Organic Acids Amino Acids (FMV) Oxidative Stress

Transcription

1 Patient: MARKO KRSMANOVIC Age: 2 Sex: M MRN: 134 Order Number: B Completed: April 28, 29 Received: March 13, 29 Collected: March 2, 29 ARL Pathology Referring Laboratory 3/568 St Kilda Road Melbourne, Victoria 34 Australia Organic Acids Amino Acids (FMV) Oxidative Stress

2 ID: B Page 2 Interpretation-at-a-Glance Anti-Oxidants Anti-Oxidants 4 Minerals 9 3-Methyl-4-OH-phenylglycol 4-Hydroxyphenylpyruvic Acid 8-OHdG Adipic Acid Alanine α-amino-n-butyric Acid α-keto-β-methylvaleric Acid α-ketoisocaproic Acid α-ketoisovaleric Acid Anserine β-alanine β-oh-β-methylglutaric Acid Carnosine Cis-Aconitic Acid Citric Acid Cystine/Cysteine Glycine Homogentisic Acid Homovanillic Acid Isoleucine Leucine Lipid Peroxides Pyroglutamic Acid Pyruvic Acid Suberic Acid H Taurine Threonine Valine Vanilmandelic Acid L α-ketoglutaric Acid Anserine Asparagine β-alanine Carnosine Citrulline Ethanolamine Histidine Isoleucine Leucine Methionine Orotic Acid H Phosphoethanolamine Phosphoserine H Pyruvic Acid >8x PPE Taurine L Valine B-Vitamins B6 Other B-Vitamins 3 Alanine α-aminoadipic Acid α-amino-n-butyric Acid Aspartic Acid β-alanine β-aminoisobutyric Acid Cystathionine Glycine Isoleucine Kynurenic Acid Leucine H Ornithine H H Serine H Threonine H Tyrosine Valine 3-Methyl-4-OH-phenylglycol Alanine α-amino-n-butyric Acid α-ketoadipic Acid α-keto-β-methylvaleric Acid α-ketoglutaric Acid α-ketoisocaproic Acid α-ketoisovaleric Acid Glutaric Acid Homovanillic Acid Isocitric Acid Isoleucine Leucine Malic Acid Pyruvic Acid Succinic Acid Valine Vanilmandelic Acid L B12 & Folate 9 1-Methylhistidine 3-Methylhistidine 3-Hydroxyproprionic Acid α-amino-n-butyric Acid β-aminoisobutyric Acid Cystathionine Formiminoglutamic Acid Glycine Histidine Methionine Methylmalonic Acid H Sarcosine H Serine - Graduated Scale recognizes relative need for nutrients/relative disease risk B6 Bio Marker 1 Bio Marker 2 7 H Bio Marker 3 Bio Marker 4 L Contributing Bio Markers Red = Functional Imbalance Interpretation-at-a-Glance Result

3 ID: B Page 3 Interpretation-at-a-Glance Gastrointestinal Dysfunctions Protein Malabsorption/ Maldigestion 8 1-Methylhistidine Phenylacetic Acid Dihydroxyphenylpropionic Acid H Phenylalanine Histidine L Succinic Acid Indoleacetic Acid Threonine Isoleucine Tryptophan Leucine Tyrosine Lysine Valine Methionine Bacterial Dysbiosis Ammonia Gamma-aminobutyric Acid Benzoic/Hippuric Acids Ratio Indoleacetic Acid β-alanine H Phenylacetic Acid Citramalic Acid Phosphoethanolamine Dihydroxyphenylpropionic Acid H Succinic Acid Ethanolamine 9 Yeast/Fungal Dysbiosis α-aminoadipic Acid Arabinose Nitrogen Balance (Excess) Nitrogen Balance (Deficiency) Alanine Anserine Arginine Asparagine Carnosine Citramalic Acid 2 Glutamine Glycine Lysine Ornithine Urea H Detoxification Dysfunction Detoxification Impairment Aspartic Acid β-alanine Cystathionine Cysteine Cystine Glutamine Impaired Methylation 4 Glycine H Lactic Acid Methionine Taurine H Urea Pyroglutamic Acid Arginine Methylmalonic Acid Creatinine L Sarcosine H Formiminoglutamic Acid Serine Glycine Vanilmandelic Acid L Methionine 4 Oxidative Stress 8-OHdG Lipid Peroxides Cis-aconitic Acid Pyroglutamic Acid Citric Acid Taurine Cystine/Cysteine Neurotransmitter Imbalance 9 2-Hydroxyphenylacetic Acid Homovanillic Acid H 3-Methyl-4-OH-phenylglycol 4-Hydroxyphenylpyruvic Acid 5-OH-Indoleacetic Acid Alanine Indoleacetic Acid Kynurenic Acid Phenylacetic Acid Phenylalanine β-aminoisobutyric Acid H Taurine Cystathionine Dihydroxyphenylpropionic Acid H Threonine Tryptophan H Gamma-aminobutyric Acid Glycine Homogentisic Acid Tyrosine Vanilmandelic Acid L

