AN APPROACH TO INBORN ERRORS OF METABOLISM1 Dr Gurpreet Singh What is inborn error of metabolism ? 2 Metabolism : chemical or physical changes undergone by substances in a biological system. Inborn error : an inherited (i.e. genetic) disorder. Genetic mutations can result in alteration of protein structure or amount of protein synthesized. Functional ability of protein whether enzyme, receptor,vehicle, membrane,structural element is compromised leading to biochemical disorders. These hereditary biochemical disorders are collectively termed inborn error of metabolism. Inborn Errors of Metabolism An inherited enzyme deficiency leading to the disruption of normal bodily 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 3 What is a metabolic disease? 4 substrate excess A B C product deficiency D toxic metabolite . Level Of Metabolic Error 5 Small molecule disease Carbohydrate Protein Lipid Nucleic Acids Organelle disease Lysosomes Mitochondria Peroxisomes Cytoplasm . Inborn Errors of 6 Metabolism • IEM as a group are not rare: occur 1 • • • • in 5000 births collectively Often treatable if diagnosed Most difficult task for clinician is to know when to consider IEM and which tests to order for evaluation Don’t be fooled--other diagnoses like sepsis. hem. pulm. ICH. may accompany IEM Clues to presence of IEM may often be found in FH . Alkaptonuria.alpha-1-anti trypsin deficiency. Defects of amino acids-Phenylketonuria(PKU). maple syrup urine disease(MSUD). pyruvate dehydrogenase deficiency. peroxisomal disorders .AMPdeaminase deficiency.lysosomal disorders . methylmalonic acidemia(MMA). Defects of lipids-Mitochondrial fatty acid oxidation defects. Fructose intolerance. Miscellaneous –wilson disease.mucopolysaccharidoses.orotic aciduria. Galactosemia.Urea cycle defects(UCDs). Defects of purines and pyrimidines-Lesh-nyhan syndrome. Organic acidemias-isovaleric acidemia.Metabolic Diseases Can Grouped as 7 Defects of Carbohydrates-Glycogen storage disease(GSD). . propoinic acidemia(PPA). . . Every child with unexplained . should be suspected of having a metabolic disorder . . . Neurological deterioration Metabolic acidosis Hypoglycemia Inappropriate ketosis Hypotonia Cardiomyopathy Hepatocellular dysfunction Failure to thrive . especially in siblings Parental consanguinity Sepsis (particularly Escherichia coli) . especially if seizures are intractable Neonate or infant with an unusual odor Symptoms indicating strong possibility of an IEM. or of similar illness.Infant Symptoms indicating possibility of an IEM (one or all) Infant becomes acutely ill after period of normal behavior and feeding. this may occur within hours or weeks Neonate or infant with seizures and/or hypotonia. particularly when coupled with the above symptoms Persistent or recurrent vomiting Failure to thrive (failure to gain weight or weight loss) Apnea or respiratory distress (tachypnea) Jaundice or hepatomegaly Lethargy Coma (particularly intermittent) Unexplained hemorrhage Family history of neonatal deaths. a negative family history is not reassuring! CONSANGUINITY.10 Index of suspicion Family History Most IEM’s are recessive . A positive family history may be helpful! .fabry disease. Mitochondrial disorders as mitochondrial DNA is acquired from mother.X-linked disorders like ornithine transcaarbamylase(OTC). ethnicity.lesch-nyhan syndrome. fetal losses maternal family history males . inbreeding unexplained neonatal deaths. jaundice .tone. seizures.myocardial dysfunction Abdo . tachypnea CVS . tense fontanelle Resp . retinitis pigmentosa CNS .Kussmaul’s.HEPATOMEGALY Skin . General – dysmorphisms (abnormality in shape or Index of suspicion Physical examination 11 size).cataracts. ODOUR H&N . apnea.Time and Pattern of Onset Intoxication phase Infants is born healthy.and coma No symptom free period Miochondrial and Peroxisomal disorders Primary lactic acidosis 12 . Lethargy. Poor feeding and vomiting followed by neurological symptoms. seizures and coma Organic acidemias and UCDs Energy Deficiencies Most common presentation Overwhelming neurologic illness.seizures. Deteriorates after symptom free period. Apnea . Patterns OF13 Presentation Neurological abnormalities Disorders