7 Phenylketonuria: Diagnosis High phenylalanine (N: <2mg/dL) and low tyrosine (N: <2mg/dL) levels,Ferric chloride test gives green color in urine (not reliable).Neonatal screening: Guthrie-card (taken between 3rd and 7th days of life)
8 Phenylketonuria:Therapy Phenylalanine restricted diet, supplementation of tyrosine, essential amino acids and trace elements.Goals of the therapy:0-10 years: phenylalanine values: mg/dL11-16 years: phenylalanine values: <15 mg/dL16+ years: phenylalanine values: <20 mg/dLPregnant mothers with PKU: phenylalanine values < 7mg/dLPrognosis: with immediate and efficient treatment, normal development and intelligence
11 Tyrosinemia Type I Enzyme defect: Fumarylacetoacetate hydroxylase Clinical findingsAcute infantile form: Severe liver failure, vomiting, bleeds, sepsis, hypoglycemia, renal tubulopathy (Fanconi syndrome)Chronic form: Hepatomegaly, cirrhosis, growth retardation, rickets, hematoma, tubulopathy, neuropathy, and abdominal pain (due to porphyrines)
12 Tyrosinemia Type I: Diagnosis High succinylacetone levels (diagnostic). tyrosine levels: normal or slightly elevated.Methionine: highDelta-aminolevulinic acid: high (colic)Alfa-feto protein: very high (marker of hepatocellular carcinoma)
13 Tyrosinemia Type I: Therapy NTBC 1 mg/kg: blocks the accumulation of toxic metabolites (succinylacetone); beware tyrosine elevation and give tyrosine-restricted dietIf this therapy fails consider liver transplantation.
14 Tyrosinemia Type I: Complications Renal failureHepatocellular carcinoma (monitor alfa-feto protein), check periodically liver ultrasongraphy and biopsy.Prognosis: Relatively good under NTBC treatment.
18 Alcaptonuria Enzyme defect: Homogentisate oxygenase Clinical findings: black discoloration in urine at acid pH; mild arthritis in adultsDiagnosis: High homogentisic acid levels in urineTherapy: Protein-restricted diet? NTBC?Prognosis: Relatively good without treatment
22 HOMOCYSTINURIADiagnosis: High methionine, high homocysteine (N: µmol/L) and low cysteine levels. Positive nitroprusside test in fresh urineTherapy: Pyridoxine (Vit. B6): mg/day + folic acid 10 mg/day.If this fails diet + betaine (100 mg/kg) up to 3X3 gGoal: Keep homocysteine <30µmol/L.
23 MILD HYPERHOMOCYSTEINEMIA Causes Methylene tetrahydrofolate reductase (MTHFR) polymorphism, thermolabile variant, homozygosity, up to 5% in Europeans, 60% in AsiasnsHeterozygosity for cystationine-ß-synthaseEndogenous and exogenous disorders of folic acid metabolismVitamin B12 deficiency
24 MILD HYPERHOMOCYSTEINEMIA Clinical findings:Premature vascular disease in the 3rd and 4th decade (infarctions, thrombosis embolies)Maternal hyperhomocysteinemia: congenital defectsNeural tube defectsCardiac output defectsRenal defectsPyloric stenosis?
26 Maple syrup urine disease Enzyme: Branched-chain alfa-ketoacid dehydrogenase complexIncidence: 1:200,000, autosomal recessiveClinical findingsSevere form: Progressive encephalopathy, cerebral edema, lethargy, coma after the 3rd day of life, “çemen” odor in urine and sweatMild form: Developmental retardation, recurrent ketoacidotic decompensation
27 Diagnosis:“Çemen” odor in urine and sweat, positive DNPH test in urine (non-spesific),Aminoacid analysis: high valine, leucine, isoleucine and alloisoleucine (diagnostic) levels.Therapy:Acute: Detoxification (dialysis, exchange transfusion)Augmentation of anabolism : Glucose + insulinChronic: Diet (monitor leucine level) ± vitamin B1 (thiamin): 5 mg/kg/day
32 LYSINURIC PROTEIN INTOLERANCE Defect: Intestinal and renal tubular reabsorption defect of the dibasic amino acids (lysine, arginine and ornithine) lead blockage of urea cycle; lysine deficiencyClinical findings: Intestinal protein intolerance, failure to thrive, osteoporosis, and hyperammonemia with progressive encephalopathyDiagnosis: Hyperammonemia, low lysine, arginine and ornithine in plasma, high LDH levels.Therapy: Citrulline substitution, protein restriction
33 CYSTINURIADefect: Renal tubular reabsorption defect of the dibasic amino acids (lysine, arginine, ornithine and cystine)Clinical findings: Neprolithiasis (cystine crystallizes above 1250 µmol/L at pH 7.5)Diagnosis: Positive nitroprusside test in urine, increased levels of acids lysine, arginine, ornithine and cystine in urine, plasma levels are generally normal.Therapy: High (>5L) fluid intake, alkalisation of the urine (urinary infections!). Consider penisillamine (1-2 g/day), mercaptopropionylglycine or captopril in selected cases.
47 Urea cycle defects: Acute therapy Stop protein intakeInterrupt catabolic state by high calorie infusion (carbohydrate + lipid)Remove ammonia when >400 µmol/L by hemodiafiltration, hemofiltration, or hemodialysis, (periton dialysis is not effective)Give arginine 350 mg/kg in order to support urea cycle.Give sodium benzoate: 350mg/kg/dayGive sodium phenylbutyrate 250mg/kg/dayAim for an ammonia concentration < 200µmol/L
48 Urea cycle defects Chronic therapy Restriction of protein intake ( g/kg/day) +arginine +sodium benzoate + sodium –phenylbutyratePrognosisPoor if there is prolonged coma (>3 days), and symptoms and signs of increased intracranial pressure
57 Fatty acid oxidation: therapy Acute therapyHigh dose glucose (7-10 mg/kg/min), no lipids (!)Carnitine (100mg/kg): not in carnitine cylce defects, and in LCHAD deficiencyChronic therapyAvoid prolonged fasting, careful monitoring during catabolic states