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Inborn Errors of Metabolism Michael Marble, MD Associate Professor of Clinical Pediatrics Division of Clinical Genetics Department of Pediatrics, LSUHSC.

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Presentation on theme: "Inborn Errors of Metabolism Michael Marble, MD Associate Professor of Clinical Pediatrics Division of Clinical Genetics Department of Pediatrics, LSUHSC."— Presentation transcript:

1 Inborn Errors of Metabolism Michael Marble, MD Associate Professor of Clinical Pediatrics Division of Clinical Genetics Department of Pediatrics, LSUHSC And Children’s Hospital

2 A 3 day old male is brought to the emergency room with a history of lethargy progressing to unresponsiveness. You take an initial history which reveals that the baby had been feeding normally for 24 hours but thereafter became irritable and progressively less interested in feeding. On exam, you notice immediately that he is breathing fast and deep and is unresponsive. Along with other possible diagnoses, you suspect metabolic disease. (4) Plasma ammonia result is 1400 micromole/L (0-80). What is the most likely diagnosis? Which tests would you send to confirm a specific metabolic disorder? Plasma amino acids (2) You obtain a complete metabolic profile which shows a normal result. Urinalysis shows elevated specific gravity but is otherwise normal. Capillary blood gas shows respiratory alkalosis: 7.53/ pCO2 20/HCO3 nl, BE nl (1) Which laboratory studies would you order to obtain quick evidence for or against metabolic disease? (3) Based on these results, what type of metabolic disease is most likely? Which test would you order next? Urea cycle disease; plasma ammonia (5)You confirm that the patient has OTC deficiency. What is the recurrence risk in the next pregnancy? Who else in the family should be tested? X-linked inheritance therefore 50% recurrence risk if mother is a carrier.

3 Urea Cycle Disorders DIET Protein  NH4 + + HCO 3 Carbamoyl Phosphate Ornithine Citrulline Argininosuccinic Acid Arginine urea(2N) UREA CYCLE Asp (N) OTC Urea cycle disorders: Ornithine transcarbamylase deficiency (X-linked) Carbamoyl phosphate synthase deficiency (AR) Citrullinemia (AR) Argininosuccinic acidemia (AR) Argininemia (AR) Hyperammonemia without metabolic acidosis (usually have respiratory alkalosis)

4 X-linked inheritance, partially affected female Headaches, recurrent vomiting, avoids meat

5 A 3 day old male is brought to the emergency room with a history of lethargy progressing to unresponsiveness. You take an initial history which reveals that the baby had been feeding normally for 24 hours but thereafter became irritable and progressively less interested in feeding. On exam, you notice immediately that he is breathing fast and deep and is unresponsive. Along with other possible diagnoses, you suspect metabolic disease. (2) You obtain a blood gas, basic metabolic profile, urinalysis and plasma ammonia which show the following: (1) Which laboratory studies would you order to obtain quick evidence for or against metabolic disease? (3) Based on these results, what type of metabolic disease is most likely? Organic acidemias UA 3+ ketones Ammonia 646 (0-36) Capillary blood gas: 7.11/CO2 19, HCO3 9, BE - 11 (4) How would you confirm a specific metabolic disorder in this case? Urine organic acids, plasma acylcarnitine profile

6 Organic Acidemias Isoleucine Valine Methionine Cholesterol Odd chain fatty acids leucine Isovaleryl CoAHMG CoA Acetyl CoA Krebs Cycle Methylmalonyl CoAPropionyl CoASuccinyl CoA biotinB12 Lysine Tryptophan Glutaryl CoACrotonyl CoA 3MCC Acetyl CoA Organic acids are intermediates in the catabolic pathways to break down amino acids, lipids and other compounds to acetyl CoA and succinyl CoA which are entry points into the Kreb cycle *Urine organic acid analysis will show elevation of organic acids proximal to the enzymatic block; the resulting pattern is interpreted by the metabolic laboratory

7 Long chain fatty acid Fatty acid Fatty acyl-CoA Fatty acyl-carnitine Fatty acyl-CoA acetyl CoA ketones Free carnitine PlasmaCytoplasm Mitochondrion Krebs Free carnitine CPT1 Detected by acylcarnitine profile Propionyl CoA propionylcarnitine Fatty acid oxidation Acylcarnitine analysis for organic acidemias: organic acidemias cause elevations of specific acylcarnitines

8 Selected Organic Acidemias Propionic Methylmalonic Isovaleric Glutaric Maple syrup urine biotin B12 riboflavin thiamine Usually severe Some respond to B12 Sweaty foot odor to urine Macrocephaly, dystonia, Maple syrup odor, elevated branched chain amino acids DiseaseCofactorOther features Abnormal MRI