of acid –base status Hypoglycemia Liver dysfunction Dysmorphic features Cardiac diseases Abnormal urine and body odour . apnea Small molecule Intoxication type Associated with vomiting.ataxia. weakness .Patterns of Neurological Abnormalities in IEMs 14 Acute encephalopathy Neonatal or early infancy Gray matter involvement Seizures. coma Chronic Progressive encephalopathy Late infancy or childhood White matter involvement Spasticity. abnormal respiration . lethargy. cardiomyopathy.hypereflexia Large molecule Energy deficiency or intoxication type Associated with liver dysfunction . hypotonia. .NEUROLOGICAL ABNORMALITIES 15 Encephalopathy.seizures seen in organic acidemias.UCDs.respiratory chain disorders. NKH .MSUD fatty acid oxidation defects Seizures predominantly present in pyridoxine dependent seizures. peroxisomal disorders Few IEM presents with predominant hypotonia such as peroxisomal disorders. FAO defects. . and defects of glycogenesis. gluconeogensis. respiratory chain. • Respiratory alkalosis is a/w hyperammonemia. pyruvate metabolism.Disorders of Acid-Base Status 16 • Metabolic acidosis with raised anion gap is an importanat feature of many IEMs. • Organic acidemias. 17 . fructose1.defects of gluconeogenesis such as glycogen storage disease.Hypoglycemia 18 • Hypoglycemia if severe and persistent without any other etiology suspect IEMs.6-diphosphatase deficiency . • Hypoglycemia a/w metabolic acidosis suggests an organic acidemia . 19 . fructose intolerance). Gilbert and Crigler-Najar syndromes) Conjugated(galactosemia. Hepatomegaly-asymptomatic in GSD.Liver Dysfunction 20 Jaundice may be unconjugated (G6PD Deficiency. Hypoglycemia wih hepatomegaly in galactosemia. Hepatocellular dysfunction in alpha-1antitrypsin deficiency. tyrosinemia.GSD. tyrosinemia. GSD IV and III. . coronary artery disease(familial hypercholesterolemia) . Few can present with arrthymias(fabry disease). Most IEM presents as cardiomyopathy.CARDIAC DYSFUNCTION 21 Associated with mitochondria disorders.FAO defects.GSDII(Pompe disease). small nose with aneverted flared alae nasi.long philtrum.lipodystrophy Glycosylation disorders . Inverted nipples.Dysmorphic Features Peroxisomal disorders Zellweger syndrome Pyruvate dehydrogenase deficiency 22 Large fontalle. flat nasal bridge. flat nasal bridge.prominent forehead. epicanthal folds.hypoplastic supraorbital ridges Epicanthal folds. intractable seizure and developmental delay PKU: Fair skin and blonde hair Multiple carboxylase deficiency skin rash and partial alopecia .Hair and skin abnormalities Menkes disease: spares kinky scalp hair associated with hypotonia. Eye abnormalities 24 Cataract:galactosemia. niemann-pick disease. sandhoff disease. marfan Blue sclera in osteogenesis imperfecta Cherry red spot in lysosomal disorder such as aysachs disease.metachromatic leukodystrophy .adrenoleukodystrophymuco polysacharidosis Lens dislocation: homocystinurea. 25 Abnormal body and urine odors Odors :- Glutaric acidemia type 2– sweaty feet Isovaleric acidemia – sweaty feet MSUD – maple syrup Hypermethioninemia– boiled cabbage Multiple carboxylase deficiency – tomcat urine PKU – mousy or musty Tyrosinemia – rancid fishy or cabbage like . Laboratory Assessment of Neonates Suspected of Having an Inborn Error of Metabolism Routine Studies Blood lactate and pyruvate Complete blood count and differential Plasma ammonia Plasma glucose Plasma electrolytes and blood pH Urine ketones Urine-reducing substances Special Studies Plasma amino acids Plasma carnitine Urine amino acids Urine organic acids . ANION GAP METABOLIC ACIDOSIS 27 Index of suspicion Laboratory Normal anion gap metabolic acidosis Respiratory alkalosis Low BUN relative to creatinine Hypoglycemia especially with hepatomegaly non-ketotic ketotic . compromised perfusion points towards organic acidemias. Respiratory alkalosis alkalosis in non ventilated babies suggests hyperammonemia.Lab tests results seen with IEM 28 CBC-Neutropenia and thrombocytopenia seen in organic acidemias. congenital lactic acidosis.GSD type Ib. . Electrolytes and ABG-Persistent metabolic acidosis w/o asphyxia.shock. Plasma Ammonia-should be done in all sick infants with features of unexplained