4 ID: B Page 4 SUGGESTED VITAMIN AND MINERAL SUPPLEMENT SCHEDULE Patient: MARKO KRSMANOVIC Supplements ARL Pathology Referring Laboratory 3/568 St Kilda Road Melbourne, Victoria 34 Australia Daily Recommended Intake (DRI) Anti-Oxidants Vitamin A & Beta-Carotene 5, IU, IU Vitamin C 75 mg 25 mg Vitamin E & Mixed Tocopherols 22 IU IU Alpha-Lipoic acid None 5 mg ID: B Personalized Daily Recommendations Provider Daily Recommendations B-Vitamins Vitamin B1 (Thiamin) 1.2 mg mg Vitamin B-2 (Riboflavin) 1.3 mg mg Vitamin B-3 (Niacin) 16 mg mg Vitamin B-6 (Pyridoxine) 1.3 mg 5 mg Vitamin B-9 (Folate) 4 mcg 1,2 mcg Vitamin B12 (Cobalamin) 2.4 mcg 5 mcg Minerals Magnesium 4 mg 8 mg Zinc 11 mg mg Iron 11 mg 6 mg Manganese 2.2 mg 4 mg Molybdenum 43 mcg 75 mcg Notes: As Written Substitution Permitted The Vitamin and Mineral Supplement Schedule presented above is based upon a comparison of the measured levels with an optimal level. Thus, a given vitamin or mineral listed for supplementation may be deficient for this individual, or it may be within the reference range but at a low-normal level. The Supplemental Schedule has been provided at the request of the ordering practitioner. Actual treatment recommendations should be made by the ordering practitioner.

5 ID: B Page 5 SUGGESTED AMINO ACID SUPPLEMENT SCHEDULE ARL Pathology Referring Laboratory 3/568 St Kilda Road Melbourne, Victoria 34 Australia Patient: MARKO KRSMANOVIC ID: B Amino Acid Arginine mg/day Asparagine Cystine Glutamine Glycine 196 Histidine Isoleucine Leucine Lysine 919 Amino Acid Methionine mg/day Phenylalanine Serine Taurine Threonine Tryptophan Tyrosine Valine Notes: As Written Substitution Permitted The Amino Acid Supplement Schedule presented above is based upon a comparison of the measured levels with an optimal level. The optimal level is set at 1.25 X the lower limit of the reference range. Thus, a given amino acid listed for the supplementation may be deficient for this individual, or it may be within the reference range but at a low-normal level. The Supplement Schedule has been provided at the request of the ordering practitioner. Actual treatment recommendations should be made by the ordering practitioner.

6 ID: B Page 6 Metabolic Analysis Markers 1 Indoleacetic Acid (IAA) 4.1 <= 9. 2 Phenylacetic Acid (PAA) 3 4 Dihydroxyphenylpropionic Acid (DHPPA) 4. Succinic Acid.7 <= 2.2 <= 2. 5 Citramalic Acid <= 7. 6 Indoleacetic Acid (IAA) 4.1 <= 9. 7 Phenylacetic Acid (PAA) 8 9 Dihydroxyphenylpropionic Acid (DHPPA) 4. Benzoic / Hippuric Acids Ratio.1 Succinic Acid.7 <= 2.2 <=.2 <= Arabinose 39.4 <= Citramalic Acid <= Lactic Acid 4.9 Pyruvic Acid Citric Acid 7.1 Cis-Aconitic Acid. Isocitric Acid α-ketoglutaric Acid (AKAA) Succinic Acid.7 <= 2. 2 Malic Acid <= Adipic Acid 1.9 Suberic Acid 1.9 <= 5.2 <= β-oh-butyric Acid (BHBA) 1.5 <= β-oh-β-methylglutaric Acid (HMG) 1.8 <= 6.7

