Inborn Error of Metabolism

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Presentation Transcript

Inborn Error Of Metabolism : 

Inborn Error Of Metabolism

IEM are a large group of hereditary biochemical diseases in which specific gene mutation cause abnormal or missing proteins that lead to alter function. : 

IEM are a large group of hereditary biochemical diseases in which specific gene mutation cause abnormal or missing proteins that lead to alter function. Inborn Error Of Metabolism

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IEM are usually Autosomal recessive. Consanguinity is always relatively common. Some are x-linked recessive condition including: Adrenoleukodystrophy. Agammaglobulinemia. Fabry’s disease. Granulomatous disease. Hunter’s Syndrome. Lesch – Nyhan Syndrome. Menke’s Syndrome. A few inherited as Autosomal dominant trait including: porphyria, hyperlipedemia, hereditary angioedema. GENETIC CHARACTERISTIC AND MODE OF INHERITANCE

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Clinical Clues: Over whelming illness. Sepsis real/apparent. Deep coma. Vomiting. Extensive dermatitis. Seizures. Chronic hiccups. Hypotonia. Unusual odor of urine or sweat. Minor dysmorphia. F/hx. of infant deaths or unexplained illness. Ethnic background. NEONATAL PERIOD

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Clinical Manifestation: Mental retardation, Macro/Microcephaly. Coarse facial features/dysmorphia. Developmental regression. Convulsion. Myopathy / cardiomyopathy. Recurrent emesis with coma and hepatic dysfunction. CHILDREN AFTER THE NEONATAL PERIOD (cont.)

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Hypertonia / hypotonia. Failure to thrive. Ophthalmic – related problems : e.g. cataract, corneal cloudiness, cherry red spot, optic atrophy. Renal failure or renal tubular acidosis. CHILDREN AFTER THE NEONATAL PERIOD (cont.)

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Specific Tests: Direct biochemical assays of metabolites or their metabolic by– products, or of an enzyme’s function. DNA studies Neuro-radiology PROCEDUES FOR DIAGNOSIC CONFIRMATION

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Non – Specific Tests: Blood glucose, ammonia, bicarbonate and PH Peripheral Blood smear – WBC or bone marrow vacuolization, foam cells or granules. Spinal fluid protein. PROCEDURES FOR DIAGNOSTIC CONFIRMATION (cont.)

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INBORN ERROR OF AMINO ACID METABOLISM ASSOSIATED WITH ABNORMAL ODOR

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Genetic: Establish diagnosis. Carrier testing. Pedigree analysis, risk counseling. Consideration of Prenatal diagnosis for pregnancies at risk. MANAGEMENT OF IEM

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Dependent on diagnosis and severity: Dietary or vitamin therapy. Drug therapy. BMT. Avoid known environmental triggers. Surgery. MEDICAL

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Family counseling and support. Education to promote increased compliance with special form of therapy such as Protein – restricted diet. Assessment of community resources and support groups. PSYCHOSOCIAL, EDUCATIONAL, FAMILIAL

AMINO ACID DISORDERS : 

AMINO ACID DISORDERS Phenyl Ketonuria: Phenylalanine Tyrosine Hydroxylase Phenylalanine Phenyl ethylamine Phenyl pyruvic acid

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Hyperactivity, athetosis, vomiting. Blond. Seborric dermatitis or eczema skin. Hypertonia. Seizures. Severe mental retardation. Unpleasant odor of phenyl acetic acid. CLINICAL FEATURES

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Screening : Guthrie Test. High Phenylalanine > 20 mg/dl. High Phenyl pyruvic acid. DIAGNOSIS

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DIET. BH4 (Tetrahydrobioptein). L – dopa and 5-hydroxytryptophan. TREATMENT

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Homocystinuria: METHIONINE Cystathionine AMINO ACID DISORDER (CONT.) Cysathionine Synthatase

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DIAGNOSIS: HIGH METHIONINE AND HOMOCYSTINE. TREATMENT: High dose of B6 and Folic Acid. Low methionine and high cystine diet, Betain (trimethylglycine) AMINO ACID DISORDER (CONT.)

