15, 16, 17, 18, 19, 20). The impaired enzymes are listed in Table 69.2 (15, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36). Because the initiation of emergency nutrition in the newborn changes with diagnostic confirmation and with increasing age, some recommended nutritional changes over the age of the child are listed in Table 69.3.

Although many patients with inherited disorders benefit from nutrition support, each disorder would require a chapter for adequate discussion. Thus, this chapter emphasizes disorders for which population-based screening, retrieval, diagnosis, and nutrition support are available to prevent irreversible, severe pathologic problems.


GENERAL PRINCIPLES OF GENETIC DISEASE MANAGEMENT

Thirteen approaches to treatment of inherited metabolic disease are discussed here. Because all these disorders are inherited, all require genetic counseling of the parents regarding recurrence risks, burden of the disease on the affected child, and alternatives in reproduction. The focus here is on direct nutrition and medical interventions for the diagnosed infant. The choice of therapy depends on the pathophysiologic mechanisms producing disease and the medical approach to returning homeostasis to the whole body. Several therapeutic approaches may be tried sequentially or used simultaneously, depending on the acuteness of the disease process.



  • Enhancing anabolism and depressing catabolism. This combined approach involves the use of high-energy feedings and appropriate amino acid mixtures for aminoacidopathies and organic acidemias. An attempt should be made to prevent the physiologic catabolic state in the 4- to 14-day-old infant, and an anabolic state should be maintained throughout childhood. This therapeutic maneuver should be common to all inborn errors involving catabolic pathways. Caution must be exercised, however, to use high-energy feedings primarily during the acute presentation, but not on a long-term basis, to prevent overweight or obesity.


  • Correcting the primary imbalance in metabolic relationships. This correction involves using both dietary restriction to reduce accumulated substrates that are toxic and provision of products that may be deficient. For example, in phenylalanine hydroxylase (PAH) deficiency, PHE is restricted and TYR is supplemented.


  • Enhancing excretion of accumulated substances that are overproduced. The kidney can aid as a dialysis organ in removing accumulated toxic precursors. Maintaining diuresis with hydration is a critical component of therapy.


  • Providing alternative metabolic pathways to decrease accumulated toxic precursors in blocked reaction sequences. Many examples of this approach exist. For instance, the accumulated ammonia in enzyme defects of the urea cycle is reduced by removing nitrogen through administration of therapeutic amounts of phenylacetic acid (less noxious precursors, phenylbutyrate are used) to form phenylacetylglutamine from glutamine with the consequent loss of two nitrogen atoms in urine. Benzoic acid is also used to force glycine adducts of hippuric acid that result in the per mole urinary excretion of one nitrogen atom. Similarly, in isovaleric acidemia, innocuous isovalerylglycine (IVG) is formed from accumulating isovaleric acid (IVA) if supplemental glycine (GLY) is provided to drive the ubiquitous glycine-N-transacylase. IVG is then excreted in the urine. Betaine is used to drive methylation of homocysteine to methionine (MET) in cystathionine β-synthase (CβS) deficiency.


  • Using metabolic inhibitors to lower overproduced products. For example, allopurinol inhibits xanthine oxidase and decreases overproduction of uric acid in gout; lovastatin and compactin suppress hydroxymethylglutaryl -coenzyme A (CoA) reductase and reduce excess endogenous cholesterol biosynthesis in familial hypercholesterolemia; and 2-(2- nitro-4-trifluorome thylbenzoyl)-1,3-cyclohexanedione (NTBC) inhibits p-hydroxyphenylpyruvic acid dioxygenase (p-OHPPAD) and thus the toxic succinylacetone production in type I tyrosinemia.


  • Supplying products of blocked secondary pathways. In cystic fibrosis, the exocrine pancreas does not function in a normal manner to produce and secrete digestive enzymes. Administration of these pancreatic enzymes partially corrects this insufficiency and may prevent the sequelae of fat-soluble vitamin deficiency in the newborn and young child.


  • Stabilizing altered enzyme proteins. The rate of bio logic synthesis and degradation of holoenzymes depends on their structural conformation. In some holoenzymes, saturation by coenzyme increases their biologic halflife and thus overall enzyme activity at the equilibrium






    produced by mutant proteins. This therapeutic mechanism is exemplified in PKU, homocystinuria, and MSUD. Tetrahydrobiopterin (BH4 [Kuvan]) is available as a drug for therapy of patients with non-PKU hyperphenylalaninemia to enhance PAH activity (37). Pharmacologic intake of vitamin B6 in homocystinuria or vitamin B1 in MSUD increases intracellular pyridoxal phosphate or thiamin pyrophosphate (TPP) and increases the specific activity of CβS or BCKAD complex, respectively (38, 39, 40, 41). Another approach is to provide chemical chaperones to stabilize mutant proteins. For example, excess intravenous infusion of D-galactose has increased defective α-galactosidase in the cardiac variant of Fabry disease (42).


  • Replacing deficient coenzymes. Various vitamindependent disorders are caused by blocks in coenzyme production and are “cured” by lifetime pharmacologic intake of a specific vitamin precursor. This mechanism presumably involves overcoming a partially impaired enzyme reaction by mass action. If reactions that are required to produce methylcobalamin (CH3-B12) or adenosylcobalamin are impaired, homocystinuria or methylmalonic aciduria (or both) will result. Daily intake of milligram quantities of vitamin B12 may cure both disorders (43). In biotinidase deficiency, the coenzyme biotin is not released from its covalently bound state. Reviews of “vitamin-dependency syndromes” have been published (39, 40, 41).


  • Artificially inducing enzyme production. If the structural gene or enzyme is intact, but suppressor, enhancer, or promoter elements are not functional, abnormal amounts of enzyme may be produced. It should be possible to “turn on” or “turn off” the structural gene and enable normal enzymatic production to occur. PAH activity has been induced in patients diagnosed with PKU when they received PHE loading for 3 days with intact protein (44, 45). Polyethylene glycol-coated phenylalanine ammonia lyase is undergoing clinical studies in patients with PKU to determine efficacy and allergenicity (46). In the acute porphyria of type I tyrosinemia, excessive σ-aminolevulinic acid (σ-ALA) production may be reduced by suppressing transcription of the σ-ALA synthase gene with excess glucose (GLU) and hematin (Figs. 69.1 and 69.2). In type I tyrosinemia, the overproduction of succinylacetone may be “turned off” by blocking an earlier enzyme p-OH-phenylpyruvate oxidase with the drug NBTC.


  • Replacing enzymes. Many attempts to replace deficient enzymes by plasma infusion and microencapsulation have been tried, with limited success. The use of polyethylene glycol coating of adenosine deaminase significantly prolonged the biologic half-life of this enzyme in treating severe combined immunodeficiency (47). The engineering of β- glucosidase with a high mannan receptor site enables intravenous use of



    alglucerase (Ceredase) to treat type I Gaucher disease. Human α-galactosidase A replacement therapy in Fabry disease reverses substrate storage in the lysosome (42). Recombinant human α-glucosidase can prevent progression and improve cardiac and muscle function in Pompe disease (48). Polyethylene glycol-coated phenylalanine ammonia lyase is undergoing clinical studies in patients with PKU to determine efficacy and allergenicity (46).