7 ID: B Page Vanilmandelic Acid.9 Homovanillic Acid OH-indoleacetic Acid Methyl-4-OH-phenylglycol <= α-ketoisovaleric Acid <= 2. 3 α-ketoisocaproic Acid <= α-keto-β-methylvaleric Acid <= Kynurenic Acid.4 <=. 33 Formiminoglutamic Acid (FIGlu) <= Methylmalonic Acid Hydroxyphenylacetic Acid.9 4-Hydroxyphenylpyruvic Acid.9 <= 19. <= 1.2 <= Homogentisic Acid <= α-ketoadipic Acid <= Glutaric Acid Hydroxypropionic Acid 3.6 <= 2.5 <= Orotic Acid <= Pyroglutamic Acid Creatinine Concentration Metabolic Analysis Reference Ranges are Age Specific

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10 ID: B Page Amino Acid Analysis (FMV) Analytes reported in micromol/gm creatinine unless stated otherwise Arginine 18 Histidine 29 Isoleucine 46 Leucine 69 Lysine 46 Methionine 37 Phenylalanine 36 Taurine 496 Threonine 257 Tryptophan 162 Valine Analytes reported in micromol/gm creatinine unless stated otherwise Anserine (dipeptide) Carnosine (dipeptide) Methylhistidine 197 β-alanine ,8 <= 17

11 ID: B Page 11 Analytes reported in micromol/gm creatinine unless stated otherwise Alanine 24 Asparagine 125 Aspartic Acid 91 Cysteine 167 Cystine 77 Glutamic Acid 75 Glutamine 312 Glycine 524 Proline 6 Serine 328 Tyrosine , Analytes reported in micromol/gm creatinine unless stated otherwise α-aminoadipic Acid 52 α-amino-n-butyric Acid 36 β-aminoisobutyric Acid 173 Citrulline Cystathionine 6-29 Ethanolamine 364 Ornithine 18 Phosphoethanolamine 45 Phosphoserine 2 3-Methylhistidine 151 Ammonia 22.1 Urea 194 γ-aminobutyric Acid 17 Sarcosine mmol/g creatinine mmol/g creatinine <= 23 <= 41

12 ID: B Page 12 Analytes reported in micromol/gm creatinine unless stated otherwise Creatinine 1.4 Glutamine/Glutamate 4 Ammonia 22.1 Arginine/Ornithine mmol/l >= mmol/g creatinine >= 1. Urine Representativeness Index Ref Range 5 7

13 ID: B Page 13 Oxidative Stress Markers 8-OHdG 12 <= 16 mcg/g Creat. Urine Lipid Peroxides 6.5 <=. umol/g Creat. Lab Comments Ammonia was confirmed. The dl value 36 umol/l was used in calculations. 3/17/29 sa The performance characteristics of all assays have been verified by Genova Diagnostics, Inc. Unless otherwise noted with as cleared by the U.S. Food and Drug Administration, assays are For Research Use Only. Commentary is provided to the practitioner for educational purposes, and should not be interpreted as diagnostic or treatment recommendations. Diagnosis and treatment decisions are the responsibility of the practitioner. The Oxidative Stress Marker reference ranges are based on an adult population. One Standard Deviation (1 S.D.) is a statistical interval representing 68% of the reference population. Values between 1 and 2 S.D. are not necessarily abnormal. Clinical correlation is suggested. (See example below) Patient values for the Oxidative Stress Markers are within Genova Diagnostics reference ranges.

