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Amino acid disorders.

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Presentation on theme: "Amino acid disorders."— Presentation transcript:

1 Amino acid disorders


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

4 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.

5 Phenylketonuria (PKU): Clinical findings
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.


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/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

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


11 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)

12 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)

13 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.

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


16 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


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

19 Methionine metabolism

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 !!!

21 Marfan syndrom

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

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

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?


26 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

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

28 Disorders of amino acid transport

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

30 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 mg/day, sun protection


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

33 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.

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

Acute intermittent form Recurrent episodes of acidotic coma Ataxia Focal neurologic signs Chronic progressive form Failure to thrive, Anorexia Chronic vomiting Hypotonia Developmental retardation

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

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

38 Features of some organic acidemias
Izovaleric acidemia Ketoacidosis, dehydration, neutropenia, thromboscytopenia, hyperammonemia, sweety feet odor Propionic acidemia Motor-mental retardation, ketoacidosis, dehydration, neutropenia, thromboscytopenia, hyperammonemia, hipoglycemia Methylmalonic acidemia Motor-mental retardation, ketoacidosis, neutropenia, thromboscytopenia, hyperammonemia, hypoglycemia, response to vit B12 (+)

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

40 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).

41 Urea cycle defects

42 Carbaglu (+)

43 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)

44 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

45 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.

46 CPS= Karbamoil fosfat sentaz OTC= Ornitin transkarbomoilaz ASA=Arjininosüksinik asit AS=Arjininosüksinat sentaz AL=Arjininosüksinat liaz(sitrüllinemi)

47 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

48 Urea cycle defects Chronic therapy
Restriction of protein intake ( 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

49 Defects of Fatty acid oxidation

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

51 Fatty acid oxidation

52 Disorders of fatty acid oxidation
During prolonged fasting mitochonrial oxidation of fatty acids provides up to 80% of the total energy requirement.

53 Fatty acid oxidation: Etiology
Carnitine transporter deficiency Defects of carnitine cycle Carnitine palmitoyltransferase I (CPTI) deficiency Carnitine translocase deficiency Carnitine palmitoyltransferase II (CPTII) deficiency ß-oxidation defects Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency Short-chain acyl-CoA dehydrogenase (SCAD) deficiency Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency Medium-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency Short-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency

54 Fatty acid oxidation: Pathogenesis
Insufficient energy production during fasting Deficiency of mitochondrial free CoA due to accumulation of toxic intermediary products

55 Clinical findings (Reyelike syndrome)
Life-threatening hypoketotic hypoglycemic coma during catabolic states (prolonged fasting, infections, operations) Liver failure Skeletal myopathy, cardiomyopathy

56 Fatty acid oxidation: Laboratory findings
Ketones: low, ammonia: high, glucose: low to normal, liver enzymes: high Total carnitine: low (high in CPTI deficiency) Acyl carnitine/total carnitine: Low Dicarboxilic acids in urine (GS-MS) Acylcarnitine profile (Diagnostic) Enzyme studies (Fibroblasts, lymphocytes)

57 Fatty acid oxidation: therapy
Acute therapy High dose glucose (7-10 mg/kg/min), no lipids (!) Carnitine (100mg/kg): not in carnitine cylce defects, and in LCHAD deficiency Chronic therapy Avoid prolonged fasting, careful monitoring during catabolic states

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