  • Transplanting organs. Liver transplantation in a host of inherited metabolic disorders benefits systemic metabolism; the return of organ function replaces deficient enzyme activity (49, 50). Bone marrow and kidney transplantations are also of benefit.


  • Correcting the underlying defect in DNA so the body can manufacture its own functionally normal enzymes. The DNA for many proteins that are functionally deficient such as adenosine deaminase, hypoxanthine-guanine phosphoribosyl transferase, and ornithine transcarbamylase (OTC) and the lowdensity lipoprotein cholesterol receptor have been cloned, and retroviral constructs containing their cDNA have been transfected into dividing somatic
    cells from affected individuals. Human gene therapy is currently contemplated for these inborn errors, although several technical problems in the toxicity of vectors, gene stability, and gene expression must be solved first. Other molecular approaches such as homologous recombination to correct mutant sequences or to inhibit RNA for dominant disorders producing antagonism to the normal allele are also future possibilities (51, 52).


  • Preventing absorption of a nutrient that is toxic in excess. Large neutral amino acids (LNAAs) free of PHE are available for preventing absorption of PHE from the intestinal tract and from passage across the blood-brain barrier (53).








TABLE 69.1 CORE AND SECONDARY TARGETS OF INBORN ERRORS OF METABOLISM WITH ONLINE MENDELIAN INHERITANCE IN MAN NUMBER RECOMMENDED FOR NEWBORN SCREENING, MARKER ANALYTES USED WITH TANDEM MASS SPECTROMETRY SCREENING, AND NUTRITION SUPPORT DURING DIAGNOSIS AND ACUTE THERAPY

































































































































































































































































































































INBORN ERROR (OMIM NO.)


MARKER ANALYTE


NUTRITION SUPPORT DURING DIAGNOSIS AND ACUTE ILLNESS


Core targets



Amino acid disorder




Argininosuccinic acidemia (No. 207900)


CIT


Rapid intervention is required


Blood NH3 >200 µmol/L


Delete protein 1-2 d only; increase L-ARG and/or L-CIT if not arginase deficient


If necessary, IV glucose and electrolytes at 150 mL/kg/24h to supply 10 mg/kg/min


Give Pedialyte and sugar-sweetened, caffeine-free soft drinks with added Polycose or Moducal to maintain energy intake at 125%-150% of RDA


Initiate oral medical food and complete diet as rapidly as tolerated Sodium benzoate, phenylbutyric acid, or phenylacetic acid is used to help decrease blood NH3




Citrullinemia (No. 215700)


CIT


Rapid intervention is required


Blood NH3 >200 µmol/L


Delete protein 1-2 d only; increase L-ARG if not arginase deficient If necessary, give IV glucose and electrolytes at 150 mL/kg/24h to supply 10 mg/kg/min


Give Pedialyte and sugar-sweetened, caffeine-free soft drinks with added Polycose or Moducal to maintain energy intake at 125%-150% of RDA


Initiate oral medical food and complete diet as rapidly as tolerated Sodium benzoate, phenylbutyric acid, or phenylacetic acid is used to help decrease blood NH3




Homocystinuria (No. 236200)


MET


Maintain adequate hydration


Administer 25-100 mg/kg pyridoxine in addition to usual infant formula for 1 mo to determine if patient is vitamin B6 responsive


If patient is not vitamin B6 responsive, restrict MET (20 mg/kg) with medical food, folate, betaine, and complete diet at end of 1 mo




Maple syrup urine disease (MSUD) (Nos. 248600, 248611, 248610, 238339)


LEU ± VAL


Rapid intervention is required


Delete BCAAs 1-2 d


Correct metabolic acidosis and electrolyte abnormalities


Provide adequate energy to suppress endogenous protein catabolism (125%-150% of RDA for age)


Monitor hydration status, electrolyte status, and clinical symptoms carefully to prevent neurologic crisis.


Add L-ILE to therapy within 1-2 d when plasma ILE concentration reaches ≈ 105 µmol/L


Plasma LEU concentration remains elevated for prolonged period if either ILE or VAL is deficient


Suspect concurrent sepsis


Initiate oral medical food and complete diet as soon as tolerated




Phenylketonuria (PKU) (No. 261600)


PHE,PHE/TYR


Delete dietary PHE 1-2 d only


For infant, offer Pedialyte with added Polycose to maintain electrolyte balance if needed


If necessary, give IV glucose, electrolytes at 150 mL/kg/24h to supply a glucose infusion rate of 10 mg/kg/min, and amino acids free of PHE to maintain anabolism


Give sugar-sweetened, caffeine-free soft drinks with added Polycose or Moducal to maintain energy intake at 100% of RDA


Initiate oral medical food and complete diet as rapidly as tolerated




Tyrosinemia type I (TyrI) (No. 276700)


TYR


Rapid intervention is required


Delete dietary PHE, TYR, 1-2 d only


For infant, offer Pedialyte with added Polycose to maintain electrolyte balance if needed


If necessary, give IV glucose and electrolytes at 150 mL/kg/24h to supply a glucose infusion rate of 10 mg/kg/min, and amino acids free of PHE and TYR to maintain anabolism


Give sugar-sweetened, caffeine-free soft drinks with added Polycose or Moducal to maintain energy intake at 120%-130% of RDA Initiate oral medical food and complete diet as rapidly as tolerated



Fatty acid oxidation disorders




Carnitine uptake deficiency (CUD) (No. 212140)


CO


Give uncooked cornstarch as needed to help prevent hypoglycemia if ≥6 mo of age


Avoid fasting


If necessary, give IV glucose at 150 mL/kg to supply a glucose infusion rate of 10 mg/kg/min


At home, give frequent feedings of fluids containing 2.5 g carbohydrate per fluid ounce


Initiate oral diet as rapidly as possible




Long-chain-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) (No. 609016)


C16-OH; C18:1-OH,


Give uncooked cornstarch as needed to help prevent hypoglycemia if ≥6 mo of age


Avoid fasting


If necessary, give IV glucose at 150 mL/kg to supply a glucose infusion rate of 10 mg/kg/min


At home, give frequent feedings of fluids containing 2.5 g carbohydrate per fluid ounce


Initiate oral diet as rapidly as possible




Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) (No. 201450)


C8/C10 ± C6, C10:1, C8


Give uncooked cornstarch as needed to help prevent hypoglycemia if ≥6 mo of age


Avoid fasting


If necessary, give IV glucose at 150 mL/kg to supply a glucose infusion rate of 10 mg/kg/min


At home, give frequent feedings of fluids containing 2.5 g carbohydrate per fluid ounce


Initiate oral diet as rapidly as possible


Avoid medium-chain triglycerides




Trifunctional protein (TFP) deficiency (No. 609015)


C16-OH, C18:1-OH


Give uncooked cornstarch as needed to help prevent hypoglycemia if ≥6 mo of age


Avoid fasting


If necessary, give IV glucose at 150 mL/kg to supply a glucose infusion rate of 10 mg/kg/min


At home, give frequent feedings of fluids containing 2.5 g carbohydrate per fluid ounce


Initiate oral diet as rapidly as possible




Very-long-chain acyl-CoA dehydrogenase deficiency (VLCAD) (No. 201475)


C14:1, C14:1/C12:1 ± C14, C16, C18:1


Give uncooked cornstarch as needed to help prevent hypoglycemia if ≥6 mo of age


Avoid fasting


If necessary, give IV glucose at 150 mL/kg to supply a glucose infusion rate of 10 mg/kg/min