14 ID: B Page 14 Metabolic Analysis Markers MARKERS CHARACTERISTIC OF INTESTINAL MALABSORPTION AND/OR DYSBIOSIS Three of these chemical markers are formed by yeast/fungal organisms, usually but not necessarily in the gut: arabinose, beta-ketoglutaric acid and citramalic acid. Citramalate can also be formed by anaerobic bacteria. The remaining chemical markers of this section are the result of malabsorption, gut bacterial action, and in some cases, hepatic detoxication of chemicals produced by dysbiotic flora. 2,3 Dihydroxyphenylpropionic acid (DHPPA) is elevated. This organic acid is a byproduct of the bacterial metabolism of phenylalanine, tyrosine, and/or tryptophan. Research has identified various species of Clostridia in the in-vitro production of this compound. Other research on quinoline demonstrates production of DHPPA by Pseudomonas species. Presence of elevated levels of DHPPA in the urine may thus suggest overgrowth of Clostridia and/or Pseudomonas, as well as a degree of malabsorption of aromatic amino acids. A comprehensive stool analysis is suggested. NEUROTRANSMITTER METABOLITES These metabolites are end products of neurotransmitter metabolism, either the adrenal catecholamines or serotonin (5-HIAA). Abnormal levels correlate with mood swings, mental dysperceptions, anxiety, or depressive disorders. Vanilmandelic Acid (VMA or 3-methoxy-4-hydroxymandelic acid) is measured to be low. VMA is a normal urine metabolite of the adrenal catecholamines, epinephrine and norepinephrine. Subnormal VMA may occur in mental depression, mood swings or bipolar disorders, or other conditions related to catecholamine insufficiency or imbalance. Low VMA can be a consequence of deficient formation of "DOPA", dopamine, or norepinephrine, deficient methylation by S-adenosylmethionine (SAM), or MAO inhibition. Nutritional factors related to deficient production of norepinephrine include inadequate levels of: phenylalanine or tyrosine, vitamin B6 as pyridoxal 5-phosphate, ascorbic acid, and copper. Copper is a cofactor for the enzyme dopamine beta-hydroxylase which forms norepinephrine from dopamine. In copper deficiency, norepinephrine (and epinephrine) formation can be slowed or erratic. Such individuals may also present fatigue if the required epinephrine stimulus of glycogenolysis is deficient. Methylation is required for the metabolism of catecholamines. Epinephrine is first methylated by S-adenosylmethionine (SAM), requiring an enzyme activated by magnesium. The resulting metanephrine is then oxidized (deaminated) by monoamine oxidase (MAO). This step requires vitamin B2 as the coenzyme FAD. Aldehyde dehydrogenase then removes hydrogen to form VMA, requiring vitamin B2 as FAD, iron, molybdenum and vitamin B3 as NAD. Low levels of any of these nutrients may be rate-limiting, resulting in low levels of VMA. Norepinephrine follows an essentially identical path to VMA. Homovanillic Acid (HVA, or 3-methoxy-4-hydroxyphenylacetic acid) is elevated. HVA is a normal metabolite of dopamine via methylation (requires SAM and a magnesium-activated enzyme), and deamination (requires vitamin B6), and oxidation by monoamine oxidase (MAO) (which uses vitamin B2 as FAD). Infants and male children typically have higher urine HVA than do older children and females. Excessive urine HVA can occur with mental disturbances and with dopaminergic dysfunction. HVA is elevated in urine when the metabolism of dopamine is impaired or dopamine turnover is increased (as may occur with administration of choline or physostigmine).

