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Metabolic Disorders-Inborn Errors of Metabolism PowerPoint Presentation

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Description : Check out this medical titled "Metabolic Disorders - Inborn Errors Of Metabolism" by DR. ABDULLAH ALOMAIR.

This medical talks about metabolic disorders, a group of conditions that occur when the bodys normal metabolic processes are disrupted, leading to abnormal chemical reactions in the body. These disorders can affect various organs and systems in the body and can result in a wide range of symptoms and health problems.

Some examples of metabolic disorders include Diabetes, Obesity, Metabolic syndrome, Hypothyroidism, and Phenylketonuria (PKU), etc.

Tags : metabolic disorders, Diabetes, Obesity, Metabolic syndrome, Hypothyroidism, Phenylketonuria, endocrinology, endocrinology

Published on : Apr 21, 2023 | Views : 2190 | Downloads : 9

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1 Metabolic Disorders Inborn Errors Of Metabolism DR. ABDULLAH ALOMAIR MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) Associate Professor of Pediatrics Consultant Pediatrician Department of Pediatrics PRESIDENT SAUDI PEDIATRIC ASSOCIATION
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2 Inborn Errors Of Metabolism (IEM) -A large group of hereditary biochemical diseases.-In autosomal dominant disorders, the structural abnormality dominates over the chemical abnormality. -Specific gene mutation cause abnormal or missing proteins that lead to altered function. Metabolic Disorders Inborn Errors Of Metabolism
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SINGLE GENE DEFECTS in synthesis or catabolism of proteins, carbohydrates, or fats. Defect in an ENZYME or TRANSPORT PROTEIN , which results in a block in a metabolic pathway. EFFECTS : - toxic ACCUMULATION of substrates before the block, - intermediates from ALTERNATIVE pathways - defects in ENERGY production and utilization caused by a deficiency of products beyond the BLOCK. Every metabolic disease has several forms that vary in AGE OF ONSET , clinical severity and, often, MODE OF INHERITANCE. Pathophysiology
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Classification Transient Hyperammonemia of Newborn Inborn Errors of Metab: Organic Acidemias Fatty Acid Oxidation def Urea Cycle Defects Amino Acidurias Non-ketotic Hyperglycinemia Molybdenum Cofactor Deficiency Sulfite Oxidase Deficiency Metal Storage Disorders: Cholesterol Disorders: Leukodystrophies, other… Krabbe disease Mitochondrial Disorders Glycogen Storage Disorders Hyperinsulinism Carbohydrate Disorders Lysosomal Disorders Mucopolysaccharidoses (X-linked Hunter’s, Hurler’s) Gaucher disease Tay-Sachs Disease Peroxisomal Disorders Zellwegger’s (Cerebro-Hepato-renal) X-linked Adrenoleukodystrophy
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7 Metabolic Disorders Due to inherited reduced activities of proteins involved in the synthesis, breakdown or transport of amino acids, organic acids, fats, carbohydrates and complex macromolecules. Most are autosomal recessive due to mutations that result in reduced enzyme activity or reduced amount of enzyme. Pathogenesis may include: accumulation of a toxic intermediate, reduced amount of a necessary end product or activation of an alternate pathway.
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8 Metabolic Disorders From history: Parental history : Consanguineous parents Previous unexplained neonatal deaths Particular ethnic group (in certain diseases) Features suggestive of metabolic disorder :
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Features suggestive of metabolic disorder : Metabolic Disorders Examination findings: Organomegaly (e.g. hepatomegaly) in the absence of viral infection. Cardiac disease Ocular involvement (e.g. cherry red spot) Skin manifestations e.g. pigmentations. Unusual odour. Due to change in the chemicals of the urine. Non-specific neurological findings. In a non-meningitis child you have to think of metabolic disorders.
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10 Neonatal and Post Neonatal Presentation Neonatal presentation Normal-appearing child at birth (some conditions are associated with dysmorphic features) poor feeding lethargy vomiting seizures coma unusual odour Hypoglycaemia is very dangerous, acidosis (in some defects)
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Neonatal and Post Neonatal Presentation Post neonatal presentation Encephalopathy without the presence of infection. Developmental regression Reye syndrome ( damage of the brain and liver eventually leading to encephalopathy). Motor deficits Seizures Intermittent episodes of vomiting, acidosis, hypoglycaemia and/or coma triggered by stress e.g. infections, surgery.
