inborn error of metabolism. inborn errors of metabolism (iem) are individually rare but collectively...
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Inborn Error of Metabolism
Inborn errors of metabolism (IEM) are individually rare but collectively numerous genetic diseases, in which specific gene mutation cause abnormal or missing proteins that lead to alter function.
Genetic Characteristics of IEM
IEM are usually Autosomal recessive. Consanguinity is always relatively common. Some are x-linked recessive condition including:
o Adrenoleukodystrophy.o Agammaglobulinemia.o Fabry’s disease.o Granulomatous disease.o Hunter’s Syndrome.o Lesch – Nyhan Syndrome.o Menke’s Syndrome.
A few inherited as autosomal dominant trait including:porphyria, hyperlipedemia, hereditary angioedema.
defective enzyme
Substrate(increased)
Product(decreased)
action
Metabolites(increased)
Co-factor A Co-factor B
otherenzymes Metabolites
(decreased)
EFFECT ON OTHER METABOLIC ACTIVITYe.g., activation, inhibition, competition
Theoretical consequences of an enzyme deficiency.
Categories of IEM
Disorders of:
•Amino acids
•Carbohydrates
•Fatty acids
•Lysosomal and peroxisomal function
•Mitochondria
•Organic acids
PROTEIN GLYCOGEN FAT
AMINO ACIDSFRUCTOSE
GALACTOSE
FREE FATTY ACIDS
AMMONIA
UREA
UREA CYCLE
ORGANIC ACIDSGLUCOSE
PYRUVATE
ACETYL CoA
KREBS CYCLE
NADH
KETONES
ATP
LACTATE
An integrated view of the metabolic pathways
Pathophysiology
Group 1. Disorders which give rise to intoxication Inborn error of intermediary metabolism, that lead to intoxication from the accumulation of toxic compounds proximal to metabolic block.Ex. IE of aminoacid catabolism Organic aicdurias Congenital urea cycle defects Metal intoxication (Wilson D., Menkes D. ) Porphyrias
Pathophysiology
Group 2. Disorders involving energy metabolism a) Mitochondrial energy defects; mostly severe and generally untreatable Ex. Congenital lactic acidemias Fatty acid oxidation defects b) Cytoplasmic energy defects; generally less severe and they partly treatable Ex. Disorders of Glycogen metabolism Disorders of Glyconeogenesis
Pathophysiology
Group 3. Disorders involving complex molecules
Almost none are treatable acutely, but enzyme replacement is now available for several disorders in this group.
Ex. Lysosomal storage disorders
Peroxisomal disorders
Signs and Symptoms of IEM
Early symptoms in the antenatal and neonatal preiod (non-specific)
Later-onset acute and recurrent attacks of symptoms such as coma, ataxia, vomiting and acidosis
Chronic and progressive generalized symptoms which can be mainly gastrointestinal, muscular or neurological Specific and permanent organ presentations suggestive
cardiomyopathy, hepatomegaly, lens dislocation etc.
Acute symptoms in neonatal period and early infancy
The neonate has a limited repertoire of responses to severe illness. IEM may present with nonspecific symptoms;Respiratory disstressHypotoniaPoor sucking reflexVomittingDiarrheaDehydratationLethargySeizures
Later onset acute and recurrent attacks
• In about 50% of the patients with IE intermediary metabolism disorders onset later. The symptom free period is often longer than one year and may extend into late childhood, adolescence or even adulthood.
• Each attack can follow a rapid course ending either in spontaneous improvement or unexplained death.
