 Recognize IEM in a neonate with non- specific signs and symptoms  Make use of simple lab tests in the diagnosis of IEM  Initial management of life threatening conditions associated with IEM

3 An inherited enzyme deficiency leading to the disruption of normal body metabolism  Accumulation of a toxic substrate (compound acted upon by an enzyme in a chemical reaction)  Impaired formation of a product normally produced by the deficient enzyme

4  Affects amino acid & protein, carbohydrate, and lipid metabolism.  Most disorders are autosomal recessive in transmission  Most disorders are evident at or soon after birth.  Early detection and treatment are essential to the prevention of irreversible cognitive impairment and early death

5 substrate excess toxic metabolite A D B C product deficiency

 Disorders of:  Amino acids  Carbohydrates  Fatty acid  Lysosomal and peroxisomal function  Mitochondrial  Organic acids

Metabolic Diseases Can Grouped as  Defects of Carbohydrates-Glycogen storage disease(GSD), Galactosemia,  Defects of amino acids-Phenylketonuria(PKU), Alkaptonuria,Urea cycle defects(UCDs).  Organic acidemias-isovaleric acidemia, propoinic acidemia(PPA), methylmalonic acidemia(MMA), maple syrup urine disease(MSUD).

 Defects of lipids-Mitochondrial fatty acid oxidation defects, peroxisomal disorders,lysosomal disorders,mucopolysaccharidoses.  Defects of purines and pyrimidines-Lesh-nyhan syndrome  Miscellaneous –wilson disease,alpha-1-anti trypsin deficiency.

 Diagnosis/ Newborn Screening ◦ Nonselective screening – screening all newborns for a limited number of common inborn errors ◦ Selective – testing of an individual known to be at increased risk (e.g. sibling) ◦ Tandem mass spectroscopy – allows clinicians to screen for > 30 disorders

 Clinical manifestations ◦ Usually appear 24 hours or more after birth, attributed to ingestion of precursor substrate of defective enzyme ◦ CNS symptoms, poor growth, failure to thrive, developmental delays, specific neurological deficits ◦ May have blatant signs (i.e. unusual odor)

 Lens dislocation : Sulfite oxidase deficiency

Skin changes : Biotinidase deficiency

 Peroxisomal disorders : Zellweger syndrome  Large fontanelle  prominent forehead  flat nasal bridge  epicanthal folds  hypoplastic supraorbital ridges

 Pyruvate dehydrogenase deficiency  Epicanthal folds  flat nasal bridge  small nose with anteverted flared alae nasi  long philtrum

 Glutaric aciduria type II  Macrocephaly  high forehead  flat nasal bridge  short anteverted nose  ear anomalies  hypospadias  rocker-bottom feet

 Cholesterol biosynthetic defects  Smith-Lemli-Opitz syndrome:  Epicanthal folds, flat nasal bridge, toe 2/3 syndactyly, genital abnormalities, cataracts

 Congenital disorders of glycosylation: Inverted nipples, lipodystrophy  Lysosomal storage disorders: Hurler-like phenotype

 Clinical manifestations – diagnosis ◦ Laboratory studies ◦ Routine  Hypoglycemia, acid-base balance, hyperammonemia, ketosis ◦ Specialized studies  Require special lab  Directed analysis for amino acids or organic acids

© 2007 Thomson - Wadsworth

 Approaches to Treatment  In most cases, treatment needs to be instituted empirically without a specific diagnosis.  The metabolic screen helps to broadly categorize the patient’s IEM (e.g. urea cycle defect, organic academia, congenital lactic acidosis etc), on the basis of which, empirical treatment can be instituted

 Aims of treatment  1. To reduce the formation of toxic metabolites by decreasing substrate availability (by stopping feeds and preventing endogenous catabolism)  2. To provide adequate calories.  3. To enhance the excretion of toxic metabolites.  4. To institute co-factor therapy for specific disease and also empirically if diagnosis not established.  5. Supportive care- -Treatment of seizures (avoid sodium valproate – may increase ammonia levels), -Maintain euglycemia and normothermia, -Fluid, electrolyte & acid-base balance, -Treatment of infection, -Mechanical ventilation if required.

 Management of hyperammonemia:  1) Discontinue all feeds. Provide adequate calories by intravenous glucose and lipids. Maintain glucose infusion rate 8- 10mg/kg/min. Start intravenous lipid 0.5 g/kg/day (up to 3 g/kg/day). After stabilization gradually add protein 0.25 g/kg till 1.5 g/kg/day.  2) Dialysis is the only means for rapid removal of ammonia, and hemodialysis is more effective and faster than peritoneal dialysis. Exchange transfusion is not useful.

 3) Alternative pathways for nitrogen excretion-: -Sodium benzoate. -Sodium phenylbutyrate -L-arginine (oral or IV) -L-carnitine (oral or IV)  4) Supportive care: Treatment of sepsis,seizures,ventilation.

 1. Determine if there is metabolic acidosis  2. Is anion gap >16?  3. Is there hypoglycemia?  4. Is there hyperammonemia? ◦ Within 24 HOL? ◦ After 24 HOL?