At home, give frequent feedings of fluids containing 2.5 g carbohydrate per fluid ounce


Initiate oral diet as rapidly as possible



Organic acid disorders




β-Ketothiolase (BKT) deficiencya (No. 248600)


C5:1, ± C5OH


Delete dietary ILE 1-2 d only


Administer L-carnitine


Offer Pedialyte with Polycose to maintain electrolyte balance if needed


Give IV glucose and electrolytes at 150 mL/kg/24h to supply a glucose infusion of 10 mg/kg/min, if required


Give sugar-sweetened, caffeine-free soft drinks with added Polycose or Moducal to maintain energy intake at 100%-125% of RDA


Initiate oral medical food and complete diet as rapidly as possible




β-Methylcrotonyl-CoA carboxylase (3MCC) deficiencya (No. 210200)


C5-OH, ± C5:1


Delete dietary LEU 1-2 d only


Administer IV L-carnitine


Provide vigorous fluid replacement


Correct metabolic acidosis and electrolyte abnormalities


Provide adequate energy to suppress catabolism (125%-150% of RDA for age)


If necessary, give IV glucose, lipid, and L-amino acids free of LEU


Initiate oral medical food and complete diet as rapidly as tolerated




Cobalamin A and B (Cbl A, B) defectsa (Nos. 251100, 251110)


C3, C3/C2


Delete ILE, MET, THR, VAL 1-2 d only


Initiate oral diet as rapidly as possible and administer pharmacologic doses of folate and IM hydroxycobalamin




Glutaric acidemia type Ia (GA-I) (No. 231670)


C5-DC


Delete LYS and TRP 1-2 d only


For infant, offer Pedialyte with added Polycose to maintain electrolyte balance if needed


If necessary, give IV glucose and electrolytes at 150 mL/kg/24h to supply a glucose infusion of 10 mg/kg/min, and amino acids free of LYS and TRP


Give sugar-sweetened, caffeine-free soft drinks with added Polycose or Moducal to maintain energy intake at 100%


Initiate oral medical food and complete diet as rapidly as tolerated




HMG-CoA lyase deficiencya (No. 246450)


C5-OH, ± C6-DC


Rapid intervention is required


Delete LEU 1-2 d only


Limit fat intake


Administer L-carnitine


Vigorous replacement of fluids


Correct severe metabolic acidosis and electrolyte abnormalities


Provide adequate energy to suppress endogenous protein catabolism (125%-150% of RDA for age)


Suspect concurrent sepsis: have a low threshold to treat after obtaining appropriate cultures


Initiate oral medical food and complete diet as rapidly as tolerated




Isovaleric acidemiaa (IVA) (No. 243500)


C5


Delete dietary LEU 1-2 d only


Administer GLY and L-carnitine


For infant, offer Pedialyte with Polycose to maintain electrolyte balance if needed


Give sugar-sweetened, caffeine-free soft drinks with added Polycose or Moducal to maintain energy intake at 100%-125% of RDA


If necessary, give IV glucose and electrolytes at 150 mL/kg/24h to supply a glucose infusion rate of 10 mg/kg/min, and amino acids free of LEU.


Initiate oral medical food and complete diet as rapidly as tolerated




Methylmalonic acidemiaa (MUT) (No. 251000)


C3, C3/C2


Rapid intervention is required


Delete ILE, MET, THR, VAL 1-2 d only


Administer L-carnitine


Provide vigorous replacement of fluids


Correct severe metabolic acidosis and electrolyte abnormalities; provide adequate energy to suppress endogenous protein catabolism (125%-150% of RDA for age)


Suspect concurrent sepsis: have a low threshold to treat after obtaining appropriate cultures




Multiple carboxylase deficiencya (MCD) (No. 253260)


C5-OH, ± C3


Biotin, 10-20 mg/d


For infant, offer Pedialyte with added Polycose to maintain electrolyte balance if needed


If necessary, give IV glucose and electrolytes at 150 mL/kg/24h to supply a glucose infusion rate of 10 mg/kg/min


Give sugar-sweetened, caffeine-free soft drinks with added Polycose or Moducal to maintain energy at 100%-125% of RDA


Initiate complete diet as rapidly as tolerated




Propionic acidemiaa (PPA) (No. 606054)


C3, C3/C2


Rapid intervention is required


Delete ILE, MET, THR, VAL 1-2 d


Administer L-carnitine


Provide vigorous replacement of fluids


Correct severe metabolic acidosis and electrolyte abnormalities Provide adequate energy to suppress endogenous protein catabolism (125%-150% of RDA for age)


Suspect concurrent sepsis: have a low threshold to treat after obtaining appropriate cultures


Initiate complete diet as rapidly as tolerated



Other disorders




Biotinidase (BIOT deficiency (No. 253260)


±C5-OH, C5:1


Biotin, 10-20 mg/d


For infant, offer Pedialyte with added Polycose to maintain electrolyte balance if needed


Give sugar-sweetened, caffeine-free soft drinks with added Polycose or Moducal to maintain energy at 100%-125% of RDA


If necessary, give IV electrolytes and glucose at 150 mL/kg/24h to supply a glucose infusion rate of 10 mg/kg/min


Initiate infant formula as rapidly as tolerated




Cystic fibrosis (CF) (No. 219700)



Refer to pediatric gastroenterologist




Galactose-1-phosphate uridyltransferase (GALT) deficiencyb (No. 606999)



Avoid lactose- and galactose-containing infant formulas.


Avoid drugs containing galactose or lactose


Secondary targets



Amino acid disorders




Argininemia (No. 107830)


ARG


Rapid intervention is required


Blood NH3 >200 7mgr;mol/L


Delete protein 1-2 d only


Give Pedialyte and sugar-sweetened, caffeine-free soft drinks with added Polycose or Moducal to maintain energy intake at 125%-150% of RDA


If necessary, give IV glucose and electrolytes at 150 mL/kg/24h to supply glucose at 10 mg/kg/min


Initiate oral medical food and complete diet as rapidly as tolerated Sodium benzoate, phenylbutyric acid, or phenylacetic acid is used to help decrease blood NH3




Biopterin regeneration (BIOPT REG) deficiency (No. 261630)


PHE, PHE/TYR




Biopterin synthesis (BS) defect (No. 261630)


PHE, PHE/TYR




Citrin deficiency (No. 603471)


CIT


High-protein, low-carbohydrate diet




Hypermethioninemia (No. 250850)


MET


Delete MET 1-2 d only


Initiate oral medical food and complete diet as rapidly as tolerated




Hyperphenylalaninemia (No. 261630)


PHE


Delete dietary PHE 1-2 d only


For infant, offer Pedialyte with added Polycose to maintain electrolyte balance if needed


If necessary, give IV glucose, electrolytes at 150 mL/kg/24h to supply a glucose infusion rate of 10 mg/kg/min, and amino acids free of PHE to maintain anabolism


Give sugar-sweetened, caffeine-free soft drinks with added Polycose or Moducal to maintain energy intake at 100% of RDA


Initiate oral medical food and complete diet as rapidly as tolerated




Tyrosinemia type II (TyrII) (No. 276600)