15 ID: B Page 15 Dopamine becomes norepinephrine using the enzyme dopamine beta-hydroxylase. This enzyme requires copper for its activation, and oxygen and ascorbic acid as cofactors. Insufficient copper or ascorbate may result in elevated urine HVA, as may other impairments in adrenal catecholamine metabolism. If elevated HVA is due to impaired dopamine-to-norepinephrine metabolism, then epinephrine formation can be slowed or erratic. Individuals with this problem may also present fatigue if the required epinephrine stimulus for glycogenolysis is deficient. ANALYTES CHARACTERISTIC OF CELLULAR ENERGY AND MITOCHONDRIAL FUNCTION These markers are metabolites from four important biochemical pathways in the body, all of which significantly impact the production and availability of energy at the cellular level: glycolysis, the citric acid cycle (Krebs cycle) and both beta-oxidation and omega-oxidation of fatty acids. These analytes provide unique insight into macronutrient catabolism and mitochondrial function in cells. Abnormal levels may be associated with fatigue, malaise, myalgia, headache, muscle weakness, myopathy, hypotonia, or acid-base imbalance. This test is intended to be a diagnostic aid for acquired disorders in these pathways. It is not intended for diagnosis of inborn errors of organic acid metabolism, as this would require extensive molecular genetics testing. However, significantly abnormal findings could be consistent with such inborn errors. If significant abnormalities persist after removal of toxics, supplementation of appropriate nutrients, dietary and hormonal adjustments, and correction of intestinal dysbiosis or infection, it is suggested that the patient be referred to a medical center with capabilities for diagnosis and treatment of congenital metabolic defects. Lactic Acid, or lactate, is measured to be low. Lactate is formed from pyruvate in anaerobic or oxygen starved (hypoxic) circumstances to allow for ongoing production of ATP in these anaerobic conditions. There are no known clinical problems associated with low lactic acid. Low levels are usually a result of reduced amounts of its precursor, pyruvic acid. Citric Acid, or citrate, is measured to be low. This key component of the citric acid cycle is formed inside the mitochondria from acetyl-coenzyme A and oxaloacetic acid by the enzyme citrate synthase. Succinate excess, as may occur with infection or intestinal dysbiosis (from bacterial transamination of non-absorbed glutamine), can inhibit citrate synthase. Citric acid can be low if cellular glucose or pyruvate is deficient or if pyruvate is elevated due to impairment of the pyruvate dehydrogenase complex that catalyzes the conversion of pyruvate into acetyl CoA. This transformation requires vitamin B1 as thiamin pyrophosphate, vitamin B2 as FAD, vitamin B3 as NAD, lipoic acid, magnesium and ATP. Impaired beta-oxidation of fatty acids, as occurs with carnitine deficiency, can reduce levels of acetyl-coa and citrate, especially in the early fasting state (12-48 hours after eating). Carnitine is necessary to transport long-chain fatty acids across the outer mitochondrial membrane for subsequent oxidation. Citric acid can also be low if oxaloacetic acid (its precursor) is insufficient. Oxaloacetic acid may be formed by oxidizing malic acid, or by transaminating aspartate. The first reaction requires B3 as NAD and the second requires B6 as pyridoxal 5-phosphate. Citric acid formation may also be low if pyruvate carboxylase is weak or in multiple carboxylase deficiency (pyruvic acid should be elevated). Pyruvate carboxylase requires biotin, ATP, magnesium and manganese. Additionally, low urinary

16 ID: B Page 16 citrate can occur with increased proximal tubular resorption in the kidneys that occurs in metabolic acidosis. This leads to hypocitraturia and can predispose the person to kidney stone formation. Cis-aconitic Acid (CAA) is measured to be low, and its precursor, citric acid, is also low. In this case, the cis-aconitic acid deficiency is considered to be secondary to the subnormal citrate level; please refer to the commentary for low citrate. Isocitric Acid is measured to be subnormal. This may be due to deficient or low-normal levels of its precursors, cis-aconitate or citrate. It may also be due to depleted alpha-ketoglutarate, which it forms in the citric acid cycle; check for low alpha-ketoglutarate in this report. The same enzyme, aconitase, forms cis-aconitic acid and isocitric acid, and requires reduced cysteine or glutathione and ferrous iron (Fe+2). Oxidant stress can inhibit it, as can arsenic, mercury or antimony. Fluoride that becomes fluorocitrate can strongly inhibit aconitase and impair formation of isocitrate. Alpha-ketoglutaric Acid (alpha-ketoglutarate or AKG) is measured to be low. Alpha-ketoglutaric acid is formed from isocitrate via the enzyme isocitrate dehydrogenase, or from the deamination or transamination of glutamate (requiring vitamin B6). Low alpha-ketoglutaric acid can be caused by weakness of isocitrate dehydrogenase, the citric acid cycle enzyme that forms it from isocitric acid. This enzyme requires vitamin B3 as NAD, magnesium and manganese, and it is strongly inhibited by aluminum. Alpha-ketoglutaric acid is a scavenger of amino groups and ammonium ions in the body. Adding an amino group to alpha-ketoglutaric acid results in glutamate formation. Therefore, nitrogen excess and hyperammonemia can reduce alpha-ketoglutaric acid levels. In such cases (and with high-protein diets), lowered alpha-ketoglutaric acid is of concern and may indicate limited nitrogen detoxication. Urinary alpha-ketoglutaric acid may be slightly lower than normal in high-carbohydrate or vegetarian diets (where metabolic need is reduced); but there is no apparent clinical significance in this circumstance. COFACTOR-DEPENDENT AND METABOLITES FROM AMINO ACID CATABOLISM These analytes are formed from essential and protein amino acids via amino group transfer or by other enzymatic transformations. Many are sensitive to vitamin functions as coenzymes and to minerals as enzyme activators. Excesses or deficiencies may lead to various conditions depending upon the particular metabolic imbalance, including fatigue, headaches, myalgias, metabolic acidoses, dietary intolerances, neurological problems, and cognitive disorders. Urine creatinine concentration is measured to be below the reference range. This may indicate reduced renal clearance, including reduced clearance for some but not necessarily all reported analytes. Because analyte results are reported as a ratio to creatinine, the representativeness of the urine result is uncertain. Creatinine concentration can also be below normal due to: excessive intake of fluids, use of diuretics, dietary deficiencies of precursor amino acids (arginine, glycine, or methionine), malnutrition, hypothyroidism, a bedridden or severely inactive state, abnormally low muscle mass, or muscular dystrophy (the latter would also express elevated creatine in blood and urine). Measurement of blood serum creatinine or a creatinine clearance test is suggested. If serum creatinine is elevated, or if clearance is subnormal, then the reported organic acid results may not be representative. If renal clearance is normal, then the reported organic acid results are representative.