lethargy and neurological intoxication.raised in UCDs. .alpha- 1-antitrypsin deficienncy.tyrosinemia. smell.29 LFTs-abnormal in galactosemias. reducing substances. Urinary ketones . organic acidemias. Increased level of long chain fatty acid with perioxisomal disorder. valine and isoleuocine Hyperglycinemia: increase glycine Urinary organic acid : in patients of metabolic acidosis. ketonuria and used for diagnosing organic acidemias. Carnitine level-elevation seen in FAO defects. . seizures.30 Specialized biochemical testing Plasma amino acid analysis Maple syrup urine disease with increase leuocine. hyperammonemia. LETHARGY.COMA ) METABOLIC DISORDER OBTAIN PL.INITIAL FINDINGS ( POOR FEEDING . NH3 INFECTION HIGH OBTAIN BLOOD Ph & CO2 NORMAL OBTAIN BLOOD Ph & CO2 NORMAL UREA CYCLE DEFECTS ACIDOSIS ORGANIC ACIDEMIAS NORMAL AMINOACIDOPATHIES GALACTOSEMIA 31 . CONVULSIONS . VOMITING . Stumbling Blocks” in Diagnosin“g Inborn Errors of Metabolism 32 Signs and symptoms are often nonspecific Routine childhood illnesses excluded 1st Inborn errors considered only secondarily Unfamiliarity with biochemical interrelationships/ diagnostic tests Inappropriate sample collection Inappropriate sample storage . liver.Galactosemia Deficiency of galactose-1 phosphate uridyl 33 transferase 1/50.000 Start early after feeding Autosomal recessive on chromosome 9p13 with male=female Affect brain. kidney and ovaries . Manifestation Symptoms begin after lactose feeding or breast 34 milk feeding Lethargy irritability and vomiting Feeding difficulty and poor weight gain Jaundice. hypoglycemia. hepatomegaly Ascites Hepatic cirrhosis . Others Polydipsia. polyurea Rickets Mental retardation Seizure 35 Cataract: perinuclear haziness to complete opacification Fulminant E-coli sepsis . 36 . Investigation • Positive clinitest and negative clinistix • Urine galactose by chromatography • Direct hyperbilirubinemia 37 • Blood galactose 1 phosphate uridyl transferase activity assay (beutler test). • Increase galactose 1phosphate in RBC . Management Lactose free formula Control seizure Consult ophthalmology Genetic counseling 38 . PKU 39 Autosomal recessive inborn error of metabolism Incidence of 1:10.000 Normally: phenylalanine tyrosine by liver enzyme phenylalanine hydroxylase (PAH) .000 to 1:15. Two Types Deficiency of PAH 40 PAH Deficient (97% of cases) Non-PAH Deficient (3% of cases) Defects in tetrahydrobiopterin or other components in related pathways . 41 . Symptoms Severe intellectual impairment Microcephaly Eczema 42 Seizures Hypopigmentation Hyperactivity Autistic behavior . 43 . 44 . .Diagnostic Criteria • Normal: 120 – 360 µmol/L 45 • PAH Deficient: – Mild: 600 – 1200 µmol/L – Classical: > 1200 µmol/L • Non-PAH Deficient: – < 600 µmol/L • Guthrie Bacterial Inhibition Assay • Ferric chloride test on urinary metabolites. Treatment Decrease amount of phenylalanine in diet 46 Possible supplementation of tyrosine to promote normal growth and development Food diary Frequent monitoring of phenylalanine levels Once weekly during 1st year Twice monthly from 1 – 12 years Monthly after 12 years Provide parental and professional support to promote normal growth and development . Tyrosinemia 47 Decreased activity of enzyme fumaryl acetoacetate. Tyrosine and methionine levels are high. Presents with hepatosplenomegaly,fanconi like syndrome,hyperbilirubinemia,growth retardation. Leads to chronic liver disease. Restriction of phenylalanine,tyrosine,methionine. ALKAPTONURIA 48 Deficiency of enzyme homogentistic acidoxidase. Homogenistic acid is excreted in urine . Accumulation in articular tissues leading to degeneration and osteoarthritis like changes. Pigment stones and nephrosis also seen. Urine shows black reaction with fehlings or benedicts s test. HOMOCYSTINURIA 49 Deficiency of cystathionine synthatase. Elevated levels of homocystine and methionine. Patients presents with subluxation of lens,recurrent thrombo embolic episodes with marfanoid features. Convulsions and cerebrospinal lesions seen due to thrombo-embolic phenomenon. Restriction of methionine and pyridoxine replacement. 