TYR


Delete dietary PHE, TYR, 1-2 d only


For infant, offer Pedialyte with added Polycose to maintain electrolyte balance if needed; give sugar-sweetened, caffeine-free soft drinks with added Polycose or Moducal to maintain energy intake at 120%-130% of RDA


If necessary, give IV glucose and electrolytes at 150 mL/kg/24h to supply a glucose infusion rate of 10 mg/kg/min, and amino acids free of PHE and TYR to maintain anabolism


Initiate oral medical food and complete diet as rapidly as tolerated




Tyrosinemia type III (TyrIII) (No. 276710)


TYR


Delete dietary PHE, TYR, 1-2 d only


For infant, offer Pedialyte with added Polycose to maintain electrolyte balance if needed


If necessary, give IV glucose and electrolytes at 150 mL/kg/24h to supply a glucose infusion rate of 10 mg/kg/min, and amino acids free of PHE and TYR to maintain anabolism


Give sugar-sweetened, caffeine-free soft drinks with added Polycose or Moducal to maintain energy intake at 120%-130% of RDA


Initiate oral medical food and complete diet as rapidly as tolerated



Fatty acid oxidation disorders




Carnitine acylcarnitine transporter (CACT) defect (No. 212138)


C16:1; C18:1


Rapid intervention is required


Avoid fasting


If necessary, give IV electrolyte and glucose at 150 mL/kg to supply a glucose infusion rate of 10 mg/kg/min.


Give uncooked cornstarch as needed to help prevent hypoglycemia if ≥6 mo of age


At home, give frequent feedings of fluids containing 2.5 g carbohydrate per fluid ounce


Initiate oral diet as rapidly as possible




Carnitine palmitoyl-transferase I (CPT IA) defect (No. 600528)


Carnitine


Give uncooked cornstarch as needed to help prevent hypoglycemia if ≥6 mo of age


Avoid fasting


If necessary, give IV glucose at 150 mL/kg to supply a glucose


i nfusion rate of 10 mg/kg/min


At home, give frequent feedings of fluids containing 2.5 g carbohydrate per fluid ounce


Initiate oral diet as rapidly as possible




Carnitine palmitoyltransferase II (CPT II) defect (No. 255110)


C16:1, C18:1


Give uncooked cornstarch as needed to help prevent hypoglycemia if ≥6 mo of age


Avoid fasting


If necessary, give IV glucose at 150 mL/kg to supply a glucose infusion rate of 10 mg/kg/min


At home, frequent feedings of fluids containing 2.5 g carbohydrate per fluid ounce


Initiate oral diet as rapidly as possible




Dienoyl-CoA reductase deficiency (DE RED) (No. 222745)



Give uncooked cornstarch as needed to help prevent hypoglycemia if ≥6 mo of age


Avoid fasting


If necessary, give IV glucose at 150 mL/kg to supply a glucose infusion rate of 10 mg/kg/min


At home, frequent feedings of fluids containing 2.5 g carbohydrate per fluid ounce


Initiate oral diet as rapidly as possible




Glutaric acidemia type IIa (GA-II) (Multiple acyl-CoA dehydrogenase deficiency) (No. 231680)


C4, C5, C5-DC, C6, 8, 12, 14, 16


Delete LYS and TRP 1-2 d only


Restrict fat


Administer L-carnitine and GLY


Administer riboflavin


Maintain anabolism, electrolyte balance and hydration


Initiate oral medical food and complete diet as rapidly as tolerated




Medium-chain ketoacyl-CoA thiolase deficiency (MCKAT) (No. 602199)


C8, C8/C10, ±C6, C6, C10:1


Give uncooked cornstarch as needed to help prevent hypoglycemia if ≥6 mo of age


Avoid fasting


If necessary, give IV glucose at 150 mL/kg to supply a glucose infusion rate of 10 mg/kg/min


At home, give frequent feedings of fluids containing 2.5 g carbohydrate per fluid ounce


Initiate oral diet as rapidly as possible




Medium-/short-chain hydroxyacyl-CoA dehydrogenase deficiency (M/SCHAD) (No. 300256)


C4-OH


Give uncooked cornstarch as needed to help prevent hypoglycemia if ≥6 mo of age


Avoid fasting


If necessary, give IV glucose at 150 mL/kg to supply a glucose infusion rate of 10 mg/kg/min


At home, give frequent feedings of fluids containing 2.5 g carbohydrate per fluid ounce


Initiate oral diet as rapidly as possible




Short-chain acyl-CoA dehydrogenase deficiency (SCAD) (No. 201470)


C4


Give uncooked cornstarch as needed to help prevent hypoglycemia if ≥6 mo of age


Avoid fasting


If necessary, give IV glucose at 150 mL/kg to supply a glucose infusion rate of 10 mg/kg/min


At home, give frequent feedings of fluids containing 2.5 g carbohydrate per fluid ounce


Initiate oral diet as rapidly as possible


Organic acid disorders




2-Methyl-3-hydroxybutyric acidemia (2M3HBA)


C5, C5:1, C5-OH


Delete dietary ILE 1-2 d only


Administer L-carnitine


Offer Pedialyte with Polycose to maintain electrolyte balance if needed


Give IV glucose and electrolytes at 150 mL/kg/24h to supply a glucose infusion rate of 10 mg/kg/min, if required


Give sugar-sweetened, caffeine-free soft drinks with added Polycose or Moducal to maintain energy intake at 100%-125% of RDA


Initiate oral medical food and complete diet as rapidly as tolerated




2-Methylbutyryl-CoA dehydrogenase deficiency (2MBG) (No. 600006)


C5


? LEU restriction




3-Methylglutaconyl hydratase deficiencya (3MGA) (No. 250950)


C5-OH


Delete dietary LEU 1-2 d only


Administer IV L-carnitine


Provide vigorous fluid replacement


Correct metabolic acidosis and electrolyte abnormalities


Provide adequate energy to suppress catabolism (125%-150% of RDA for age) If necessary, give IV glucose, lipid, and L-amino acids free of LEU


Return to oral medical food and complete diet as rapidly as tolerated




Cobalamin C and D (Cbl C, D) defectsa (Nos. 277410, 277400)


C3/C2


Delete ILE, MET, THR, VAL 1-2 d only


Initiate oral diet as rapidly as possible and administer pharmacologic doses of folate and IM hydroxycobalamin




Isobutyryl-CoA dehydrogenase deficiency (IBG) (No. 611283)


C4


Delete dietary LEU 1-2 d only


Increase GLY, VAL and L-carnitine


For infant, offer Pedialyte with Polycose to maintain electrolyte balance if needed


If necessary, give IV glucose and electrolytes at 150 mL/kg/24h to supply a glucose infusion rate of 10 mg/kg/min, and amino acids free of LEU


Give sugar-sweetened, caffeine-free soft drinks with added Polycose or Moducal to maintain energy intake at 100%-125% of RDA


Initiate oral medical food and complete diet as rapidly as tolerated




Malonic (MAL) acidemia (No. 248360)


C3


Restrict fat


Administer L-carnitine and medium-chain triglycerides Avoid fasting


Give uncooked cornstarch as needed to help prevent hypoglycemia if ≥6 mo of age


If necessary, give IV glucose at 150 mL/kg to supply a glucose infusion rate of 10 mg/kg/min