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Newborn Screeningthe earlier its detected the fewer the complications PKU - in NICU even if not advanced to full feeds Galactosemia Hypothyroidism Hemoglobinopathies Biotinidase defic, CAH (21-OH’ase def), Maple syrup urine disease ( MSUD ) - GUTHRIE TEST: it’s a cheap test that requires only one drop of blood to check for multiple metabolic disorders.
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13 Specific Tests: Direct biochemical assays of metabolites or their metabolic by-products, or of an enzyme’s function. DNA studies Neuro-radiology PROCEDURES FOR DIAGNOSIC CONFIRMATION Non – Specific Tests: Blood glucose, ammonia, bicarbonate and pH Peripheral Blood smear – WBC or bone marrow vacuolization , foam cells or granules. C.S.F. glycine , other amino acids , lactate. Amino acids shouldn’t be present in the CSF if its there it indicates a metabolic disorder. Bone marrow transplantation is a treatment of both inborn errors of metabolism
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14 INBORN ERRORS OF AMINO ACID METABOLISM ASSOSIATED WITH ABNORMAL ODOR
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They may come with flattened mid-face, indistinct philtrum, low nasal bridge and single palmar crease. Small chin is called micrognathia
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Low-set ears: >1/3rd of the ears lower than the line connecting the 2 pupils. Low nasal bridge: common sign, which is also seen in Down.
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19 Genetic: Establish diagnosis. Carrier testing. Pedigree analysis, risk counseling. Consideration of Prenatal diagnosis for pregnancies at risk. MANAGEMENT OF IEM
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20 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 MANAGEMENT OF IEM
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TREATMENT OF GENETIC DISEASES Modify environment, e.g., diet, drugs Avoid known environmental triggers BMT Surgical, correct or repair defect or organ transplantation Modify or replace defective gene product, megadose vitamin therapy or enzyme replacement Replace defective gene Correct altered DNA in defective gene
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22 Galactosemia
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23 : Carbohydrates Galactosemia Enzyme deficiency: Galactose-1-phosphate uridyl transferase deficiency. It is a rare autosomal recessive. Follows feeding with lactose containing (breast milk / formula) Patient feeds poorly , have vomiting, jaundice, hepatomegaly and hepatic failure Chronic liver disease Cataracts Developmental delay develop if condition is untreated., if they were given galactose free diet you will avoid the social and mental damage but they might complain of dyslexia.
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CYSTIC FIBROSISCause : Loss of 3 DNA bases in a gene for the protein that transports Cl ions so salt balance is upset. Causes .a build up of thick mucus in lungs and digestive organs. It is diagnosed by sweat test: measuring the chloride concentration in the sweat
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25 AMINO ACID DISORDERS Phenyl Ketonuria (PKU) Phenylalanine Tyrosine Hydroxylase Phenylalanine Phenyl ethylamine Phenyl pyruvic acid Phenyl pyruvic acid is what gives the urine its smell because its ketonic and acidic.
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26 Phenylketonuria PKU
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27 Hyperactivity, athetosis, vomiting. Blond. Seborric dermatitis or eczema skin. Hypertonia. Seizures. Severe mental retardation. Unpleasant odor of phenyl acetic acid. PKU DIAGNOSIS Screening : Guthrie Test. High Phenylalanine > 20 mg/dl. High Phenyl pyruvic acid. TREATMENT DIET. BH4 (Tetrahydrobiopterin). L – dopa and 5- hydroxytryptophan. CLINICAL FEATURES
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28 PKU
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29 Albinism
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Iris had fibrous tissue, and it’s colourless and is red due to vessels.
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31 Homocystinuria Elevated homocystine levels affect collagen , result in a Marfanoid habitus, ectopia lentis but lens dislocation in homocystinemia is downward unlike in marfan its upward, mental retardation and strokes, its harmful to the bones and body. Araachnodyctly.
