1 / 57

Amino acid disorders

Amino acid disorders. Phenylketonuria (PKU). Enzyme defect : phenylalanine hydroxylase (12th chromosome): more than 400 mutations I ncidence : Average 1:10,000 (Highest incidence in Turkey, 1: 4,0 00). Phenylketonuria (PKU) : Variants.

urban
Download Presentation

Amino acid disorders

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Amino acid disorders

  2. Phenylketonuria (PKU) • Enzyme defect: phenylalanine hydroxylase (12th chromosome): more than 400 mutations • Incidence: Average 1:10,000 (Highest incidence in Turkey, 1: 4,000)

  3. Phenylketonuria (PKU): Variants 1. Classical phenylketonuria (complete or near complete enzyme deficiency): phenylalanine levels above 20 mg/dL (<1200 mmol/L) require diet therapy • Atypical phenylketonuria (partial enzyme deficiency):(enzyme activity %1-5) require partial diet therapy • Benign phenylketonuria. phenylalanine levels below: 10 mg/dL (<600 mmol/L) no clinical findings, not requiring diet therapy 3. Malign phenylketonuria: Tetrahydrobiopterin (BH4=cofactor of phenylalanine hydroxylase): Severe neurologic findings, does not respond diet therapy. Dopamine and setotonin may be helpful.

  4. Severe brain damage, progressive motor-mental retardation Spasticity Paralysis Convulsions Self-mutilation Light colored skin and eye (yellow hair, blue eyes; tyrosine deficiency) Mouse-like odor in urine and sweat. Phenylketonuria (PKU): Clinical findings

  5. 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)

  6. Phenylketonuria:Therapy • Phenylalanine restricted diet, supplementation of tyrosine, essential amino acids and trace elements. Goals of the therapy: • 0-10 years: phenylalanine values: 0.7-4 mg/dL • 11-16 years: phenylalanine values: <15 mg/dL • 16+ years: phenylalanine values: <20 mg/dL • Pregnant mothers with PKU: phenylalanine values < 7mg/dL Prognosis: with immediate and efficient treatment, normal development and intelligence

  7. Maternal PKU= phenylketonuric fetopathy • Normal phenylalanine levels • Microcephaly • Cardiac defects • Motor-mental retardation • No therapy

  8. Tyrosinemia Type I Enzyme defect: Fumarylacetoacetate hydroxylase Clinical findings • Acute 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)

  9. Tyrosinemia Type I: Diagnosis • High succinylacetone levels (diagnostic). tyrosine levels: normal or slightly elevated. • Methionine: high • Delta-aminolevulinic acid: high (colic) • Alfa-feto protein: very high (marker of hepatocellular carcinoma)

  10. Tyrosinemia Type I: Therapy • NTBC 1 mg/kg: blocks the accumulation of toxic metabolites (succinylacetone); beware tyrosine elevation and give tyrosine-restricted diet • If this therapy fails consider liver transplantation.

  11. Tyrosinemia Type I: Complications • Renal failure • Hepatocellular carcinoma (monitor alfa-feto protein), check periodically liver ultrasongraphy and biopsy. Prognosis: Relatively good under NTBC treatment.

  12. Tyrosinemia Type II • Enzyme defect: Cytosolic tyrosine aminotransferase • Clinical findings: Painful corneal lesions (lacrimation, photophobia, scars), mild mental retardation • Diagnosis: High tyrosine and phenylalanine levels • Therapy: Tyrosine and phenylalanine-restricted diet

  13. Alcaptonuria • Enzyme defect: Homogentisate oxygenase • Clinical findings: black discoloration in urine at acid pH; mild arthritisin adults • Diagnosis: High homogentisic acid levels in urine • Therapy: Protein-restricted diet? NTBC? • Prognosis: Relatively good without treatment

  14. Methionine metabolism

  15. CLASSICAL HOMOCYSTINURIA • Enzyme defect: Cystationine-ß-synthase • Mechanism: Accumulation of homocysteine (collagen disorder) • Clinical findings: Progressive disease, usually starting with school age. Marfan-like appearance (archnodactyly), progressive myopia (the earliest finding), lens dislocation, epilepsy, mental retardation, osteoporosis, thromboembolism !!!

  16. Marfan syndrom

  17. HOMOCYSTINURIA • Diagnosis:High methionine, high homocysteine (N: 0-3.5 µmol/L) and low cysteine levels. Positive nitroprusside test in fresh urine • Therapy: Pyridoxine (Vit. B6): 50-1000 mg/day + folic acid 10 mg/day. • If this fails diet + betaine (100 mg/kg) up to 3X3 g • Goal: Keep homocysteine <30µmol/L.

  18. MILD HYPERHOMOCYSTEINEMIACauses • Methylene tetrahydrofolate reductase (MTHFR) polymorphism, thermolabile variant, homozygosity, up to 5%in Europeans, 60% in Asiasns • Heterozygosity for cystationine-ß-synthase • Endogenous and exogenous disorders of folic acid metabolism • Vitamin B12 deficiency

  19. MILD HYPERHOMOCYSTEINEMIA Clinical findings: • Premature vascular disease in the 3rd and 4th decade (infarctions, thrombosis embolies) Maternal hyperhomocysteinemia: congenital defects • Neural tube defects • Cardiac output defects • Renal defects • Pyloric stenosis?

