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Metabolism I
PATHOPHYSIOLOGIC
CLASSIFICATION OF INBORN
METABOLIC DISEASES
Inborn errors of metabolism
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The diseases are rare individually, but they collectively contribute
significantly to mortality and morbidity (up to 1-2% of population).
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A positive family history of unexplained child death could be obtained
in most of the cases.
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Early diagnosis and treatment are essential for normal long-term
neurologic development.
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Considerable amount of metabolic diseases could be treated
effectively.
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Early diagnosis requires that the possibility of metabolic disease to
be considered in every sick neonate or motor-mental retarded child.
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A positive family history of unexplained child death could be obtained
in most of the cases.
Urine and/or body odor
Odor
Substace
Disease
Mouse
Maple syrup
Sweaty feet
Phenylacetate
Sotolone
Isovaleric acid
Cat urine
Cabbage
Rancid butter
ß-OH isovaleric acid
2-OH butyric acid
2-keto-4-methiolbutyrate
Acidic
Rotten fish
Methylmalonic acid
Trimethyamine
Dimethyglycine
Sulphur
Hydrogen sulphate
Phenylketonuria (PKU)
Maple syrup urine disease (MSUD)
Isovaleric aciduria
Glutaric aciduria
ß-methylcrotonylglycinuria
Multiple carboxylase def.
Tyrosinemia type I
Methionine malabsorption
Tyrosinemia type I
Methylmalonic aciduria
Trimethyaminuria
Dimethyglycinuria
Cystinuria
Urine color
Color
Substace
Disorder
Blue
Indigo
Hartnup disease
Blue-brown
or black
Homogentisic acid Alkaptonuria
Brown
Methemoglobin
Myoglobinuria
Red-brown
Hemoglobin
Hemoglobinuria
Urine
• Ferric chloride test (phenylalanine, tyrosine, homogentisic acid,
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histidine, aspirin)
• Ketone
• Reducing substances (glucose, fructose, galactose, homogentisic acid)
• Ketoacids (DNPH)
• Sulfites (cyanide-nitroprusside test)
• Heparan and dermatan sulphate (CTAB test)
• pH, sediment (crystals), uric acid
Blood
• Complete blood count, glucose, blood gases
• Electrolytes, ammonia, uric acid
• Beta-hydroxybutyric acid, acetoacetic acid, lactic acid, pyruvic acid
DIFFERENTIAL DIAGNOSIS OF
NEONATAL METABOLIC DISEASES
• Sepsis
• Central nervous system diseases
• Cardiopulmonary diseases
• Perinatal asphxy (hypoxic ischemic
encephalopathy)
• Gastrointestinal tract obstruction
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Specific tests
- Amino acid chromatography (urine, serum)
- Oligosaccharide chromatography (urine, serum)
- Mucopolysaccharide electrophoresis (urine)
- Amino acids (quantitative)
- Organic acids (gas chromatography-mass spectrophotometry)
- Carnitine (plasma, urine, total, free)
- Free fatty acids, very long chained fatty acids
- Orotic acid (urine)
- Galactose-1-phosphate uridyl transferase (Beutler test)
• Tissue enzymes,
• DNA investigations (leukocytes, liver, fibroblasts)
SIGNS AND SYMPTOMS OF
NEONATAL METABOLIC DISEASE
Central nervous system
• Poor suck
• Lethargy
• Irritability
• Hypo-or hypertonia
• Seizures
• Coma
Gastrointestinal tract
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Poor feeding
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Vomiting
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Diarrhea
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Abdominal distention
Cardiopulmonary system
• Apnea
• Tachypnea (compensation of
metabolic acidosis)
• Respiratory distress
Miscellaneous
• Abnormal skin or urine odor
• Cataracts
• Dysmorphic facies
I. Intoxication type small
diffusible molecule disease
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Results from an acute or progressive intoxication from
accumulation of toxic compounds proximal to the
metabolic block.