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MSUD (Maple – syrup Urine Disease) PROTEIN SYNTHESIS Valine Isoleucine Leucine 1. ? Ketoisovoloric acid ? Keto ? methyl ? Keto carporic acid Vuloric 2. Isobutyric acid 2 methyl Iso ? vuloric butoric acid 1- Branched chain ketoacid dehydrogenase 2- Thiamine pyrophosphatase AMINO ACID DISORDER (CONT.)

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Clinical Features: Normal at Birth. Poor Feeding, vomiting during 1st week of life, lethargy – coma. Hypertonocity alternating é flaccidity . Hypoglycemia, acidosis. Seizures. AMINO ACID DISORDER (CONT.)

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Diagnosis: MS order Hypoglycemia High plasma and urine valine, leucine and isolucine. Low alanine AMINO ACID DISORDER (CONT.)

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Treatment: FLUID AND HCO3- PD. DIALYSIS. MSUD DIET. AMINO ACID DISORDER (CONT.)

ORGANIC ACIDEMIA : 

ORGANIC ACIDEMIA Disorder Methyl malonic Acidemia. Propionic Acidemia. Multiple carboxylase deficiency. Ketothiolase deficiency . Enzyme Methyl malony COA mutase. Propionyl COA Carboxylase. Malfunction of all carboxylase. 2 methylacetyl COA thiolase def.

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Clinical Features: Vomiting, ketosis. Thrombocytopenia , neutropenia. Osteoporosis. Mental retardation. ORGANIC ACIDEMIA

ORGANIC ACIDEMIA : 

ORGANIC ACIDEMIA

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Treatment: Hydration / alkali. Calories to ? catabolic state. Exchange transfusion. Low protein diet. ORGANIC ACIDEMIA

LIPIDOSES : 

LIPIDOSES

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Disease Enzyme Hurler’s Syndrome ? - idurondase Hunter’s Syndrome Iduronate Sulfatase Sanfilipo’s Syndrome Heparan – N – Sulfatase Morquio’s Syndrome A N – Galactosamine – 6 – sulfate sulfatase B ? - glactosidase DISORDERS OF MUCOPOLYSACCHARID METABOLISM

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Marteaux – lamy Syndrome Galactosamine – 4 – Sulfates Sly’s Syndrome Scheie’s Syndrome Hurlur – Scheie Syndrome Sanfilippo Syndrome DISORDERS OF MUCOPOLYSACCHARID METABOLISM

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Due to dysfunction of a single or multiple peroxisomal enzymes, or to failure to form or maintain a normal number of functional peroxisomes. Peroxisomes = Subcellular organelles involved in various essential anabolic or catabolic processes, biosynthesis of Plasmanogens and bile acids. PEROXISOMAL DISORDER

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Clinical Manifestations: Hypotonia. Dysmorphia. Psychomotor delay and seizures. Hepatomegaly. Abnormal eye findings such as retinitis pigmentosa or cataract. Hearing impairment. PEROXISOMAL DISORDER

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Diagnosis: Immunochemical studies for Peroxisomes. ? VLCFA level. C.V.S. or/ aminocytes culture ? ? Plasmanogens synthesis. PEROXISOMAL DISORDER

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Zellweger syndrome (cerebrohepatorenal syndrome). Neonatal adrenoleukodystrophy. Infantile Refsum disease. Hyperpipecolic acidemia. GROUP I : BIOGENSIS OF PEROXISOME

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Refsum disease. X - linked Adreo-Leuko-Dystrophy. Pseudo – Zellweger syndrome. Hyperoxaluria….etc. GROUP II : PERSOXISOMAL ENZYME DEFECTS.

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Zellweger – Like. Pseudo – infantile Refsum disease. Rhizomelic chondro-dysplasia punctata. GROUP III: POSITIVE PEROXISOMES BUT MULTIPLE DEFECTIVE ENZYME

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Supportive, multidisciplinary interventions. Diet: ? VLCFA, ? phytanic acid. Organ transplantation. TREATMENT