50 . Homocystinuria . Lethargy. Quick removal of branched chain amino acids and their metabolities from tissues . valine and their respective ketoacids. Poor feeding. maple syrup odor in body fluids. Ketoacids detected in urine by 2.4-DNPH reagent forming yellow precipitate.body fluids Special low branched amino acids diet . High plasma and urine levels of leucine.Maple Syrup Urine Disease 52 Autsomal recessive . coma. vomiting during first week. isoleucine. deficiency of branched-chain alpha-ketoacid dehydrogenase. muscular rigidity with severe opisthotonus. seizures. 53 . hyperammonemia.leuine. anion gap metabolic acidosis. thrombocytopenias. Most infants presents with severe vomiting. lethargy. metabolic acidosis with large anion gap.Organic Acidemias 54 Autosomal reccesive disorders due to deficency of degradative enzymes involving catabolism of branched amino acids valine. . neutropenia. coma.isoleucine. hypotonia. hypoglycemia. poor feeding . Labroratory findings severe ketoacidosis . convulsions. 55 Most common organic acdemias are isovaleryl acidemia (IVA). Propionyl acidemia(PPA). Restriction of protein intake (1-2 g/kg/24hr) alongwith carnitine ( 50-1oo mg/kg/24hr). . 10% glucose solution with electrolytes correction with intravenous lipids . Management includes hydration and infusion of bicarbonate to correct acidosis. Methyl malonic acidemia(MMA). 56 . 57 . 58 . lethargy. Diagnosis: Plasma ammonia in the blood is higher than 300mmol/L(in range of 500-1500mmol/L) elevated circulating glutamine -Other samples include plasma amino acids. coma. High index of suspicion should be kept for neonates thought to septic without microbiological evidence of infection. hypotonia.Urea Cycle Defects Disorders present in infants: Symptoms: : Infants presents with poor feeding. urinary amino acids. 59 . organic acids. apnea. vomiting. Patients may have seizures. hyperventilation b/w age of 1 to 5 days. and increased intracranial pressure. orotic acid determination. 60 . Carbamyl phosphate synthatase and Nacetylglutamate(NAG) synthatase deficiencies presents with hyperammonemia with out any specific amino acid elevation.61 Most common UCD is Ornithine Transcarbamylase (OTC) Deficiency with lab. . All other UCDs presents with elevation of specific amino acid elevation prior to their enzymatic deficiency. without any specific increase in any amino acid and marked increase in urinary orotic acid . Features of hyperammonemia. 62 . sodium phenylacetate. fluid and electrolyes are provided i. with minimal amount of proteins.Management of hyperammonemia 63 Adequate calories. . Intiate of hemodialysis or peritoneal dialysis. arginine is given.v. Priming doses of sodiun benzoate . Alternate Pathways for Removal of Ammonia 64 Sodium benzoate SODIUM BENZOATE + GLYCINE HIPPURATE Cleared by the kidney at 5X the GFR Each mole of benzoate removes one mole of ammonia as glycine . + GLUTAMINE ACETATE Easily excreted in the urine One mole of phenylacetate removes 2 moles of ammonia as glutamine .Alternate Pathways for Removal of Ammonia 65 Sodium phenylacetate PHENYlACETYL GLUTAMINE PHENYL. Alternate Pathways for Removal of Ammonia Arginine supplementation provides the urea cycle with 66 ornithine and n-acetylglutamate Abbreviated version of the urea cycle continues not recommended for use in arginase deficiency or organic acidemias . 67 . Asphyxia.Management of acute 68 metabolic disease Rule out : Infection. Intracranial hemorrhage • Treatment include : 1) Hydration 2) Correction of biochemical abnormalitiesMetabolic Acidosis Hypoglycemia Hyperammonemia • . 3) Reversal of catabolism/Promotion of anabolism 4)Elimination of toxic metabolite 5)Treatment of precipitating factor 6)Cofactor supplementation 69 .Contd…. Monitoring Mental state changes Overall fluid balance Evidence of bleeding (thrombocytopenia) Evidence of infection (Neutropenia) Biochemical parameters Complete blood count Urine for ketones and specific gravity 70 . CAH (21-OH’ase def).Newborn Screening PKU .must do on all infants in NICU even if not advanced to full feeds. MSUD . GalactosemiaHypothyroidism Sickle cell anemia Biotinidase def. What to do for the Dying Infant Suspected of Having an IEM Autopsy--pref. performed within 4 hours of death Tissue and body fluid samples Blood-clotted and heparinized Urine samples CSF (ventricular tap) skin biopsy-for chromosomal and enzyme assay liver biopsy-frozen in liquid nitrogen Photographs and skeletal radiological screening for dysmorphic features . Case 1 73 Patrick: 2 yr 4 mo male Developmental delay Seizures . 