Copyright ©1998 American Academy of Pediatrics

 Healthy NB  rapidly ill, ◦ Ketoacidosis, poor feeding  Vomiting, dehydration  Hypotonia, lethargy  Tachypnea, seizures  Coma, unusual odors Organic acidemia

 Labs:  Urine organic acids  Ketonuria (in the NB)- pathognomonic of IEM  Neutropenia, thrombocytopenia  +/- hyperammonemia  Abnormal acylcarnitine

 Treatment:  Stabilize  Get rid of organic acid intermediates, and ammonia-  hemodialysis  Carnitine  After stabilization, may resume oral feeds  Consult dietitian, and metabolic specialist

 No acidosis (respiratory alkalosis)  No ketones (unlike organic acidemia)  No hypoglycemia  But with hyperammonemia

 Treatment:  Remove ammonia  Hydration with D10 + electrolytes  D/C all protein x 24 hours—calories from CHO and fat  Na phenylacetate/Na benzoate  Give arginine  Protein restriction for life

 Prognosis: guarded  Even with Treatment, many will die  Definitive treatment: liver transplant

 An inborn error of carbohydrate metabolism in which the hepatic enzyme (galactose-1-phosphate uridyl transferase), GALK1 or GALE, which normally converts galactose into glucose is absent.  Autosomal recessive pattern  Incidence It occurs in approximately 1 out of every 60,000

 Galactose-1 phosphate uridyl transferase deficiency (classic galactosemia, the most common and most severe form)- (GALT) Type I  Deficiency of galactose kinase – (GALK1)Type II  Deficiency of galactose-6-phosphate –epimerase (GALE)-Type III

 Jaundice, vomiting  poor feeding  infections  Failure to thrive  hepatomegaly  Speech disabilities,  mental retardation

Galactosemia clinical pictures

 Mild  Cataract in the infant

 The only way to treat galactosemia is through dietary restrictions  from the first days of life  No brest feeding  Soya- based formula The newborn with questionable results on newborn screening should continue to be treated with soy- based formula pending definitive results of confirmatory testing.

 Why? If unscreened and untreated, galactosemia is a life-threatening disorder.  When? Neonatal period: 4 th day  How? Screening of every neonates, followed by confirming tests. Thereby, affected infants are treated before they become ill.

 Phenylketonuria is a genetic disorder where the body’s enzyme, phenylalanine hydroxylase,is missing or malfunctioning so that it cannot properly break down the amino acid, phenylalanine.

 Mental Retardation  Seizures  Microcephaly (small head size)  Skin rashes  Stunted growth  Hyperactivity  “Musty or mousy” body odor from the excess phenylalanline  Fair skin, hair, and eyes (phenylalanine is linked to melanin production)

 PKU is usually diagnosed after birth with a blood test taken from the infant’s heel or the crook of their arm. ◦ If there are abnormal amounts of phe, then further tests (blood and urine) are taken to ensure that the child has PKU.  Another option of diagnosis is through the chorionic villus sampling (CVS) process.

Treatment Once diagnosed, babies are fed diets containing protein without phenylalanine for the first 7-10 days. Special infant formula called Lofenalac Recently, there’s been a special medical (pill) formula discovered for PKU patients called Kuvan. It’s possible to have a wide range of PKU, from mild to severe, but it’s suggested to stick to a diet regiment for life.

 There’s usually a general list of foods that should not be consumed for PKU patients like: ◦ Dairy  Milk, eggs, Cheese ◦ Nuts ◦ Beans ◦ Peas ◦ Meat (Poultry, beef, pork, duck etc.) ◦ Chocolate ◦ the sweetener aspartame can act as poisons for people with phenylketonuria

Prevention:  Unfortunately, if PKU is already diagnosed in an infant, there are no preventive measures one can take for their child to not have PKU.  If a pregnant individual has PKU, then she’s able to prevent her child from PKU symptoms if she follows a diet low in protein.

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51  Inherited as an autosomal recessive trait  caused by mutations in the IDU Agene (4p16.3)  Metabolic defect: inability ◦ The body's to make an enzyme:  lysosomal alpha-L-iduronase

52  Approximately 1 in 150,000 infants are affected  Newborn infants with this defect appear normal at birth  By the end of the first year, signs of impending problems begin to develop

© 2007 Thomson - Wadsworth

 Coarse facial features (86.4%)  Corneal clouding (70.9%)  Heaptomegaly (70.0%)  Kyphosis/gibbus (70.0%)  Hernias (58.9%)  Airway-related symptoms, such as sleep disturbances/snoring (51.6%)  Splenomegaly (50.9%)  Cardiac valve abnormalities (48.9%)  Cognitive impairment (46.4%)  Dystosis multiplex (43.6%) © 2007 Thomson - Wadsworth

56 Hurler syndrome (type I)

57 Key Symptom Images Claw hand Coarse facial features Corneal clouding Hernia Mucopolysaccharidosis I (MPS I) Disease (Hurler, Hurler-Scheie, Scheie Syndromes)

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60  X-linked  Coarse, thick, facial features  Progressive stiffness  decreased mental development  Hepatomegaly  Splenomegaly  Abnormal bone x-rays