9 Glutaric Acidemia Type 1 Severe movement disorder

10 Urea cycle disease versus organic acidemias lethargy/coma vomiting hyperammonemia metabolic ketoacidosis primary respiratory alkalosis UCD OA ++/

11 You are called to the newborn nursery regarding an 8 hour old female infant who is listless and not interested in feeding. On exam, the baby is severely hypotonic and lethargic but no other obvious abnormalities are noted. Accucheck shows normal glucose. Blood gas, complete metabolic profile, CBC, plasma ammonia, lactate and urinalysis all show normal results. Chest X-ray comes back normal. Along with other possibilities, you suspect a neuromuscular disorder and consult neurology. Maintenance IVFs are started. Pregnancy history is significant for decreased fetal movements. While awaiting neurology consult, the baby has apnea spells and develops myoclonic jerks. and is intubated. An EEG is performed and shows a “burst suppression” pattern. (2) How would you confirm the diagnosis? CSF/plasma glycine ratio (3) What is the prognosis? Very poor, despite treatment (1) What is the most likely diagnosis? Nonketotic hyperglycinemia

12 * Defect in glycine catabolism autosomal recessive symptoms in first 24 hours hypotonia/encephalopathy, seizures, burst suppression EEG increased CSF/plasma glycine Tx: benzoate, dextramethorphan poor prognosis, diet ineffective Glycine NH3 + CO2 *Diagnosis based on elevated CSF/Plasma glycine ratio

13 A 15 month old female, previously healthy, was brought to the emergency room after the mother had difficulty arousing her in the morning. Over the past 2 days, the child had had a low grade fever, cough, mild diarrhea and 3 episodes of vomiting. Due to poor appetite, the patient did not eat very much for dinner and missed her ususal bedtime snack the night before presentation. In the ER, she was noted to have a depressed mental status but was partially responsive. Initial lab testing showed the following: The ER physician starts an IV and gives a bolus of glucose to correct hypoglycemia. The physician also gives normal saline boluses for rehydration. Then IVFs with D5 ¼ normal saline is started at 1.5 maintenance fluids. Followup labs show normal serum glucose but no change in acid-base status. The patient’s mental status worsens and she becomes comatose. She is transferred to the PICU. Plasma ammonia level is found to be mildly elevated at 101 micromoles/L. CBC: WBC mildly elevated CMP shows sodium 144, Cl 104, CO2 13 BUN 28 Cre 0.6, glucose 37, mild elevation of ALT and AST Urinalysis negative for reducing substances and ketones, specific gravity is elevated Based on the above presentation and lab results, the patient most likely has a disorder within which category of inborn error of metabolism? Fatty acid oxidation defects How would you confirm a specific diagnosis? Plasma acylcarnitine profile Patient who presented with hypoglycemia and altered mental status

14 Diagnosis of fatty acid oxidation disorders by acylcarnitine analysis Long chain fatty acid Fatty acid Fatty acyl-CoA Fatty acyl-carnitine Fatty acyl-CoA MCAD SCAD acetyl CoA ketones Free carnitine PlasmaCytoplasm Mitochondrion fatty acyl CoAs + Fatty acyl-carnitine (C6-C12) Detected by acylcarnitine analysis

15 Fatty acids fasting ketones acetyl CoA Krebs cycle *key pathway for adaptation to fasting VLCAD LCHAD MCAD SCAD CPT1/CPT2 + Brain Fatty acid oxidation Distinguishing feature of FAOD is hypoketotic hypoglycemia MCAD deficiency is most common and has a 25% risk of death with first episode LCHAD, VLCAD and carnitine uptake disorder are variably associated with, hepatomegaly, liver disease, hypertrophic cardiomyopathy and potential arrythmias All are autosomal recessive

16 LCHAD deficiency Hypoketotic hyoglycemia, hypotonia, failure to thrive At diagnosis On dietary treatment

17 Variable Clinical presentations of fatty acid oxidation Hyoketotic hypoglycemia in neonatal period Later onset hypoketotic hypoglycemia Sudden infant death syndrome Hypertrophic cardiomyopathy, arrythmias Liver disease Adolescent or adult onset myopathy Acute rhabdomyolysis Asymptomatic

18 Disease Typical presentation Comments Probably benign Most common FAOD, may be associated with “SIDS” SCAD MCAD VLCAD Hypoketotic hypoglycemia N/A Variable: hypoketotic hypoglycemia, hypertrophic cardiomyopathy, myopathy, liver dz Extemely variable ranging from neonatal to adult onset LCHAD Variable: hypoketotic hypoglycemia, hypertrophic cardiomyopathy, myopathy, liver dz Extremely variable, need low fat diet Fatty acid oxidation disorders Diagnosis is based on the specific pattern of acylcarnitine elevations