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Aminoacidopathies (phenylketonuria, MSUD,
homocystinuria, tyrosinemia)
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Organic acidopathies (pyruvic, isovaleric,
methylmalonic acidemias)
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Urea cycle defects (OTC deficiency, sitrullinemia etc)
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Sugar intolerances (galactosemia, fructosemia etc)
I. Intoxication type small diffusible molecule
disease/Clinical presentation
• There is a symptom free interval ranging
from one day to several weeks or months. It
depends on the residual enzyme activity,
situations of increased catabolism (infections,
stresses, operations, increased intake of
proteins, stopping breast-feeding)
• Clinical signs and symptoms may be earlyonset acute (neonatal), late-onset
acute/recurrent, or chronic progressive.
• Diagnosis
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Diagnosis is generally easy and relies
mostly on amino acid and organic acid
analyses.
• Treatment
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Treatment requires removal of the
toxins by special diets, dialysis, drug
and megavitamin therapy.
Energy-deficient type small
diffusible molecule disease
This group of diseases consists of intermediary
metabolism with symptoms due at least partly to a
deficiency in energy production or utilization
resulting from a defect in liver myocardium, muscle
or brain.
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Gluconeogenesis defects (G-6-Pase, PC, F-1, 6-diP,
PEP carboxykinase)
Glycogenolysis defects (GSD III, GSD V, and GSD
VI)
Glycogenesis defects (GSD 0, GSD IV)
Lactic acidemias (PDH deficiency, electron
transport chain diseases)
Fatty acid oxidation defects (carnitine, MCAD,
SCAD)
Energy-deficient type small diffusible
molecule disease / Clinical presentation
• Hypotonia, myopathy, cardiomyopathy,
failure to thrive, malformations, sudden
infant death syndrome, hypoglycemia,
hyperlactatemia
III. Diseases that disturb the synthesis
or the catabolism of complex molecules
• Lysosomal diseases (Tay-Sachs, Gaucher, Neimann-Pick etc)
• Peroxisomal diseases (Zellweger, Refsum, adrenolekodystrophy)
• Synthesis defects (alpha-1-antitrypsin deficiency, carbohydrate
deficient glycoprotein syndrome)
• Clinical presentation: Chronic progressive mental-motor
retardation
• Diagnosis: Enzyme and DNA studies
• Therapy: Enzyme therapy (İf available)
Treatment-General principles
1. Removal of toxic metabolites
a. Mechanical removal: (hemodialysis, peritoneal dialysis, hemofiltration
and exchange transfusion).
b. Diet therapy
c. Drug therapy: carnitine, sodium benzoate, phenylacetic acid, NTBC
2. Addition of deficient product: glucose, arginine
3. Augmentation of residual enzyme activity (megavitamin therapy)
4. Enzyme therapy (Gaucher disease, MPS I, MPS II, MPS VI, alfa-1antitripsin deficiency, ADA deficiency)
5. Correction of defective gene
a. Organ, tissue or bone-marrow transplantation
b. Somatic gene therapy (ADA deficiency)
EMERGENCY TREATMENT
1. Stop protein intake
2. Interrupt catabolic state
High dose energy substitution: IV 10-20 % glucose (10 mg/kg/min)
(Check lactic acid and limit glucose intake when PDH deficiency
suspected)
b. 10-20% intralipid solutions (exclude ß-oxidation defects)
3. Ensure adequate intake of fluid (150mL/kg/day) and electrolyte
(0.2% Na Cl): Aim for a sodium concentration ≥140 mEq/L to reduce
the risk of cerebral edema
4. Correct acidosis: Aim for a bicarbonate concentration ≥18 mEq/L
5. Removal of toxic metabolites
a.
Mechanical removal: (hemodialysis, peritoneal dialysis,
hemofiltration and exchange transfusion).
b.
Carnitine: 50-100 g/kg/day