• Between attacks the patient may appear normal Coma,strokes and attacks of vomiting with lethargy
Acute psychiatric symptoms (UCD, congenital hyperammonemia)
Dehydratation
Chronic and progressive general symptoms
Gastrointestinal symptoms occur in a wide variety of IEM;
persistent anorexia, feeding difficulities
chronic vomiting, diarrhea Muscle symptoms such as severe hypotonia,
muscular weakness Neurological symptoms are very frequent in IEM;
progressive psychomotor retardation
seizures
defects of peripheral and central nervous system
psychiatric symptoms
Specific organ symptoms
A number of clinical and biological abnormalities can be associated with inherited IEM;Cardiac (cardiomyopathy, cardiac failure, arrythmias)Dermatology (alopecia, hyperkeratosis, xanthoma)Hepatic (jaundice, cirrhosis, liver failure)Ocular (cataracts, corneal opacity)Dysmorphism (coarse face)
Main Metabolic Presentations
• Metabolic acidosis
• Ketosis
• Hyperlactatemia
• Hyperammonemia
• Hypoglycemia
Metabolic acidosis
Metabolic acidosis is a very common finding in pediatrics. It can be observed in a large variety of acquired conditions, including infections, severe catabolic states, tissue anoxia, severe dehydration, and intoxication, all of which should be ruled out.
•pH <7.35
•Excess H+
•HCO3 deficit
•Calculate anion gap
– Na – (Cl + HCO3)
– Normal is 8-16meq/l
Metabolic Acidosis
• If Chloride is increased- HCO3 wasting
GI or renal disorders
• If Chloride is Normal and
Anion gap is > 16--- excess acid production
Approach is to give Na HCO3
• If unresponsive to HCO3-- IEM
Ketosis
Ketonuria should always be considered abnormal in neonates,
while it is a physiological result of catabolism in late infancy, childhood and even adolescence.
A general rule, hyperketosis at a level that produces metabolic acidosis isn’t physiological.
Hyperlactatemia
Lactate and pyruvate are normal metabolites.
Their plasma levels reflect the equilibrium between their cytoplasmic production from glycolysis and their mitochondrial consumption by different tissues.
The blood levels L/P ratio reflect redox state of the cells.
Hyperammonemia
• Normal ammonia level- < 50 umol/l
• > 200 -- IEM
• If within 24 hours of life; preterm
• After 24 hours- IEM
The differential diagnosis of hyperammonemia is wide.
In the neonatal period, the most common DD are organic acidemias (Propionic and methylmalonic).
Hypoglycemia
• Glucose level helps in the differential diagnosis
• Approach to hypoglycemia is based on four major clinical criteria;
– Liver size
– Characteristic timing of hypoglycemia
– Association with lactic acidosis
– Association with hyperketosis or hypoketosis
Approach to the patient with IEM
1. Determine if there is metabolic acidosis
2. Is anion gap >16?
3. Is there hypoglycemia?
4. Is there hyperammonemia? Within 24 hours of life
After 24 hours of life
• Metabolic acidosis + hyperammonemia
• Request for specific lab studies
• Consult metabolic specialist
• Initial therapy- stabilize patient!
• Long term treatment- based on specific IEM
Copyright ©1998 American Academy of Pediatrics
Newborn Screening for IEM
• Basic concept– Goal is to detect diagnostic markers of metabolic
disease in asymptomatic infants
– Disease should be frequent enough to have a favorable cost-benefit ratio
– Should screen for diseases we can do something for, i.e., therapy available
– Low false positive and false negative rates
Newborn Screening for IEM
First applied to the detection of phenylketonuria (PKU) by a bacterial inhibition assay in 1961 by Guthrie.
Newborn Screening In Turkey..
• PKU• Congenital hypothyroidism
Disorders of Amino Acid Metabolism
IE of Amino Acid Metabolism with Abnormal Urine Odor
IEM Urine OdorGlutaric acidemia typeII Sweaty feed
Hawkinsuria Swimming pool
Isovaleric acidemia Sweaty feed
Maple Syrup Urine Disease Maple Syrup
Hypermethioninemia Boiled cabbage
Multiple carboxylase def. Tomcat urine
PKU Mousy
Tyrosinemia Boiled cabbage
Phenylketonuria (PKU)
Autosomal recessive inherited IEM caused by mutations in the gene of phenylalanine hydroxylase (PAH) enzyme. (500 different mutations)
Defects in either phenylalanine hydroxylase PAH or the production of tetra hydrobiopterin (BH4) may result hyperphenilalaninemia. (dihydropterine reductase deficiency)
Phenylketonuria (PKU)
• Severe PAH deficiency which results in blood phenylalanine greater than 1200 after normal protein intake, is referred to as classical PKU
• Milder defects associated with levels between 600-1200 are termed hyperphenylalaninemia (HPA).