At home, give frequent feedings of fluids containing 2.5 g carbohydrate per fluid ounce


Initiate oral diet as rapidly as possible


Other disorders




Galactokinase (GALK) deficiencyb (No. 230200)



Same as for normal infant


Avoid formula, food, and drugs containing galactose or lactose Initiate oral diet as rapidly as tolerated




Galactose epimerase (GALE) deficiencyb (No. 230350)



Same as for normal infant


Avoid formula, food, and drugs containing galactose or lactose Initiate oral feedings as soon as tolerated


Colon (:) followed by number, double bonds; ARG, arginine; BCAA, branched-chain amino acid; C, acyl group or carbon chain; CIT, citrulline; CoA, coenzyme A; DC, dicarboxyl; GLY, glycine; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; ILE, isoleucine; IM, intramuscular; IV, intravenous; LEU, leucine; LYS, lysine; MET, methionine; NH3, ammonia; O, oxygen; OH, hydroxy; OMIM, Online Mendelian Inheritance in Man; PHE, phenylalanine; RDA, recommended dietary allowance; THR, theronine; TRP, tryptophan; TYR, tyrosine; VAL, valine.


a One or more amino acids involved in disorder.


b Screened for by measuring blood galactose.


Data from references 2 and 12 to 20, with permission.









TABLE 69.2 CHROMOSOMAL LOCATION, GENE SIZE, NUMBER OF MUTATIONS, TISSUE DISTRIBUTION OF GENES, AND GENOTYPE/PHENOTYPE CORRELATIONS





















































































































































































































































































































































































































































ENZYME


CHROMOSOMAL LOCATION


GENE SIZE (kb)


NUMBER OF MUTATIONS


TISSUE DISTRIBUTION


GENOTYPE/ PHENOTYPE CORRELATION


Enzymes of amino acid metabolism



Phenylalanine hydroxylase


12q22-q24.1


>90


>500


Liver, kidney


Genotype broadly predicts metabolic and clinical phenotype



Dihydropteridine reductase


4p15.1-p16.1



21


Liver, fibroblasts, erythrocytes, leukocytes, platelets


?



Guanosine triphosphate cyclohydrolase


14q22.1-q22.2


30


42


Liver


None



6-Pyruvoyltetrahydropterin synthase


11q22.3-q23.3


?


>28


Liver, erythrocytes


Genotype associated with phenotype



Pterin-4 α-carbinolamine dehydratase


10q22



7


Lymphocytes, scalp hair root cells


Mild phenotypes



Fumarylacetoacetate hydrolyase


15q23-q25



34


Liver, renal tubules, lymphocytes, erythrocytes


Genotype not clearly associated with phenotype



Maleylacetoacetate isomerase


14q24.3


?


3


Liver, fibroblasts, kidney


?



Tyrosine aminotransferase


16q22.1


10.9


15


Liver, kidney


None



4-Hydroxyphenylpyruvate dioxygenase


12q24-qter


21


?


Liver


?



Cystathionine β-synthase


21q22.3


30


30


Liver, fibroblasts, brain, phytohemagglutininstimulated lymphocytes, amniotic fluid cells, chorionic villus cells


Genotype associated with phenotype I278T: vitamin B6 responsive T353M: African, not vitamin B6 responsive G307S: Celtic, not-vitamin B6 responsive


Methionine-Sadenosyltransferase


10q22


20


17


Liver (22, 28)


Genotype not clearly associated with phenotype


Enzymes of organic acid metabolism



Branched-Chain α-Ketoacid Dehydrogenase Complex




E1α (decarboxylase)


19q13.3


55


12


Liver, fibroblasts, leukocytes, muscle


Y393W (Mennonite) (classic phenotype)




E1β (stabilizes E1α)


6q1.4


100


4


Liver, fibroblasts, leukocytes, muscle


11bp del → stop




E2 (transacylase)


1p31


68


6


Liver, fibroblasts, leukocytes, muscle


E163X R183P, common in Ashkenazi?




E3 (lipoamide dehydrogenase)


7p22


20


10


Liver, fibroblasts, leukocytes, muscle


Affects pyruvate and α-ketoglutarate dehydrogenases as well




E1α kinase (inactivating)


16p13.12


40


2


Liver, fibroblasts, leukocytes, muscle


Inhibited by tumor necrosis factor α and produces cancer cachexia




E1α phosphatase (activating)


?


?


?


Liver, fibroblasts, leukocytes, muscle


Actives branchedchain- α-ketoacid dehydrogenase complex




Isovaleryl-CoA dehydrogenase


15q14-q15


2.1-4.6


20


Liver, fibroblasts


Genotype not associated with phenotype




3-Methylcrotonyl-CoA carboxylase


?


?


?


Fibroblasts, lymphocytes


Genotype associated with phenotype




3-Methylglutaconyl-CoAhydratase (type 1)


?


?


?


Fibroblasts, lymphocytes


?




3-Hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase)


1p35.1.36.1


?


?


Liver


Genotype associated with phenotype




2-Methylbutyryl-CoA dehydrogenase (Acyl-CoA dehydrogenase-SBCAD)


10q26.13


20


>12


Fibroblasts (15, 21)


None reported




Multiple carboxylase (Holocarboxylase synthetase)


?


?


>30


Liver, fibroblasts, leukocytes (32)


Genotype associated with phenotype




Glutaryl-CoA dehydrogenase


19p13.2


7


>90


Liver, kidney, fibroblasts, leukocytes, amniotic fluid cells, chorionic villus cells.


None between genotype and clinical severity Specific mutations correlate with severity of organic aciduria




Propionyl-CoA carboxylase





Heart, kidney, liver cells


None





α-Subunit


13q32


100


?





β-Subunit


3q13.3q22


?


?




Methylmalonyl-CoA mutase


6p12-p21.2


?


22


Kidney, liver, placenta cells


Genotype associated with phenotype




Biotinidase


3p25


?


>100


Serum leukocytes, fibroblasts (25)


None reported




β-Ketothiolase (mitochondrial acetoacetyl-CoA thiolase)


11q22.3-q23.1


1.5


>40


Liver (26)


None reported




2-Methyl-3-hydroxybutyryl-CoA dehydrogenase


XP11.2 H517B10 gene (35)


1.3


?


All human tissue Highest in liver and kidney


?




Isobutyrl-CoA dehydrogenase


ACAD8gene




Fibroblasts




Malonyl-CoA decarboxylase


MLYCD gene (30)



22


Fibroblasts (29)


None reported




Cobalamin A


4q31.21


?


?


Liver, skeletal muscle (24)


?




Cobalamin B


12q24 (24)


1.1


?


Liver, skeletal muscle, fibroblasts (36)


?




Cobalamin C


1P34.1 MMACHC protein (34)


?


>42


Fibroblasts


None reported




Cobalamin D


2q23.2 MMADHC protein (23)




Fibroblasts (27)


None reported


Enzymes of nitrogen metabolism



Mitochondrial




Carbamylphosphate synthetase 1


2q35


122


>32


Liver, intestine, kidney (trace)


Genotype associated with phenotype




N-acetylglutamate synthetase


17q21.31


?


?


Liver, intestine, kidney (trace), spleen


Genotype associated with phenotype




Ornithine transcarbamylase


Xp21.1


73


>230


Liver, intestine, kidney (trace)


Genotype associated with phenotype




Citrin


7q21.3


?