74 Birth History: Full Term. healthy No Prenatal exposure to alcohol. Labor & Delivery Mother 24 yr old. drugs. 3.620 gm Uncomplicated Pregnancy. known teratogens Discharged home on day of life 2 . infection. 4 m Stand alone – 14 m First word – 18 m Phrases – not yet Walk alone – 2 yr . no focal spike/wave MRI – decreased grey/white differentiation and cortical atrophy Developmental Hx Rolled over – 3 months Social smile . tonic/clonic Total – 4 seizures EEG – diffuse slowing.Case 1 (CONTINUED) 75 Seizure History First – 11 m Generalized. Case 1 (CONTINUED) 76 Seizure History First – 11 m Generalized.4 m Stand alone – 14 m First word – 18 m Phrases – not yet Walk alone – 2 yr . tonic/clonic Total – 4 seizures EEG – diffuse slowing. no focal spike/wave MRI – decreased grey/white differentiation and cortical atrophy Developmental Hx Rolled over – 3 months Social smile . Case 1(Cont) 77 Physical Exam Growth Blond hair.??? . brisk reflexes DIAGNOSIS. blue eyes Non-dysmorphic child Neurological exam: Decreased tone. NH4 50mmol/l. high plasma. Start convulsing Thrombocytopenia.no abnormalities Metabolic acidosis. and hypotonic RR 40. neutropenia with normal LFT CASE STUDY-2 What is the diagnosis? . and grunting CXR. recurrent vomiting. ketotic. 78 A week old baby boy Breast milk only Lethargic. dehydrated. intercostal recession. 79 NEONATAL SEPSIS . . 81 . 82 . 83 . Severe Hurler MPS I H Severe mental retardation More progressive Severe respiratory disease Obstructive airway disease Death before age 10 years Spectrum of Disease Intermediate Hurler-Scheie MPS I H/S Little or no intellectual defect Respiratory disease Obstructive airway disease Cardiovascular disease Joint stiffness/contractures Skeletal abnormalities Decreased visual acuity Death in teens and 20’s 84 Mild Scheie MPS I S Normal intelligence Less progressive physical problems Corneal clouding Joint stiffness Valvular heart disease Death in later decades . Multi-systemic Involvement 85 MPS I leads to disease in multiple tissues/organ systems -L-iduronidase deficiency Lysosomal Storage of GAG • Respiratory • Connective tissue • Cardiovascular • Gastrointestinal • Ocular • Neurologic • Skeletal . Argininosuccinic acidemia Metabolic Diseases of the Urea Cycle Anginase Deficiency Type II Hyperammonemia: Citrullinuria Type I 86 . increased ASA Nl. THN Incr.87 Flow Diagram to Evaluate Hyperammonemia Sig incr Plasma amino acids citrulline citrullinemia Nl. ASA CPS OTC . low urine Orotic acid Low or absent Incr. Or sl. fluids and electrolytes Minimize protein intake Provide alternate pathways for ammonia removal May require exchange transfusion.Treatment of Ammonemia Prior to Further 88 Diagnosis Prevent further catabolism by providing adequate calories. peritoneal dialysis or hemodialysis for ammonia removal . Tay-Sachs 89 . 90 TSD is a fatal genetic disorder in children that causes progressive destruction of the central nervous system . . which is necessary for breaking down GM2 gangliosides in nerve cells. The accumulation of GM2 is toxic and eventually causes death. Hex A normally codes for the alpha sub unit of the hexosaminidase A protein.Chromosome and Type of Mutation Tay Sachs is caused by a mutation in the Hex A gene on 91 chromosome 15. There is also adult Tay-Sachs and the symptoms include muscle weakness. eventually. . paralyzed and unaware of its surroundings. slurred speech.Symptoms and Conditions 92 Symptoms of classical Tay-Sachs disease first appear at 4 to 6 months of age when an apparently healthy baby gradually stops smiling. crawling or turning over. loses its ability to grasp or reach out and. Death occurs by age 5. and behavioral changes. cramps. becomes blind. • There is no cure or effective treatment for Tay- Treatment 93 Sachs disease. but to date has not been successful in reversing or slowing damage to the central nervous system in babies with Tay-Sachs. This approach holds great promise