• Disorders of BH4 metabolism called malignant PKU or malignant HPA.
Clinical PresentationNewborn;
•Vomiting
•Urine odor (mouse)
Late childhood
•Severe mental retardation
•Reduced hair, skin and iris pigmentation
•Microcephaly
•Epilepsy
•Eczema
Prevalence of PKU varies between different populations: Turkey 1/4200
Finland 1/1.000.000 Consanguineous marriage Compound heterozygosity
NEWBORN SCREENING!!!
Diagnosis
• Newborn Screening : Blood PHE is normal at birth but rises rapidly within the first days of life (after feeding)
• Positive result requiring further investigation ;– Blood PHE levels >1200M Classical
PKU– 600-1200 M Hyperphenylalaninemia– <600; >5% residual PAH activity– Cofactor defects (BH4) Malignant PKU
Treatment
The principle of treatment in PKU is to reduce blood PHE concentration sufficiently to prevent the neuropathological effects.
DIET
BH4 (Tetrahydrobioptein).
L – dopa and 5-hydroxytryptophan.
Maternal PKU !!!The offspring born to mothers with PKU are at risk of damage from the teratogenic effects of PHE.High PHE in maternal blood associated with;
Facial dysmorphismMicrocephalyMental retardationDevelopmental delayCongenital heart diseases
Girls with PKU = life-long diet
Disorders of Tyrosine Metabolism
Five inherited disorders of tyrosine metabolism;
1- Tyrosinemia typeI
2-Tyrosinemia type II
3-Tyrosinemia type III
4- Alkaptonuria
5- Hawkinsuria
Alkaptonuria
First disease to be interpreted as an IEM in 1902 by Garrod.
Homogentisate dioxygenase deficiency.
Darkening of urine when exposed to air !!
Clinical symptoms first appear in adulthood.
Symptoms relate joint and connective
tissue, aortic or mitral valve
calcifications and urolithiasis.
Disorders of Methionine Metabolism
• Homosistinemia type I– Cystathione synthase deficiency leads to tissue
accumulation of methionine, homocysteine.
• Homosistinemia type II
• Homosistinemia type III
• Sistationemia
Branched-Chain Organic Acidemias / Acidurias
Result from an abnormality of specific enzymes involving the catabolisms of branched-chain amino acids (BCAA)
Maple Syrup Urine Disease (MSUD) Isovaleric Aciduria (IVA) Propionic Aciduria (PA) Methylmalonic Aciduria (MMA)
Disorders of the Urea Cycle Enzymes
Six inherited disorders of the Urea Cycle are well described;
Carbamoyl phosphate synthetase deficiency
Ornitine transcarbamoylase deficiency
Argininosuccinate synthetase deficiency
Argininosuccinate lyase deficiency
Arginase deficiency
N-acetylglutamate synthetase deficiency
All these defects are characterized by hyperamonaemia
Disorders of Carbohydrate Metabolism
1. The Glycogen Storage Disorders
2. Disorders of Galactose Metabolism
3. Disorders of the Pentose Phosphate Pathway
4. Disorders of Fructose Metabolism
5. Disorders of Glucose Transport
Glycogen Storage Disorders
The glycogen storage diseases (GSD) are caused by defects of glycogen degradation, glycolysis and paradoxically glycogen synthesis.
Glycogen is found in most tissues, but is especially abundant in liver and muscle.
Despite some overlap the GSDs can divided in 3 main groups:
1.The Liver Glycogenoses
2.The Muscle Glycogenoses
3.The Generalized Glycogenoses and Related Disorders
Deficient Enzyme Main Tissue Common Name
GSD Type I glucose-6-phosphatase Liver, kidney Von-Gierke's disease
GSD Type II Lysosomal -glucosidase General (lysosomes)
Pompe disease
GSD Type III Debranching enzyme Liver, muscle Cori's disease
GSD Type IV Branching enzyme Liver Andersen disease
GSD Type V Glycogen phosphorylase Muscle McArdle disease
GSD Type VI Glycogen phosphorylase Liver Hers' disease
GSD Type VII Phosphofructokinase Muscle, erythrocytes
Tarui's disease