30


Liver, kidney, heart, small intestine (31, 33)


?



Cytosol




Argininosuccinate synthetase


9q34.1 (many pseudogenes) 7cen-q11.2


53


14


Liver, kidney, fibroblasts, brain (trace)


Genotype associated with phenotype




Argininosuccinate lyase


?


?


12


Liver, kidney, brain, fibroblasts


Genotype associated with phenotype




Arginase


6q23


13


2


Liver, erythrocytes, lens, brain (trace)


Genotype associated with phenotype


Enzymes of galactose metabolism




Galactose-4-epimerase


1p36-35


4


9


Erythrocytes, fibroblasts, liver


Unclear




Galactokinase


17p24


7.3


13


Liver


Cataracts only




Galactose-1-phosphate uridyltransferase


9p13


4.3


>150


Erythrocytes, leukocytes, fibroblasts, intestinal mucosa, liver


Genotype associated with phenotype Q188R (white) S135L (black), Δ5 kb (Ashkenazi)


CoA, coenzyme A.









TABLE 69.3 APPROXIMATE DAILY REQUIREMENTS FOR SELECTED NUTRIENTSa BY INFANTS AND CHILDREN WITH SELECTED INHERITED DISORDERS OF AMINO ACID AND ORGANIC ACID METABOLISM


















































































































































































































































































































AGE


NUTRIENT


UNIT


0 < 6 mo


6 < 12 mo


1 < 4 y


4 < 7 y


7 < 11 y


11 < 15 y


15 < 19 y


Energy


kcal/kg


145-95


135-80









kcal/d




1,300


1,700


2,400


2,200-2,700


2,100-1,800




(range)




900-1,800


1,300-2,300


1,650-3,300


1,500-3,700


1,200-3,900


Fluid


mL/kgb


160-135


145-120


95


90


75


50-55


50-65


Proteinc


g/kg


3.5-3.0


3.0-2.5









g/d




30-55


35-65


40-75


50-90


50-95


Fat


g/d


31


30







Linoleic acid


g/d


4.4


4.6


7.0


10


10-12


16


16


α-Linolenic acid


g/d


0.5


0.5


0.7


0.9


1.0-1.2


1.0-1.2


1.1-1.6


Isoleucined



MSUDd


mg/kg


90-30


90-30


85-20


80-20


30-20


30-20


30-10



PPA/MMAd


mg/kg


100-70


90-60


80-50


70-40


60-30


50-25


40-20


Leucined



MSUDd


mg/kg


100-60


75-40


70-40


65-35


60-30


50-30


41-15



Isovaleric acidemiad


mg/kg


150-70


130-70


100-60


90-50


80-40


70-30


60-25


Lysined



GA-Id


mg/kg


100-70


90-40


80-30


75-25


65-25


60-20


55-15


Methionined



HCUd


mg/kg


35-20


35-15


30-10


20-10


20-10


20-10


10-5



PPA/MMAd


mg/kg


50-30


45-25


40-20


35-15


30-10


25-10


20-10


Phenylalanined,



PKUd


mg/kg


70-20


50-15


40-15


35-15


30-15


30-15


30-10


Tyrosinemiasd


mg/kg


95-45


90-35


85-30


80-25


70-20


70-20


65-15


Threonined



PPA/MMAd


mg/kg


80-50


70-40


60-30


55-25


50-25


45-25


40-25


Tyrosined



PKUd


mg/kg


350-300


300-250


230


175


140


110-120


110-120



Tyrosinemias


mg/kg


95-45


75-30


60-30


50-25


40-20


30-15


30-10


Tryptophand



GA-I


mg/kg


40-10


30-10


20-10


15-8


10-6


8-5


8-4


Valined



MSUD


mg/kg


95-40


60-30


85-30


50-30


30-25


30-20


30-15



PPA/MMA


mg/kg


85-50


80-45


75-45


70-40


60-30


60-30


50-30


GA-I, glutaric acidemia type I; HCU, homocystinuria; MMA, methylmalonic acidemia; MSUD, maple syrup urine disease; PKU, phenylketonuria; PPA, propionic acidemia.


aAll known essential amino acids, essential fatty acids, minerals, and vitamins must be provided in adequate amounts.


b At least 1.5 mL of fluid should be offered for each kilocalorie of energy ingested by the infant and 1 mL/kcal by children and adults.


c Mean daily protein intake by physiologically normal children by age is as follows: 2 < 4 years, 54.9 g; 4 < 9 years, 66.1 g; 9 < 4 years, 80.9 g; 14 < 19 ayears, 96.5 g.


d After 1 to 2 days of deleting appropriate amino acids, introduce those amino acids at the maximum noted for age. Monitor plasma concentrations frequently, and modify the amino acid prescription appropriately.







Fig. 69.1. Metabolism of aromatic amino acids. The metabolic flow and nutrient interaction in disorders of phenylalanine and tyrosine are diagrammed. The black bars represent impaired enzymes in biopterin biosynthesis, phenylketonuria, and tyrosinemia. GTP, guanosine triphosphate; NAD, nicotinamide adenine dinucleotide (NADH is the reduced form).






Fig. 69.2. Inhibition site in heme biosynthesis of relevance to diagnosis and treatment of tyrosinemia type I. The black bar represents the partial block in acute intermittent porphyria with resultant overproduction of σ-aminolevulinic acid (σ-ALA) and porphobilinogen (PBG) with decreased heme biosynthesis. In type I tyrosinemia, succinylacetone is produced and inhibits σ-ALA dehydratase with accumulation of σ-ALA alone, which is neurotoxic. σ-ALA accumulation can be reduced by addition of excess dietary glucose (GLU) and by hematin infusions that negatively control σ-ALA synthase at levels of both enzyme and gene expression. CoA, coenzyme A.

Nutrition management remains a principal component in treating all these inherited disorders, and some practical considerations for nutrition support should be considered. Foremost is the need to maintain normal growth, which cannot be achieved without adequate intake of energy, amino acids, and nitrogen. Energy requirements are greater than normal when intact protein is restricted and free amino acids supply protein equivalent (54). Free amino acids administered in one daily dose are oxidized to a much greater extent than when the same dose is divided and administered throughout the day (55). Nitrogen balance was improved considerably when free amino acids were ingested in several doses throughout the day with intact protein rather than in one dose (56). With total protein intakes (protein equivalent [g N x 6.25 from free amino acids = g protein equivalent] plus intact protein) 25% or more greater than RDA for intact protein for age (1) and closer to actual intakes by physiologically normal children in the United States (57), patients with PKU in the United States have grown normally in height (58). If adequate energy and amino acids cannot be ingested to support normal growth through oral feedings, then nasogastric, gastrostomy, or parenteral feedings should be used. Failure to adapt nutrient intake to the individual needs of each patient can result in mental retardation, metabolic crises, neurologic crises, growth failure, and, with some inherited metabolic diseases, death. When specific amino acids or nitrogen require restriction, total deletion of the toxic nutrient for 1 to 3 days in the presence of excess energy intake is the best approach to initiating therapy. Longer deletion or overrestriction may precipitate deficiency of the amino acids or nitrogen. Because the most limiting nutrient in the diet determines growth rate, overrestriction of an amino acid, nitrogen, or energy will result in further intolerance of the toxic nutrients.

