prof. rai muhammad asghar dean of paediatrics rawalpindi ... · purposeless movements hypertonia...
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Prof. Rai Muhammad Asghar
Dean of Paediatrics
Rawalpindi Medical University
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Inborn Errors of Metabolism
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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
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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
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Defect in Metabolism of Lipids
Adrenoleukodystrophy
Lipoprotein → Hyperlipidemia
Lipidosis → GM1 Gangliosidosis
GM2 Gangliosidosis
Gaucher disease
Niemann Pick Disease
Metachromatic leukodystrophy
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Defect in Metabolism of Carbohydrate
Glycogen Storage disease
Galactosemia
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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
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Disorder of Purine & Pyrimidine Metabolism
Gout
Lesch Nyhan Syndrome
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Defect of Heme Biosynthesis
Porphyrias:
Acute Intermittent Porphyria
Porphyria Cutanea Tarda
Erythropoietic Protoporphyria
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Clinical manifestations
Neonatal period
Normal at birth
Usually severe, often lethal
Nonspecific, similar to sepsis
Lethargy, poor feeding
Convulsions
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Vomiting
Altered consciousness
Consanguinity
History of neonatal deaths
Hepatomegaly
Unusual odor
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After Neonatal period
Episodic/intermittent
Triggered by stress or infection
Always consider if
1- Unexplained mental retardation
2- Development delay
* Motor deficit
* Convulsions
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3- Unusual odor
4- Intermittent episodes of unexplained
vomiting, acidosis, mental deterioration
5- Hepatomegaly
6- Renal stones
7- Muscle weakness or cardiomyopathy
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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
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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
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Phenylketonuria (PKU)
Autosomal recessive
Incidence 1: 20, 000
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Clinical manifestations of PKU
Normal at birth
Vomiting
Lighter complexion
Seborrhea
Mousy odor
Purposeless movements
Hypertonia
Mental retardation
Microcephaly
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Diagnosis
Plasma Phenylalanine Level
Urinary Phenylketones
Newborn Screening test: Guthrie
Fluorometric and tandem mass spectrometry
Prenatal diagnosis
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Galactosemia
Incidence: 1:60,000
Autosomal Recessive
Galactose-1-phosphate uridy transferase deficiency
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Clinical manifestations (Galactosemia)
Jaundice
Hepatomegaly
Vomiting
Hypoglycemia
Convulsions
Cataract
Hepatic cirrhosis
Ascites
Mental retardation
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Diagnosis
1- Positive Reducing substance in urine
2- Galactosuria on chromatography
3- Decrease activity of Galactose-1-
phosphate uridy transferase deficiency
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Management
Galactose free diet
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Gaucher Disease
Lipid storage disease
Autosomal recessive
Deficiency of Enzyme Acid b –Glucosidase
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Clinical Manifestations (Gaucher Disease)
Type I
Progressive Hepatomegaly
Massive splenomegaly
Anemia, bruising
Bone pain
Type IIRapid Neurodegeneration
Hypertonia
Strabismus
Stridor
Type IIISubacute neuropathic
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Diagnosis
Gaucher cells in Bone marrow
(Charactric wrinkle paper appearance due to
intracytoplasmic substrate inclusions)
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Management
Supportive
Enzyme replacement therapy
Acid beta glucosidase (imiglucerase) 60 IU/kg
Bone Marrow Transplantation
Gene therapy
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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
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Type I [Von Gierke]
Autosomal Recessive
Deficiency of glucose 6-phosphatase enzyme
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Clinical Manifestations
Doll face, fat cheeks
Thin extremities
Short stature
Protuberant abdomen
Massive hepatomegaly
Hypoglycemic seizures
Enlarged kidneys
Hypoglycemia
Lactic acidosis
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Diagnosis
Hypoglycemia
Glucagon test
Liver biopsy—Enzyme level
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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
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TYPE II Pompe Disease
Autosomal Recessive
Lysosomal α Glycosidase
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Clinical Manifestations
Uniformly lethal
Hypotonia
Cardiomegaly
Feeding Difficulty
Macroglossia
Hepatomegaly
Heart Failure
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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
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Management
Enzyme Replacement therapy (Myozyne)
High protein Diet
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Mucopolysaccharidoses
Hurler syndrome
Clinical Manifestations
Coarse Facial features
Mental Retardation
Corneal Clouding
Hepatosplenomegaly
Cardiac defects
Large tongue
Joint stiffness
Short stature
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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
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Management
Supportive
Enzyme Replacement
Bone marrow transplantation
Gene Therapy
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Thank You