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32 METHIONINE CYSTATHIONINE Homocystinuria Cysathionine Synthatase DIAGNOSIS: High methionine and homocystine. TREATMENT: High dose of B6 and Folic Acid. Low methionine and high cystine diet, Betain (trimethylglycine)
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33 Homocystinuria
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Amino acid disorders :Urea cycle defects and hyperammonemia All present with lethargy, seizures, ketoacidosis, neutropenia, and hyperammonemia Ornithine carbamyl transferase (OTC) deficiency Carbamyl phosphate synthetase deficiency Citrullinemia Arginosuccinic Aciduria Argininemia Transient tyrosinemia of prematurity
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First Steps in Metabolic Therapy for IEM Reduce precursor substrate load Provide caloric support Provide fluid support Remove metabolites via dialysis Divert metabolites Supplement with cofactor(s)
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Therapeutic Measures for IEM D/C oral intake temporarily Usually IVF’s with glucose to give 12-15 mg/kg/min glu and at least 60 kcal/kg to prevent catabolism (may worsen pyruvate dehydrogenase deficiency) Bicarb/citrate Carnitine/glycine Na Benzoate/arginine/citrulline Dialysis--not exchange transfusion Vitamins--often given in cocktails after labs drawn before dx is known Biotin, B6, B12, riboflavin, thiamine, folate
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Important IEM Treatment supplements: Carnitine for elimination of Organic Acid through creation of carnitine esters. Sodium Benzoate, phenylacetate and phenylbutyrate for Hyperammonemia elimination.
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CARNITINE METABOLISM An essential nutrient found in highest concentration in red meat. Primary function : Transport long-chain fatty acids into mitochondria for oxidation. Carnitine supplementation in fatty acid oxidation disorders and organic acidosis may augment excretion of accumulated metabolites , but may not prevent metabolic crises in such patients . Carnitine is an endogenous metabolite but can be given as supplementations.
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CARNITINE METABOLISM Primary defects of carnitine transport manifest as Reye syndrome , cardiomyopathy or skeletal myopathy with hypotonia Secondary carnitine deficiency is due to diet ( esp. I.V alimentation or ketogenic diet ) , renal losses , drug therapy ( esp. valproic acid) and other metabolic disorders ( esp. disorders of fatty acid oxidation and organic acidemias ) Prognosis depends on the cause of the carnitine abnormality. Free and esterified carnitine can be measured in blood. Oral or I.V. L-carnitine is used in carnitine deficiency or lnsufficiency in doses of 25-100mg/kgm/day or higher. 39
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40 ORGANIC ACIDEMIA Disorder Methyl malonic Acidemia. Propionic Acidemia. Multiple carboxylase deficiency. Ketothiolase deficiency . Enzyme Methyl malonyl COA mutase. Propionyl COA Carboxylase. Malfunction of all carboxylase. 2 methylacetyl COA thiolase def.
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41 ORGANIC ACIDEMIA Clinical Features Vomiting, ketosis. Thrombocytopenia , neutropenia. Osteoporosis. Mental retardation. Treatment Hydration / alkali. Calories to  catabolic state. Exchange transfusion. Low protein diet.