Diet restrictions to correct imbalances in metabolic relationships require the use of elemental medical foods. These medical foods must be accompanied by small amounts of intact protein that supply the restricted amino acids. Intact proteins seldom supply more than 50%, and often supply much less, of the protein requirements of patients. Nitrogen-free foods that provide energy are limited in their range of nutrients. Consequently, care must be taken to provide all nutrients required in adequate amounts (1), particularly because certain minerals are not well absorbed (59) and some vitamins may not be metabolized normally.

Elemental medical foods consist of small molecules that often provide an osmolality that exceeds the physiologic tolerance of the patient. Abdominal cramping, diarrhea, distention, nausea, and vomiting result from hyperosmolar feedings. Aside from gastrointestinal distress, more serious consequences can occur, such as hypertonic dehydration, hypovolemia, hypernatremia, and death. Osmolalities of selected medical foods intended for inherited diseases of amino acid metabolism have been published (60).


AROMATIC AMINO ACIDS

Inborn errors of the aromatic amino acids were historically the first to respond to nutrition support. PKU was discovered in 1933, and the prevention of its resultant mental retardation by dietary intervention is classic.


Biochemistry

The essential amino acid PHE is used for tissue protein synthesis and hydroxylation to form TYR. The hydroxylation reaction requires PAH, oxygen (O2), BH4, dihydropteridine reductase (DHPR), and nicotinamide adenine dinucleotide (NAD) plus hydrogen ion (H+) (see Fig. 69.1). The normal adult uses only 10% of the RDA for PHE for new protein synthesis, and approximately 90% is hydroxylated to form TYR. The growing child uses 60% of the required PHE for new protein synthesis, and 40% is hydroxylated to form TYR. Mass spectrometry and stable isotope studies of patients with PKU provide information on other pathways available for PHE metabolism. These alternative pathways (see Fig. 69.1) are minor in the metabolism of PHE at 50 µmol/L concentration in the plasma of physiologically normal individuals. Byproducts become apparent when PHE is not hydroxylated to TYR and accumulates to more than 500 µmol/L, however (61).

TYR is the normal immediate product of PHE and is essential to five pathways (see Fig. 69.1), including synthesis of protein, catecholamines, melanin pigment, and thyroid hormones. TYR also provides energy when it is catabolized through p-OHPPAD to fumarate and acetoacetate. Enzymes required in this latter degradative pathway include TYR aminotransferase, p-OHPPAD, homogentisic acid oxidase, and fumarylacetoacetic acid hydrolase (FAH) (see Fig. 69.1).


Phenylketonuria

PKU is a group of inherited disorders of PHE metabolism caused by impaired PAH activity. The disease is expressed at 3 to 6 months of age and is c haracterized by developmental delay, microcephaly, abnormal electroencephalogram (EEG), eczema, musty odor, and
hyperactivity. If not treated before 2 weeks of age, the metabolic imbalance produces mental retardation that is worsened with increasing time to treatment. The defect in metabolism in classic PKU is associated with less than 2% of the activity of normal PAH, and these classic mutations are now defined (62). The enzyme is expressed primarily in liver.


Molecular Biology

Five of the most frequent mutations in a US clinic include I65T, R408W, Y414C, L348V, and IVS10nt546, which account for more than 50% of mutant PAH alleles. Genotypes with R408W and IVS10nt546 result in more severe PAH impairment, whereas Y414C and I65T have relatively mild phenotypes (62). Heterozygous parents for classic PKU have 50% enzyme activity, and in the absence of known DNA changes, they can be identified by increased ratios of midday semifasting PHE squared to TYR (P2/T) in vivo (63).

The genetic bases for disorders of PAH followed localization of the PAH gene to chromosome 12q22-q24.1 and cloning of the gene, which has 90 kilobases (kb), 13 exons, and 12 introns (see Table 69.3). More than 500 different mutations have been identified that cause the “PKU phenotype,” and these involve deletions in coding frames, missense mutations, and intron splice site mutations. Ethnic variation occurs in the type and frequency of PAH mutations (64). Cloning of the PAH gene and identification of different mutations have assisted in genotyping probands, counseling families, and predicting the amount of dietary PHE that will be required (62). Immediate and lifelong avoidance of excess PHE in the diet continues to be the principal therapy of PKU.

Several investigators have reported oral 6-R-1-erythro-5,6,7,8- BH4 responsiveness within 24 to 48 hours at doses of 5 to 10 mg/kg in patients with selected mild mutations in the PAH gene (65, 66, 67, 68, 69). An hypothesis has been proposed whereby oral administration of BH4 makes it possible for the mutant enzymes to suppress their low binding affinity for BH4, thus enabling patients with this subset of PAH mutations to perform the PHE hydroxylation reaction (69). Although certain genotypes, such as those containing L485, may respond with increased PAH gene expression, other missense mutations may have effects on increased catalysis or increased PAH stability. Many patients with “classic” PKU fail to respond to BH4 (70).

Other forms of PKU may result from defects in other enzymes involved in the overall reaction. DHPR, an enzyme normally present in many tissues, reduces the quinonoid form of dihydrobiopterin to BH4 (see Fig. 69.1). The gene for DHPR is located on chromosome 4p15.1-p16.1. Several other types of PKU result from defects in the synthesis of BH4 (see Fig. 69.1) (see Table 69.3). In addition to functioning as a coenzyme for PAH, BH4 is also required by TYR hydroxylase and tryptophan (TRP) hydroxylase (see Fig. 69.1). Because these enzymes produce essential neurotransmitters, defects in biopterin synthesis are associated with progressive neurologic disease unless BH4, L-3,4-dihydroxyphenylalanine (L-DOPA), and serotonin are replaced (71).

Although the precise pathogenesis of mental retardation in classic PKU is not known, accumulation of PHE or its catabolic byproducts, deficiency of TYR or its products, or all four circumstances will produce central nervous system (CNS) damage if PHE accumulates in plasma at greater than normal concentrations during critical periods of brain development. The pathologic consequence varies with the time in brain development at which the chemical insult occurs. Deficient myelination and abnormalities in brain proteolipids or proteins occur in late gestation and during the first 6 to 9 months of life (72). During this period, oligodendroglia migration may also be impaired, resulting in irreversible brain damage later in childhood. Protein synthesis in the brain is also depressed, probably owing to competitive inhibition by high PHE concentrations on blood-brain barrier transport with consequent imbalance in intraneuronal amino acid concentrations (73). In the mature brain, neurodegeneration (74), behavioral difficulties, and prolonged performance times may result from depressed neurotransmitter synthesis. Impairment of these neuropsychologic functions in the mature brain may be reversible when PHE returns toward normal concentrations in cells and blood (75, 76).


Screening

The disorders of PHE metabolism require identification, diagnosis, and appropriate therapy before clinical expression of the disease. Nutrition and possibly other therapy should be instituted before the third week of life. Thus, a tetrapartite public health program involving screening, retrieval, diagnosis, and treatment must be coordinated and efficient to prevent mental retardation. A screening test of dried blood on filter paper that uses MS/MS (11) detects potential cases in the newborn population. The actions taken in retrieval depend on the concentration of blood PHE, days of age, and protein intake at the time of screening.