17 ID: B Page 17 Amino Acid Markers = Unable to calculate results due to less than detectable levels of analyte. Commentary is provided to the practitioner for educational purposes, and should not be interpreted as diagnostic or treatment recommendations. Diagnosis and treatment decisions are the responsibility of the practitioner. REPRESENTATIVENESS INDEX Urine amino acid levels usually are representative of blood levels and reflect dietary uptake and metabolism as well as excretion. However, abnormal renal clearance, loss of urine during the collection period, decay or spoilage, and presence of blood in the urine could cause the urine specimen to be unrepresentative. The possibility of such problems can be judged from analytical measurements which are portrayed in the first section of the report: Markers for Urine Representativeness. The glutamine/glutamate ratio can indicate specimen decay. When aged or improperly preserved, urine glutamine decays to glutamic acid and ammonia. However, in metabolic acidosis some glutamine is transformed into glutamic acid and ammonium ion as a ph-balancing mechanism. Also, high glutamic acid occurs in gout. Hence, low glutamine/glutamate ratio may reflect decay or it may be of metabolic origin. High glutamine/glutamate ratio is metabolic and does not reflect on specimen representativeness. The ammonia concentration, if elevated, usually indicates overall decay of amino acids. An exception would be elevated ammonia concentration with hyperammonemia of metabolic or bacterial origin. Very low ammonia concentration suggests low urine nitrogen levels and may occur in protein-deficient diets. Blood amino acid levels may then be normal or low-normal. The arginine/ornithine ratio generally reflects whether the sample is purely urine or whether hematuria is present. A low ratio is consistent with blood in the urine. This is not foolproof, because high ornithine relative to arginine also may occur with a specific urea cycle weakness (OCT enzyme dysfunction, rare), and with pyridoxal phosphate or transamination weakness affecting ornithine. Urine should not be collected for acid analysis by women during menses. Blood in urine can notably distort the results. The computer scores the above four Markers for Representativeness and computes a Representativeness Index. An index of means all markers are within expected limits. An index below 5 suggests a repeat amino acid analysis with a new urine specimen. Creatinine is measured to be low in the urine specimen. Creatinine is a measure of renal clearance and is low in kidney failure. However, low creatinine also occurs with malnutrition and dietary protein insufficiency, physical inactivity, hypothyroidism and in muscle-wasting diseases. If kidney clearance is subnormal, the urinary levels of amino acids could be low while blood levels could be high. A creatinine clearance test is suggested when significantly low creatinine levels are reported and causative factors uncertain. Carnosine, a dietary peptide, is measured to be lower than the reference range. Carnosine comes from certain meat and fish protein. It is typically low or absent for individuals who eat low protein diets or who follow vegetarian or vegan diets. There is no clinical significance for low carnosine. Beta-aminoisobutyric acid (B-AIB) is a product of catabolism of pyrimidine nucleotides and it is an intermediate of valine-to-succinic acid metabolism. In valine-to-succinic acid metabolism, B-AIB is directly formed from methylmalonic acid semialdehyde. B-AIB is elevated for this individual which implies one of four possible conditions. 1. Vitamin B12 coenzyme function (as adenosylcobalamin) is weak. Elevated methylmalonic acid in urine (methylmalonic aciduria) would confirm this. Vitamin B12 deficiency or adenosylcobalamin coenzyme defect would be causative. 2. Vitamin B6 coenzyme function (as pyridoxal phosphate) is weak. B-AIB also transaminates to its keto analog. 3. The specific B-AIB-to-pyruvic acid transaminase is weak or absent. This is considered a benign variant of metabolism