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42 ORGANIC ACIDEMIA
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43 LYSOSOMAL STORAGE DISORDERS Glycogen Storage Diseases Sphingolipidoses common in eastern jews (Lipidoses And Mucolipidoses) Mucopolysaccharidoses
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44 Lysosomal Storage Disease
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Glycogen Storage Diseases
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47 Principle Groups of Glycogen Storage Diseases
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48 Von Gierke Disease
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49 LYSOSOMAL STORAGE DISORDERS Lipidoses And Mucolipidoses
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50 Gauch. cell In gaucher liver is enlarged but the rest of the body is very thin
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In gaucher you see the cherry red spot appearance in the macula
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52 Sandhoff - Dense thalam
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53 Cerebral palsy --- scissoring of the legs Lipid-retina Lipid accumalation around the retinal arteries and veins
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54 LYSOSOMAL STORAGE DISORDERS Mucopolysaccharidoses
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55 Clinical And Pathological Ultra structure Of Mucopolysaccharidoses
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56 Hurler’s
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57 Hurler’s In hurler : Nasal bridge is depressed , increase distance of philthrum , epicanthal folds, bossing of the head , thick eyebrows , upturn nostrils
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58
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59 Mcopolysacch. Morquio
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60 Peroxisomes = Subcellular organelles involved in various essential anabolic or catabolic processes, biosynthesis of Plasmalogens and bile acids. Due to dysfunction of a single or multiple peroxisomal enzymes, or to failure to form or maintain a normal number of functional peroxisomes. PEROXISOMAL DISORDERS
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61 Hypotonia. Dysmorphia. Psychomotor delay and seizures. Hepatomegaly. Abnormal eye findings such as retinitis pigmentosa or cataract. Hearing impairment. PEROXISOMAL DISORDERS Clinical Manifestations:
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Peroxisomal Disorders Zellweger Syndrome is autosomal recessive disorder. (Cerebro-hepato-renal syndrome) Typical and easily recognized dysmorphic facies. Progressive degeneration of Brain/Liver/Kidney, with death ~6 mo after onset. When screening for PDs. obtain serum Very Long Chain Fatty Acids- VLCFAs
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63 Zellweger
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64 Diagnosis: Immunochemical studies for Peroxisomes.  V. Long Chain FA ( VLCFA ) level. Chor. Vill. Samp. or/ amniocytes culture   Plasmalogens synthesis. PEROXISOMAL DISORDERS Treatment: Supportive, multidisciplinary interventions. Diet:  VLCFA,  phytanic acid. Organ transplantation.
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65 Peroxisomal Disorders GROUP II : PERSOXISOMAL ENZYME DEFECTS GROUP I : BIOGENSIS OF PEROXISOME GROUP III : POSITIVE PEROXISOMES BUT MULTIPLE DEFECTIVE ENZYME Zellweger syndrome (cerebrohepatorenal syndrome). Neonatal adrenoleukodystrophy. Infantile Refsum disease. Hyperpipecolic acidemia. Refsum disease. X - linked Adreno-Leuko-Dystrophy. Pseudo – Zellweger syndrome. Hyperoxaluria….etc. Zellweger – Like. Pseudo – infantile Refsum disease. Rhizomelic chondro-dysplasia punctata
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66 Mitochondrial Disorders Classically involve mutations in mitochondrial DNA Follow a maternal pattern of inheritance Highly variable with regard to penetrance and expressivity based on the variability in tissue distribution of abnormal mitochondria
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67 Mitochondrial Syndromes Presenting in Childhood to Adult
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68
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Transient Hyperammonemia of Newborn: Markedly high NH4 in an infant less than 24 HOL (hours of life), or first 1-2 DOL (day of life) before protein intake occurs. Often in context of large, premature infant with symptomatic pulmonary disease. Very sick infant. Unknown precipitant, unknown etiology (possible slow delayed urea cycle initiation), with potential for severe sequelae (20-30% death, 30-40% abnl dev.) if not treated. Does not recur after being treated.
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70 Clinical Presentation of Amino Acid Disorders
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71 Metabolic Profiles Organic and Amino Acid Disorders Newborn screening is available dependent on population frequency for some Expanded newborn screening for fatty acid defects recently offered
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72 CHILDREN AFTER THE NEONATAL PERIOD Clinical Manifestation Mental retardation, Macro/Microcephaly. Coarse facial features/dysmorphia. Developmental regression. Convulsion. Myopathy / cardiomyopathy. Recurrent emesis with coma and hepatic dysfunction. Hypertonia / hypotonia. Failure to thrive. Ophthalmic – related problems : e.g. cataract, corneal cloudiness, cherry red spot, optic atrophy. Renal failure or renal tubular acidosis.
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Management of IEM - NICU Stop nutrient triggering disorder e.g. protein, galactose Give high-energy intake NICU care to correct tissue perfusion, dehydration, acidosis Hyperammonemia Rx with Na benzoate, Na phenylbutyrate, arginine Dialysis Insulin to control hyperglycemia and reduce catabolism Vitamins e.g Biotin, B6, B12 Specific therapy e.g. carnitine, glycine
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77 Dependent on diagnosis and severity: Dietary or vitamin therapy Drug therapy BMT Avoid known environmental triggers Surgery MEDICAL