for curing Tay-Sachs. However. Another avenue of research is gene therapy in which scientists transfer a normal gene into cells to replace an abnormal gene. Bone marrow transplantation has been attempted also. . Scientists are exploring enzyme replacement therapy to provide the Hex-A that is lacking in babies with Tay-Sachs. researchers are pursuing several approaches to finding a cure. bone marrow.Gaucher Disease Lysosomal storage disease (Sphingolipidose) Deficiency of glucocerebrosidase causes buildup of glucocerebroside Gaucher cells. alveolar spaces. liver. brain tissue 94 . store sphingolipid in spleen. Symptoms Anemia Reduced platelet count Bone demineralization 95 Jaundice Hepatosplenomegaly Neurologic effects (ataxia. …) . seizures. 000 live births .000 live births Death usually occurs w/in 1 year Type III (Chronic neuropathic/Norbottnian) 1 in 50.Diagnosis 96 Three recognized types: Type I (Noncerebral juvenile) Most common in Ashkenazi Jew lineage (1:450) Type II (Infantile cerebral) 1 in 100. Treatment 97 Splenectomy (rarely cures) Gene therapy Enzyme replacement Placental glucorcerebrosidase (Ceredase) $382.200/year for 70kg patient! Bone marrow transplantation Treatment of choice in advanced disease Chemical chaperone treatment Found to aid folding of N370S mutation . Hunter’s syndrome – XLR( vs Hurler’s syndrome –AR) . Fabry’s disease – XLR.IEM Associations All are AR inherited other than 98 Leach Nyhan syndrome – XLR. OTC deficiency – XLR. Sach’s disease ( eastern european Jews) Sandoff’s disease ( pan ethnic) .IEM Associations Cherry red spot 99 Sialidosis Nieman –Pick’s disease Gaucher’s disease (flank shaped osteolytic lesions) GM1 gangliosidosis Tay. painful joints . urate ureterolithiasis) .subcutaneous nodules. • Farber’s disease arthropathy . dementia. hyperuricemia .IEM Associations 100 • Wolman’s syndrome adrenals enlarged & calcified. • Lesch-Nyhan’s self mutilation . hyperuricosuria . gouty arthritis . • Metachromatic leukodystrophy ataxia . 101 . These genes are inserted via viruses or liposomes. .Gene Therapy Gene therapy is an experimental treatment 102 that involves introducing genetic material (DNA or RNA) into a person’s cells to fight disease. 103 . 104 Gene Therapy ☺ Normal gene inserted into defective cell ☺ Compensates for the missing or dysfunctional gene, in somatic cells only ☺ Can be inserted into mature cell (ly) ☺ Can be inserted into stem cell (bone marrow) ☺ Used to treat e.g. ADA deficiency, CF, … 105 A novel way to treat metabolic disease 106 Gene therapy : The treatment of inherited disease of humans by administration of genes Etiology of metabolic disease : accumulation of metabolic intermediates or loss of products Inborn errors of metabolism or function treat by replacing the gene rather than to replace the defective or missing enzymes Logic : to fix what is broken Lesh-Nyhan syndrome, adenosine deaminase deficiency, sickle cell anemia, thallasemias, hemophilia, Gaucher’s disease, cystic fibrosis, alpha-1 antitrypsin deficiency, inborn errors of metabolism At the time of the infant’s second immunization. where examination revealed an enlarged liver. she became fussy and was seen by a pediatrician. The baby was referred to a gastroenterologist and later diagnosed to have Glycogen Storage Disease Type IIIB 107 .Case Description A female baby was delivered normally after an uncomplicated pregnancy. .• When108 to Suspect Metabolic Diseases? History of parental consanguinity Unexplained neonatal deaths Severe illness in the immediate family. How do metabolic diseases present in the 109 neonate ?? The “sick” newborn infant Cardiomegaly/cardiomyopathy Eye anomalies / Gastrointestinal abnormalities Hair and skin abnormalities Hematological / Hepatic dysfunction Sepsis Unusual odor . acidosis. ketosis. hypoglycemia. TypeIII and Type IV .GSDs with predominant liver dysfunction 110 TypeI GSD with Features of hepatomegaly. Glycogenolysis . cardiac muscles.CNS. .112 Type II GSD or pompes disease presents with lysos osmal storage of glycogen in skeletal muscles. large QRS complexes. Dilated cardiomyopathy with left axis deviation short PR interval.
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