18 ID: B Page 18 and is present in about 25% of Chinese and Japanese individuals and in about 8% of Scandinavian and Northwestern Europeans. 4. Accelerated catabolism of DNA and RNA is occurring. Catabolism of damaged or diseased tissue, tumors and malignancy feature increased formation and excretion of B-AIB. In addition to the above conditions, Downs syndrome individuals usually are B-AIB excretors. It is not known whether one of the above four mechanisms is responsible. Beta-alanine is measured to be high in the urine. Often this amino acid is elevated when the dietary peptides anserine and carnosine are elevated because they contain beta-alanine. Beta-alanine also is a breakdown product of the pyrimidine bases cytosine and uracil. Catabolism of damaged or diseased body tissue, tumors and malignancy feature increased production and urinary disposal of beta-alanine. Some beta-alanine is produced by normal gut flora which also make pantothenic acid from it. Elevated levels of staphylococcus or streptococcus, use of antibiotics, and breakdown of yeast or fungi in the body can result in increased levels of urinary beta-alanine. Continuously elevated beta-alanine can be detrimental by impairing renal conservation of taurine. The normal-appearing result for taurine is questionable, because of the elevated beta-alanine. It is possible that blood or tissue levels of taurine are limited or deficient. Cystinuria, or elevated urine cystine, appears among the abnormal results for this individual. Cystinuria is a renal transport disorder that features poor renal conservation and increased urinary excretion of cystine and of other multi-amino-group amino acids. Typically one or more of lysine, arginine and ornithine also are elevated in urine; occasionally, glutamine also is elevated. Cystinuria is considered to be an inherited trait that involves both renal tubules and intestinal mucosal transport. Often it is worsened by allergic reactivities and by diet or disease resulting in acidosis. With subacute cystinuria, the individual presents elevated urinary cystine that is below the solubility limit of this amino acid (167 micromoles or 4 mg per liter at ph = 7.). Cystine crystals then are not present in the renal tract or urine. Acute cystinuria features higher levels of cystine wasting and presence of cystine precipitates as stones or calculi. Clinical manifestations of cystinuria may be lacking or insignificant in mild cases. The condition may include increased inflammatory responses and reduced ability to detoxify if limited glutathione results. Cystinuria may feature weakened hair strands, hair loss or poor fingernail/toenail structure, or may lead to hypertension and colic with urinary tract obstruction in more severe cases. Appropriate remedial actions for cystinuria include drinking at least two liters of pure water per day (teenagers and adults), a low sodium diet, and avoidance of high-acidity food and drink. (Citric acid and citrates are not detrimental, because they are systemic alkalizers.) A urine ph near 7 is desirable; cystine solubility decreases with decreasing ph. Several authorities suggest a glass of water at bedtime to counteract normal concentration of urine at night. Avoidance of allergic or inflammatory substances is generally beneficial and can decrease the degree of heterozygous or subacute cystinuria. Dietary limitation of high-cystine and high-methionine foods may be beneficial: eggs, most meat-fish-fowl, soy protein, Brazil nuts and cheeses. Significant dietary supplementation of methionine, cystine, cysteine, N-acetylcysteine, and glutathione is contraindicated in cystinuria. Tryptophan is elevated in the urine. Other elevations that would be expected in Hartnup syndrome are not present, so the tryptophan elevation probably is not due to a general (hereditary) transport defect for monoamine-monocarboxylic acids. This elevation of tryptophan suggests lowered blood tryptophan and perhaps low serotonin. Blood plasma tryptophan may be measured by plasma amino acid analysis; serotonin should be measured in blood platelets. Symptoms consistent with tryptophan deficiency are mainly those of serotonin insufficiency and may include: insomnia, anxiety, enhanced response to external stimuli (light, sound), and abnormal food cravings. Cystathionine is an intermediary metabolite of the essential amino acid methionine, and cystathionine is subnormal per the urine analysis. Cystathionine is preceded by homocysteine, and it leads to cysteine and alpha-ketobutyric acid. Cystathionine formation from homocysteine requires the amino acid serine and vitamin B6 as

