prof. rai muhammad asghar dean of paediatrics rawalpindi ... · purposeless movements hypertonia...

Prof. Rai Muhammad Asghar

Dean of Paediatrics

Rawalpindi Medical University

Inborn Errors of Metabolism

Inborn Errors of Metabolism

Hereditary biochemical disorders

Gene mutation that encode specific proteins

Alteration of primary protein structure or amount

of protein

Functional ability of protein is compromised

Manifest in newborn period

Defect in Metabolism of Amino Acids

Phenylalanine → Phenylketonuria (PKU)

Tyrosine → Tyrosinemia, Alcaptonuria, albinism

Methionine → Homocystinuria

Valine, Leucine, → Organic acidemia (MSUD)

Isoleucine

Arginine, Citrulline, → Urea cycle defects & Hyperammonemia

Ornithinine

Aspartic Acid → Canavan disease

Defect in Metabolism of Lipids

Adrenoleukodystrophy

Lipoprotein → Hyperlipidemia

Lipidosis → GM1 Gangliosidosis

GM2 Gangliosidosis

Gaucher disease

Niemann Pick Disease

Metachromatic leukodystrophy

Defect in Metabolism of Carbohydrate

Glycogen Storage disease

Galactosemia

Muccopolysaccharidoses

MPS I Hurler

MPS I-S Scheie

MPS II Hunter

MPS III Sanfilippo

MPS IV Marquio

MPS VI Maroteaux- Lamy

MPS VII Sly

MPS IX

Disorder of Purine & Pyrimidine Metabolism

Gout

Lesch Nyhan Syndrome

Defect of Heme Biosynthesis

Porphyrias:

Acute Intermittent Porphyria

Porphyria Cutanea Tarda

Erythropoietic Protoporphyria

Clinical manifestations

Neonatal period

Normal at birth

Usually severe, often lethal

Nonspecific, similar to sepsis

Lethargy, poor feeding

Convulsions

Vomiting

Altered consciousness

Consanguinity

History of neonatal deaths

Hepatomegaly

Unusual odor

After Neonatal period

Episodic/intermittent

Triggered by stress or infection

Always consider if

1- Unexplained mental retardation

2- Development delay

* Motor deficit

* Convulsions

3- Unusual odor

4- Intermittent episodes of unexplained

vomiting, acidosis, mental deterioration

5- Hepatomegaly

6- Renal stones

7- Muscle weakness or cardiomyopathy

Clinical Approach to a newborn infant with a

suspected metabolic disorder

Metabolic disorder Infection

Obtain plasma ammonia

High Normal

Obtain Blood

pH and CO2

Obtain blood pH

and CO2

Normal High anion gapNormal anion gap

Acidosis

Urea cycle defects Organic acidemias Aminoacidopathies

or galactosemia

Inborn Errors of Amino Acid Metabolism

Associated with Abnormal Odor

Inborn Errors of Metabolism Urine Odor

Glutaric acidemia (type II) Sweaty feet

Isovaleric acidemia Sweaty feet

Tyrosinemia Boiled cabbage,

rancid butter

Hypermethioninemia Boiled cabbage

Hawkinsinuria Swimming pool

Maple syrup urine disease Maple syrup

Phenylketonuria Mousy or musty

Trimethylaminuria Rooting fish

Phenylketonuria (PKU)

Autosomal recessive

Incidence 1: 20, 000

Clinical manifestations of PKU

Normal at birth

Vomiting

Lighter complexion

Seborrhea

Mousy odor

Purposeless movements

Hypertonia

Mental retardation

Microcephaly

Diagnosis

Plasma Phenylalanine Level

Urinary Phenylketones

Newborn Screening test: Guthrie

Fluorometric and tandem mass spectrometry

Prenatal diagnosis

Galactosemia

Incidence: 1:60,000

Autosomal Recessive

Galactose-1-phosphate uridy transferase deficiency

Clinical manifestations (Galactosemia)

Jaundice

Hepatomegaly

Vomiting

Hypoglycemia

Convulsions

Cataract

Hepatic cirrhosis

Ascites

Mental retardation

Diagnosis

1- Positive Reducing substance in urine

2- Galactosuria on chromatography

3- Decrease activity of Galactose-1-

phosphate uridy transferase deficiency

Management

Galactose free diet

Gaucher Disease

Lipid storage disease

Autosomal recessive

Deficiency of Enzyme Acid b –Glucosidase

Clinical Manifestations (Gaucher Disease)

Type I

Progressive Hepatomegaly

Massive splenomegaly

Anemia, bruising

Bone pain

Type IIRapid Neurodegeneration

Hypertonia

Strabismus

Stridor

Type IIISubacute neuropathic

Diagnosis

Gaucher cells in Bone marrow

(Charactric wrinkle paper appearance due to

intracytoplasmic substrate inclusions)

Management

Supportive

Enzyme replacement therapy

Acid beta glucosidase (imiglucerase) 60 IU/kg

Bone Marrow Transplantation

Gene therapy

Glycogen Storage Disease

Type I Von Gierke

Type II Pompe

Type III Forbes

Type IV Andersen

Type V Mc Ardle

Type VI Hers

Type VII Tauri

Type VIII

Type I [Von Gierke]

Autosomal Recessive

Deficiency of glucose 6-phosphatase enzyme

Clinical Manifestations

Doll face, fat cheeks

Thin extremities

Short stature

Protuberant abdomen

Massive hepatomegaly

Hypoglycemic seizures

Enlarged kidneys

Hypoglycemia

Lactic acidosis

Diagnosis

Hypoglycemia

Glucagon test

Liver biopsy—Enzyme level

Management

Continuous administration of glucose and uncooked

cornstarch

Avoid sucrose, frucose and sarbitol

Multivitamin, Calcium

Allopurinol

Lipid lowering drugs (statin and fibrate)

ACE inhibitirs for microalbuminuria

Granulocyte and granulocyte - macrophage colony

stimulating factors

Liver transplantation

TYPE II Pompe Disease

Autosomal Recessive

Lysosomal α Glycosidase

Clinical Manifestations

Uniformly lethal

Hypotonia

Cardiomegaly

Feeding Difficulty

Macroglossia

Hepatomegaly

Heart Failure

Diagnosis

Elevated Serum, creatine kinase

Aspartate Aminotransferase

Lactate dehydrogenase

Chest x-ray showing massive cardiomegaly

ECG high voltage QRS and short PR interval

Muscle Biopsy vacuoles stained positively for

glycogen

Enzyme Level is confirmatory

Management

Enzyme Replacement therapy (Myozyne)

High protein Diet

Mucopolysaccharidoses

Hurler syndrome

Clinical Manifestations

Coarse Facial features

Mental Retardation

Corneal Clouding

Hepatosplenomegaly

Cardiac defects

Large tongue

Joint stiffness

Short stature

Diagnosis

Clinical

Urine for metabolic screening

Radiological ( Dysostosis Multiplex)

Enlarged and elongated skull

Beaking of vertebral bodies

Oar shaped ribs

Bullet shaped phalanges

Madelung’s deformity of radius and ulna

Enzymes Level - Confirm

Management

Supportive

Enzyme Replacement

Bone marrow transplantation

Gene Therapy

Thank You