  20. Maple syrup urine disease Enzyme: Branched-chain alfa-ketoacid dehydrogenase complex Incidence: 1:200,000, autosomal recessive Clinical findings • Severe form: Progressive encephalopathy, cerebral edema, lethargy, coma after the 3rd day of life, “çemen” odor in urine and sweat • Mild form: Developmental retardation, recurrent ketoacidotic decompensation

  21. 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 + insulin • Chronic: Diet (monitor leucine level) ± vitamin B1 (thiamin): 5 mg/kg/day

  22. Disorders of amino acid transport

  23. Methionine Malabsorption • Methionine malabsorption in renal tubules and intestines. • Clinical findings: White hair, convulsions,, diarrhea, edema , mental retardation, odor (like beer). • Therapy: Diet deficient inmethionine.

  24. HARTNUP DISEASE • Defect: Intestinal and renal tubular reabsorption defect of the neutral amino acids (alanine, valine, threonine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, histidine, glycine; tryptophan deficiency leads nicotinic acid and serotonine deficiency. • Clinical finding: Photodermatitis, cerebellar ataxia; often asymptomatic • Diagnosis: High levels of neutral amino acids in urine low levels of neutral amino acids in plasma. • Therapy: Nicotinamide 40-300 mg/day, sun protection

  25. 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 deficiency • Clinical findings: Intestinal protein intolerance, failure to thrive, osteoporosis, and hyperammonemia with progressive encephalopathy • Diagnosis: Hyperammonemia, low lysine, arginine and ornithine in plasma, high LDH levels. • Therapy: Citrulline substitution, protein restriction

  26. CYSTINURIA • Defect: 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.

  27. ORGANIC ACIDEMIAS Pahogenesis • Mitochondrial accumulation of related CoA-metabolites Clinical findings Acute neonatal form • Lethargy * Coma • Feeding problems * Hypotonia/hypertonia • Myoclonic jerks * Cerebral edema • Dehydration * Unusual odor

  28. ORGANIC ACIDEMIAS: Forms Acute intermittent form • Recurrent episodes of acidotic coma • Ataxia • Focal neurologic signs Chronic progressive form • Failure to thrive, Anorexia • Chronic vomiting • Hypotonia • Developmental retardation

  29. ORGANIC ACIDEMIAS Laboratory findings • Acidosis (increased anion gap) • Hyperammonemia • Hyperlactatemia Diagnosis • Organic acids in urine (GC-MS) • Enzyme and DNA studies

  30. ORGANIC ACIDEMIAS:Therapy Acute • Remove toxins: dialysis, hemofiltration and exchange transfusion • Interrupt catabolic state • Stop protein intake • Give carnitine (100-300 mg/kg) Long term • Protein restricted diet (special formulas if available) • Carnitine • Vitamins (Vit. B12, Vit. B1, Vit. B2, biotin)

  31. Features of some organic acidemias

  32. Biotinidase deficiency Biotin (complex) Biotinidase Biotin (free) piruvate carboxylase asetyl CoA carboxylase propionyl CoA carboxylase beta-methylcrotonyl CoA carboxylase

  33. Biotinidase deficiency Incidense World. 1:60,000 Turkey: 1:10,000 Clinical and laboratory findings • Severe metabolic acidosis • Alopecia • Seborrheic skin eruptions • Refractory convulsions Therapy 5-10 mg/day biotin (life long).

  34. Urea cycle defects

  35. Carbaglu (+)

  36. Urea cycle defects Incidence: 1:10,000 (cumulative) Genetics • Ornitine transcarbabamylase deficiency (most common urea cycle defect, X-linked) • Argininosuccinate synthase deficiency (citrullinemia, (the second most common urea cycle defect, OR) • Carbamylphosphate synthase I deficiency (OR) • Argininosuccinate lyase deficiency (argininosuccinic aciduria, OR) • Arginase deficiency (argininemia, OR)

  37. Urea cycle defects: Clinical findings Main symptom (acute/or chronic encephalopathy) is related to high protein intake, increased catabolism, infections or stress Neonates: * Poor feeding * Temperature lability * Lethargy * Hyperventilation (respiratory alkalosis) * Loss of reflexes * Intracranial hemorrhages * Seizures * Progressive encephalopathy Infants and children * Failure to thrive * Episodic encephalopathy * Feeding problems * Ataxia * Nausea, vomiting * Convulsions Adolescents and adults * Chronic neurologic symptoms * Episodic encephalopathy * Chronic psychiatric symptoms *Behavioral problems

  38. Urea cycle defects Laboratory findings • Hyperammonemia (generally >400 µmol/L in urea cycle defects) • Amino acids in serum • Organic acids in urine Differential diagnosis • Organic acidurias: • Liver diseases: neonatal hepatitis, galactosemia, tyrosinemia,respiratory chain defects • Transient hyperammonemia of newborn due to patent ductus venosus.

  39. CPS= Karbamoil fosfat sentaz OTC= Ornitin transkarbomoilaz ASA=Arjininosüksinik asit AS=Arjininosüksinat sentazAL=Arjininosüksinat liaz(sitrüllinemi)

  40. Urea cycle defects: Acute therapy • Stop protein intake • Interrupt 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/day • Give sodium phenylbutyrate 250mg/kg/day • Aim for an ammonia concentration < 200µmol/L

  41. Urea cycle defects Chronic therapy • Restriction of protein intake (1.0-1.5 g/kg/day) +arginine + • sodium benzoate + sodium –phenylbutyrate Prognosis • Poor if there is prolonged coma (>3 days), and symptoms and signs of increased intracranial pressure

  42. Defects of Fatty acid oxidation

  43. Fatty acid (plasma) Carnitine Carnitine enzymes Fatty acid (mitochondria) • Beta-oxidation • (acyl CoA dehydrogenases) 3-ketothiolase (tioforase) • Asetil CoA Keton bodies Krebs cycle HMG CoA- liase HMG CoA- synthase 131 ATP Fatty acidoxidation

More Related