1. An Approach to Inborn Errors of Metabolism
Mohamed Waheed Elsharief
And
By Dr.Ebtihal Eltyeb
MD (SMSB), Arab board
Assistant professor of pediatrics
Jazan university

2. Objectives: By the end of this lecture the student should be able to:
List the different types of IEM
Differentiate between the clinical presentations of it.
Interpret the investigations findings.
Outline management of a child with it.

3. definition
. Inborn errors of metabolism result from a genetic deficiency in a metabolic pathway; signs and symptoms result from the accumulation of metabolites related to the pathway. These metabolites may be toxic or may destroy cells because of storage in organelles.

4. 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

5. Types of inborn errors of metabolism
Defects in Metabolism of Amino Acids
Organic Acid Disorders
Defects in Metabolism of Lipids
Defects in Metabolism of Carbohydrates
Lysosomal Storage Disorders (Mucopolysaccharidoses)

6. Most of metabolic disorders inherited as autosomal recessive except few disorders.
Most inborn errors of metabolism presenting in the neonatal period are lethal if treatment is not initiated immediately.

7. clinically
History :
symptoms are usually nonspecific and similar to those seen in infants with sepsis.
Consanguineous parents
Previous unexplained neonatal deaths
Particular ethnic group (in certain diseases)

8. clinically examination: Dysmorphic faces Organomegaly
Signs of CNS involvement
Ocular involvement (e.g. cherry red spot)
Skin manifestations e.g. pigmentations.
Unusual odor. Due to change in the chemicals of the urine.

9. investigations

10. investigations
C.S.F. glycine , other amino acids , lactate. Amino acids shouldn’t be present in the CSF if its there it indicates a metabolic disorder.
Direct biochemical assays of metabolites or their metabolic by-products, or of an enzyme’s function.
DNA studies
Neuro-radiology

11. Newborn Screening
PKU - must do on all infants in NICU even if not advanced to full feeds
Galactosemia
Hypothyroidism
Hemoglobinopathies sickle cell anaemia
Biotinidase def, CAH (21-OH’ase def),
MSUD
GUTHRIE TEST: it’s a cheap test that requires only one drop of blood to check for multiple metabolic disorders

13. Treatment of the Acutely Sick Child
General Therapy
Maintain vital functions
Oxygenation
Hydration
Acid/Base balance
Glucose
Specific Therapy
Treat infection
High dose I.V. glucose
Carnitine supplementation(for elimination of Organic Acid through creation of carnitine esters).
TRY TO IDENTIFY PRIMARY METABOLIC DISORDER

14. Treatment (cont) Stop oral intake temporarily
Na benzoate/arginine/citrulline ( ttt of hyperammonemia).
Dialysis
Vitamins--often given in cocktails after labs drawn before diagnosis is known
Biotin, B6, B12, riboflavin, thiamine, folate

15. 1.Defects in Metabolism of Amino Acids
result of the inability to catabolize specific amino acids derived from protein.
Usually a single amino acid pathway is involved.
Clinically it cause toxicity to various organs, such as the brain, eye, skin, or liver.
Treatment is usually involves dietary restriction of the accumulative amino acid and supplementation with special formulas to deficient one.

16. Defects in Metabolism of Amino Acids
PHENYLKETONURIA (PKU ): Phenylalanine tyrosine Affected infants are normal at birth, but severe mental retardation (IQ 30) develops in the first year of life. The clinical syndrome classically described of blond hair, blue eyes, eczema, and mousy odor of the urine is rarely seen because of neonatal screening for PKU.

18. Other types of amino acid defects
TYROSINEMIAS
HOMOCYSTINURIA
MAPLE SYRUP URINE DISEASE
CYSTINURIA

19. Urea Cycle Defects and Hyperammonemia
All present with lethargy, seizures, ketoacidosis, neutropenia, and hyperammonemia
Ornithine carbamyl transferase (OTC) deficiency
Carbamyl phosphate synthetase deficiency
Citrullinemia
Arginosuccinic Aciduria
Argininemia
Transient tyrosinemia of prematurity

20. 2.Organic Acid Disorders
result from a metabolic block in the pathways of catabolism of amino acids.
There is accumulation of specific organic acids in the blood and urine.
Treatment is by restriction of precursor substrates and administration of enzyme cofactors when available . Also liver transplant is successful in some patients.

21. 2.Organic Acid Disorders
Some examples:
Propionic acidemia
Methylmaonic acidemia
Isovaleric acidemia
Glutaric acidemia

22. 3. Fat Metabolic Disorders
Fatty acids are derived from hydrolysis of triglycerides and catabolism of fat.
The fatty acids important in human biology range in chain length from 18 carbons to 6 carbons.
MCAD is the most common disorder.
Hypoketotic hypoglycemia is a common manifestation.

23. Fat Metabolic Disorders
Sudden infant death syndrome is common in MCAD.
Treatment consists of a high-carbohydrate diet, carnitine supplements, avoidance of fasting, and aggressive administration of dextrose during stresses.

24. 4. Carbohydrate Disorders
GLYCOGEN STORAGE DISEASES :
Glycogen is the storage form of glucose and is found most abundantly in the liver.
Usually suspected in cases with hypoglycemia and hepatomegaly.
There are 11types classified according to affection of this disorder on the liver , muscles or blood glucose.

25. Carbohydrate Disorders
nocturnal intragastric feedings of glucose during the first 1 or 2 years of life then snacks or nocturnal intragastric feedings of uncooked cornstarch may be satisfactory.
No specific treatment exists for the diseases of muscle .

26. GALACTOSEMIA
deficiency of the enzyme galactose-1-phosphate uridyl transferase.
neonate when fed milk exhibits liver failure (Hyperbilirubinemia, disorders of coagulation, and hypoglycemia), disordered renal tubular function (acidosis, glucosuria, and aminoaciduria), and cataracts.
Treatment by the elimination of dietary galactose.

27. Lysosomal Storage Disorders
Usually has late presentation
Mucopolysaccharidoses:
e.g: Hurler , Hunter, Sanfilippo…..etc
Lipidoses :
e.g: Gaucher , Niemann-Pick

29. Message to take homes IEM should be suspected in
every very sick newborn till prove other wise.
IEM is common with consanguinity
Unexplained history of neonatal deaths
The goal of management of IEM is to stabilize the infant rather to reach the final diagnosis.
newborn screening is the gold slandered way for early diagnosis of IEM but it is never cover all the metabolic disorder.

30. references Nelson essential of pediatrics 5th edition
Behrman Nelson textbook of pediatrics 17th edition.
Current essential pediatrics.
Inborn Errors of Metabolism: Robert D. Steiner, MD. OHSU.
Metabolic Disorders; Inborn Errors Of Metabolism:Dr. Abdullah Al Omair lecture.