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

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.

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.

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

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)

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.

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)

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.

investigations

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

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

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

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

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.

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.

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

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

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.

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

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.

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.

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.

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 .

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.

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

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.

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. https://www.ncbi.nlm.nih.gov/pubmed/9118832