1. Inborn Error of Metabolism

2. 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.

3. Genetic Characteristics of IEM
IEM are usually Autosomal recessive.
Consanguinity is always relatively common.
Some are x-linked recessive condition including:
Adrenoleukodystrophy.
Agammaglobulinemia.
Fabry’s disease.
Granulomatous disease.
Hunter’s Syndrome.
Lesch – Nyhan Syndrome.
Menke’s Syndrome.
A few inherited as autosomal dominant trait including:
porphyria, hyperlipedemia, hereditary angioedema.

4. Theoretical consequences of an enzyme deficiency.
defective enzyme
Substrate
(increased)
Product
(decreased)
action
Co-factor B
Co-factor A
other
enzymes
Metabolites
(decreased)
Metabolites
(increased)
EFFECT ON OTHER METABOLIC ACTIVITY
e.g., activation, inhibition, competition

5. Categories of IEM Disorders of: Amino acids Carbohydrates Fatty acids
Lysosomal and peroxisomal function
Mitochondria
Organic acids

6. An integrated view of the metabolic pathways
GLYCOGEN
FAT
PROTEIN
FRUCTOSE
GALACTOSE
AMINO ACIDS
GLUCOSE
FREE FATTY ACIDS
ORGANIC ACIDS
AMMONIA
PYRUVATE
LACTATE
ACETYL CoA
UREA CYCLE
KETONES
UREA
KREBS CYCLE
NADH
ATP
An integrated view of the metabolic pathways

7. 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

8. 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

9. 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

11. 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.

12. 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 disstress
Hypotonia
Poor sucking reflex
Vomitting
Diarrhea
Dehydratation
Lethargy
Seizures

13. 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

14. 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

15. 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)

16. Main Metabolic Presentations
Metabolic acidosis
Ketosis
Hyperlactatemia
Hyperammonemia
Hypoglycemia

17. 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

18. 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

19. 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.

20. 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.

21. 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).

22. 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

23. 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

24. Metabolic acidosis + hyperammonemia
Request for specific lab studies
Consult metabolic specialist
Initial therapy- stabilize patient!
Long term treatment- based on specific IEM

25. Copyright ©1998 American Academy of Pediatrics

27. 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

28. Newborn Screening for IEM
First applied to the detection of phenylketonuria (PKU) by a bacterial inhibition assay in 1961 by Guthrie.

29. Newborn Screening In Turkey..
PKU
Congenital hypothyroidism

30. Disorders of Amino Acid Metabolism

31. IE of Amino Acid Metabolism with Abnormal Urine Odor
IEM Urine Odor
Glutaric 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

32. 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)

33. Phenylketonuria (PKU)
Severe PAH deficiency which results in blood phenylalanine greater than 1200 mM after normal protein intake, is referred to as classical PKU
Milder defects associated with levels between mM are termed hyperphenylalaninemia (HPA).
Disorders of BH4 metabolism called malignant PKU or malignant HPA.

36. Clinical Presentation
Newborn;
Vomiting
Urine odor (mouse)
Late childhood
Severe mental retardation
Reduced hair, skin and iris pigmentation
Microcephaly
Epilepsy
Eczema

37. Prevalence of PKU varies between different populations: Turkey 1/4200
Finland 1/
Consanguineous marriage
Compound heterozygosity
NEWBORN SCREENING!!!

38. 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 >1200mM Classical PKU
mM Hyperphenylalaninemia
<600mM; >5% residual PAH activity
Cofactor defects (BH4) Malignant PKU

39. 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.

40. 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 dysmorphism
Microcephaly
Mental retardation
Developmental delay
Congenital heart diseases
Girls with PKU = life-long diet

41. 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

42. 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.

43. Disorders of Methionine Metabolism
Homosistinemia type I
Cystathione b-synthase deficiency leads to tissue accumulation of methionine, homocysteine.
Homosistinemia type II
Homosistinemia type III
Sistationemia

44. 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)

45. 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

46. Disorders of Carbohydrate Metabolism

47. The Glycogen Storage Disorders
Disorders of Galactose Metabolism
Disorders of the Pentose Phosphate Pathway
Disorders of Fructose Metabolism
Disorders of Glucose Transport

48. 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:
The Liver Glycogenoses
The Muscle Glycogenoses
The Generalized Glycogenoses and Related Disorders

49. Deficient Enzyme
Main Tissue
Common Name
GSD Type I
glucose-6-phosphatase
Liver, kidney
Von-Gierke's disease
GSD Type II
Lysosomal a-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
Hers' disease
GSD Type VII
Phosphofructokinase
Muscle, erythrocytes
Tarui's disease