DR.AHMED HOZAYEN

INBORN ERRORS OF

METABOLISM

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

Objectives

Inborn Errors of Metabolism

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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

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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

What is a metabolic disease?

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substrate excess

toxic metabolite

A

D

B C product deficiency

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

Categories of IEM

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)

Abnormal urine odor

Lens dislocation : Sulfite oxidase deficiency

Miscellaneous

Skin changes : Biotinidase deficiency

Peroxisomal disorders : Zellweger syndromeLarge fontanelle prominent forehead flat nasal bridge epicanthal folds hypoplastic supraorbital

ridges

Dysmorphic Features

Pyruvate dehydrogenase deficiencyEpicanthal folds flat nasal bridge small nose with

anteverted flared alae nasi

long philtrum

Dysmorphic Features

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

Dysmorphic Features

Cholesterol biosynthetic defects Smith-Lemli-Opitz

syndrome: Epicanthal folds, flat nasal

bridge, toe 2/3 syndactyly, genital abnormalities, cataracts

Dysmorphic Features

Congenital disorders of glycosylation: Inverted nipples, lipodystrophy

Lysosomal storage disorders: Hurler-like phenotype

Dysmorphic Features

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

Organic acidemia

Treatment: Stabilize Get rid of organic acid intermediates, and

ammonia- hemodialysis Carnitine After stabilization, may resume oral feeds Consult dietitian, and metabolic specialist

Organic acidemia

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

Urea cycle disorder

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

Urea cycle disorder

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

Urea cycle disorder

Galactocemia

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

Dietary Lactose Galactose Galactose 1-Phosphate Glucose

BRAINMental retardation

LIVER Jaundice Hetaptomegaly Cirrhosis

EYEScataracts

Galactocemia: How does it happen?

Three forms of galactosemia

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

Classic galactosemia – type I

Galactosemia clinical pictures

Clinical pictures of Galactosemia Type II

Mild Cataract in the

infant

How is treated galactosemia?

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.

Galactosemia screening Why? If unscreened and untreated,

galactosemia is a life-threatening disorder. When? Neonatal period: 4th day

How? Screening of every neonates, followed by confirming tests. Thereby, affected infants are treated before they become ill.

Phenylketonuria (PKU)

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)

Symptoms

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 & Prevention

TreatmentOnce 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.

Treatment & Prevention

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

Treatment & Prevention

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.

Treatment & Prevention

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Hurler syndrome type I

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Causes of the Hurler syndrome

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

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incidence & and risk factors

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

© 2007 Thomson - Wadsworth

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Hurler syndrome (type I)

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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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Hunter syndrome type II

(Sulpho-idoronide sulphatase deficiency )

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Hunter syndrome type II

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X-linkedCoarse, thick, facial featuresProgressive stiffness decreased mental development HepatomegalySplenomegalyAbnormal bone x-rays

Hunter syndrome type II

Thank you