Protein ingestion may not be required for a positive PKU screen, but quantitative normal concentrations during the first 48 hours of life are needed for comparison (77). Almost all infants with PKU have blood PHE concentrations greater than normal during the first day of life, even before the first feeding if they have classic PKU mutations (71). Neonates with PAH gene mutations resulting in less severely impaired PAH may take longer to develop an elevated blood PHE concentration. Some infants with a relatively mild elevation of blood PHE have serious neuropathologic features that are progressive because of a defect in synthesis of BH4.

Newborn screening in all 50 states, in conjunction with aggressive, rapid approaches to retrieval and diagnosis, has led to early institution of diet therapy and prevention
of mental retardation (77). With the present early infant discharge from the newborn nursery and the increase in breast-feeding, lower PHE concentrations of 121 to 242 µmol/L (2 to 4 mg/dL) are considered positive, and follow-up is initiated (78). Approximately 1 in 14,000 white newborns in the United States is affected with PKU (79), whereas 1 in 132,000 newborns in the black population is affected (80). For non-PKU hyperphenylalaninemia without TYR elevation, the estimated incidence is 1 in 48,000 for all newborns (79).




Maternal Phenylketonuria

Pregnant women with PKU who are untreated at conception and during gestation have children with intrauterine growth retardation, microcephaly, and congenital anomalies, often severe and incompatible with life. Mental retardation is common in children of mothers whose plasma PHE concentration is higher than the normal range (145). The pathogenesis of the fetal damage is uncertain but is believed to be related to elevated maternal blood PHE concentration (146) because PHE is actively transported across the placenta to the fetus (147). Fetal plasma PHE concentrations are one and one half to two times those of maternal blood (148). Such elevated fetal plasma PHE concentrations are again concentrated twofold to fourfold
by the fetal blood-brain barrier (149). Intraneuronal PHE concentrations of 600 µmol interfere with brain development by one or more of the several previously described mechanisms, including abnormal oligodendroglial migration and myelin and other protein synthesis (150). Thus, it is extremely important to maintain normal plasma PHE concentrations in the reproductive-age woman with PKU before conception and throughout gestation. Surviving children of untreated women fail to grow and develop normally (151). In fact, Kirkman (152) predicted that if the fertility of these women is normal and they are not treated with dietary control of PHE intake, the incidence of PKU-related mental retardation could return to the prescreening level after only one generation.

In 1984, the Maternal Phenylketonuria Collaborative Study (MPKUCS) was initiated to answer questions related to diet and reproductive outcome in women with PKU (153). Results of the MPKUCS supported the premise that a PHE-restricted diet, plasma PHE concentrations lower than 360 µmol/L, and the gestational age at which the diet is initiated affect reproductive outcome (154).

Nutrition Support of Maternal Phenylketonuria. The PHE-restricted diet should be initiated at least 3 months before a planned pregnancy by women who have PKU, if they have previously discontinued the diet. The objectives of therapy for pregnant women with PKU are a healthy mother and a normal, healthy newborn. To obtain adequate protein and fat storage in early pregnancy to support third-trimester fetal growth, careful attention must be paid to diet and nutrition status. Although the plasma PHE concentration most likely to yield the best reproductive outcome is unknown, one group of investigators suggested that these objectives may be achieved by a PHE-restricted diet that maintains plasma PHE concentration between 60 and 180 µmol/L (155). Plasma PHE concentrations lower than 60 µmol/L may lead to maternal muscle wasting and poor fetal growth. The recommended PHE intake to prescribe for initiating therapy is given in Table 69.7 (1, 112, 116). Other indices of nutrition status should be in the normal range for pregnant women. After initiation of diet with the minimum recommended PHE prescription (see Table 69.7), the plasma PHE concentration should be monitored twice weekly to maintain the targeted plasma PHE concentration.

Even after the plasma PHE concentration is stabilized in the treatment range, frequent changes in the individualized diet prescription are required as pregnancy progresses, based on concentrations of plasma PHE, TYR, and other amino acids and on weight gain. PHE and TYR requirements of each pregnant woman depend on genotype, age, state of health, protein intake, and trimester of pregnancy (112). At approximately midpregnancy, PHE tolerance increases considerably.








TABLE 69.7 RECOMMENDED PHENYLALANINE, TYROSINE, PROTEIN, FAT, ESSENTIAL FATTY ACID, AND ENERGY INTAKES FOR PREGNANT WOMEN WITH PHENYLKETONURIA




































































































































NUTRIENTS


TRIMESTER AND AGE (y)


PHENYLALANINEa,b (mg/d)


TYROSINEb (mg/d)


PROTEIN (g/d)


FATc (g/d)


LINOLEIC ACID (g/d)


α-LINOLENIC ACID (g/d)


ENERGYc (kcal/d)


MEAN


RANGE


Trimester 1 (0 < 14 wk gestation)



15 < 19


200 < 820


≥7,600


≥76


36-132


13


1.4


2,500


1,600-3,400



19 < 24


180 < 800


≥7,400


≥74


47-124


13


1.4


2,500


2,100-3,200



≥ 24


180 < 800


≥7,400


≥74


47-132


13


1.4


2,500


2,100-3,400


Trimester 2 (14 < 27 wk gestation)



15 < 19


200 < 1000


≥7,600


≥76


36-132


13


1.4


2,500


1,600-3,400



19 < 24


180 < 1000


≥7,400


≥74


47-124


13


1.4


2,500


2,100-3,200



≥ 24


180 < 1000


≥7,400


≥74


47-132


13


1.4


2,500


2,100-3,400


Trimester 3 (27 < 41 wk gestation)



15 < 19


330 < 1200


≥7,600


≥76


36-132


13


1.4


2,500


1,600-3,400



19 < 24


310 < 1200


≥7,400


≥74


47-124


13


1.4


2,500


2,100-3,200



≥ 24


310 < 1200


≥7,400


≥74


47-132


13


1.4


2,500


2,100-3,400


a Recommended range of phenylalanine (PHE) intake covered approximately 80% of women studied in the Maternal Phenylketonuria Collaborative Study (MPKUCS). Initiate the diet with the lowest amount recommended for the trimester and age. Frequent monitoring of plasma PHE is essential to prevent deficiency or excess. Modify the prescription based on the following: frequent plasma PHE and tyrosine (TYR) concentrations; intakes of PHE, TYR, protein, and energy; and maternal weight gain. Recommended iron intake is from MPKUCS data in Acosta PB, Michals-Matalon K, Austin V et al. Nutrition findings and requirements in pregnant women with phenylketonuria. In: Platt LD, Koch R, de la Cruz F, eds. Genetic Disorders and Pregnancy Outcome. New York: Parthenon, 1997:21-32.


b L-TYR is very insoluble in water. Consequently, any supplemental L-TYR should be mixed with fruit purees, mashed potatoes, or soup for ingestion. Recommended intake is from MPKUCS data in Acosta PB, Michals-Matalon K, Austin V et al. Nutrition findings and requirements in pregnant women with phenylketonuria. In: Platt LD, Koch R, de la Cruz F, eds. Genetic Disorders and Pregnancy Outcome. New York: Parthenon, 1997:21-32.


c Modified from Otten JJ, Hellwig JP, Meyers LD. Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. Washington, DC: National Academies Press, 2006. For some women, energy requirements may be greater than the upper limit of the range given to obtain appropriate weight gain.

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