19 ID: B Page 19 coenzyme pyridoxal 5-phosphate (P 5-P). Low cystathionine with normal (or high) methionine and normal homocystine may indicate limited serine but usually indicates increased need for vitamin B6 or pyridoxal phosphate. Depending upon need for and levels of cysteine, cystine and taurine, this problem may or may not have associated symptoms and may only be a transient physiological imbalance. However, if low cystathionine reflects a significant weakness in the activity of its formation enzyme (cystathionine beta-synthase), then clinical abnormalities could be associated with this finding. Pathologies associated with impaired cystathionine beta-synthase include: ectopia lentis, myopia, osteoporosis, scoliosis, CNS disorders, and arterial and venous thromboemboli. Elevation of the amino acids glutamic and aspartic acid (and sometimes alpha-amino adipic acid) has been described in the literature as dicarboxylic hyperaminoaciduria. This is a rare disorder of autosomal recessive inheritance, and features renal wasting (due to a renal tubule transporter defect) of dicarboxylic-structured amino acids. Unpublished clinical observations of several cases link the condition to toxic chemical exposures or to use of narcotics or street drugs. Few patients have been described worldwide, and those identified have ranged from asymptomatic to exhibiting neurocognitive changes. There are no therapeutic interventions. Clinical attention should be directed to ruling out factors which may mimic or contribute to increased urinary aspartate and glutamate excretion. Sources that may contribute to an increased urinary aspartate level include consumption of the non-nutritive sweetener, aspartame; foods such as dairy products, beef, poultry, luncheon meats, sausage meat, wild game, sprouting seeds, oat flakes, avocado, and asparagus; and dietary supplements. Sources that may contribute to an increased urinary glutamate level include dietary intake of monosodium glutamate (MSG), a common flavor enhancer found diffusely in commercially-prepared foods, food additives and seasonings. MSG is found in commonly ingested substances like Chinese food, yeast extract, hydrolyzed protein, gelatin, whey and soy protein concentrates, soy sauce, bouillon cubes and broth, and barley malt. Folic acid deficiency or dysfunction may increase urinary glutamate levels (formiminoglutamic aciduria) as might gout, pre-gout or other disorders of purine metabolism. Sarcosine, or N-methylglycine, is an intermediate of the choline-to-serine catabolism sequence. It is formed by oxidative demethylation of dimethylglycine and it is then catabolized by further demethylation. Sarcosine is elevated in this individual's urine which suggests three possibilities. 1. Recent dietary supplementation of dimethylglycine, "DMG". 2. Deficiencies of the cofactors associated with sarcosine catabolism. These are folic acid as tetrahydrofolate, THF, and Vitamin B2, riboflavin, bound to the sarcosine dehydrogenase enzyme as FAD. The methyl group fragment removed from sarcosine is at the oxidative level of CHO and can form formaldehyde if tetrahydrofolate is insufficient. This would slow down sarcosine's catabolism while making it somewhat toxic. 3. Genetic weakness in sarcosine dehydrogenase with metabolic hypersarcosinuria and possibly hypersarcosinemia. Hereditary (severe) hypersarcosinuria is rare with an incidence of less than 1 in 4, newborns. Unpublished clinical observations associate some cases of acquired, mild sarcosinuria (below 5 micromoles/24 hour) with past exposures to organic chemical solvent and petrochemicals. At such levels sarcosine itself is not known to be toxic. However, folic acid supplementation is suggested whenever sarcosine is elevated. Citrulline, a urea cycle intermediate, is elevated. However, urea is not depressed, and amino acid elevations characteristic of ammonia excess are not presented. Therefore, a serious metabolic problem related to citrulline is very unlikely. More likely is a limitation in the cofactors associated with citrulline metabolism - ATP, aspartic acid, and magnesium. Also possible is a urinary tract infection or a contaminated urine specimen where bacterial action reduces arginine and produces citrulline.