19 Diagnosis of fatty acid oxidation disorders by acylcarnitine analysis Long chain fatty acid Fatty acid Fatty acyl-CoA Fatty acyl-carnitine Fatty acyl-CoA MCADSCAD acetyl CoA ketones FC PlasmaCytoplasm Mitochondrion fatty acyl CoAs + Fatty acyl-carnitine (C6-C12) Detected by acylcarnitine analysis LCHADVLCAD CPT1 CPT2 CACT

20 Disorders of carnitine metabolism (1)Carnitine transports long chain fatty acids into the mitochondria (2)Carnitine deficiency can be primary or secondary (3)Primary carnitine deficiency is caused by abnormal transport of carnitine itself into the cells (carnitine uptake disorder, AKA “systemic carnitine deficiency”) (4) Secondary carnitine deficiency is causes by other metabolic disorders through the formation of carnitine esters (acylcarnitines) by abnormal organic/fatty acids Decreased total carnitine Decreased free carnitine Normal acyl/free ratio Normal total carnitine Normal or increased free carnitine Normal acyl/free ratio Plasma: Urine: Primary (CUD) Decreased/normal total carnitine Decreased free carnitine Increased acyl/free ratio Decreased/normal total carnitine Decreased free carnitine Increased acyl/free ratio Plasma: Urine: MCAD, organic acidemias etc

21 A 6 day old female who is breast fed is brought to the emergency room due to poor feeding, vomiting and jaundice? Initial laboratory studies show the following: Total Bilirubin 19 Direct bilirubin 5.2 AST 987 ALT 767 Which metabolic disorder do you suspect? galactosemia Which other routine tests should you order? PT, PTT, urine reducing substances How would you confirm the diagnosis? Enzyme assay, DNA How would you treat this patient? Galactose free diet What are the acute and long term complications of this disorder? Liver disease, E coli sepsis, cataracts, MR, speech delay, ovarian failure

22 Lactose Galactose glucose Gal-1-P galactokinase (galactose-glucose) Glucose-1-P glycolysis galactose-1-P uridyltransferase UDP galactose UDP glucose pyruvate epimerase (cataracts) (classical) (benign) Breast milk, cow’s milk Glucose-6-P Galactose Metabolism Treatment: galactose free diet, ophthalmology and developmental followup

23 A 9 year old male is brought to the emergency room due to acute vomiting and lethargy shortly after a birthday party. Past medical history is significant for failure to thrive in late infancy which resolved without determination of a diagnosis. He had had several bouts of vomiting in the past, usually after consuming candy or soft drinks at parties. He has had no dental cavities. Laboratory results in the ER are as follows: Total Bilirubin 6.4 Direct bilirubin 5.2 AST 767 ALT 987 What is the most likely metabolic diagnosis? Hereditary fructose intolerance

24 A 3 month old female is found to have hepatomegaly on routine exam. She is asymptomatic. Lab testing shows hypoglycemia, lactic acidemia, hyperuricemia, hyperlipidemia and elevated AST and ALT. What is the most likely diagnosis? Glycogen storage disease How would you confirm the diagnosis? DNA, liver biopsy What is the treatment? dietary

25 Glycogen Storage Disease 1a “Von Gierke disease”

26 weakness hepatomegalyfacial features Hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia, neutropenia Glycogen Storage Disease 1b

27 Sibling with same disorder Autosomal recessive

28 Glycogen Glucose – 1- P Glucose – 6- P Glucose-6- phosphatase Glucose Glut 2 glucose cytoplasm plasma pyruvate Lactic acidosis gluconeogenesis glycolysis Pentose phosphate shunt (hyperuricemia) GSD types 1a and 1b ER Glycogen is a storage form of glucose: Liver glycogen releases glucose into the circulation Muscle glycogen is used locally Krebs cycle Acetyl CoA Malonyl CoA Stimulates fatty acid synthesis and inhibits fatty acid breakdown (Hyperlipidemia)

29 Disease Typical presentation Other features Hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia Puffy cheeks, neutropenia Von Gierke (GSDIa) GSDIb Pompei (GSD II) Puffy cheeks Weakness, hypotonia, cardiomyopathy EKG: short PR intervals, wide QRS Similar to Von Gierke but milder, normal lactate Muscle, including cardiac may be involved Hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia Debrancher deficiency (GSD III) McCardle disease (GSD VI) Only muscle involvement Risk of rhabdomyolysis Brancher deficiency (GSD IV) Fatal liver disease (amylopectinosis) Other organ involvement Selected glycogen storage diseases Treatment Nocturnal NG feedings, avoid fasting Nocturnal NG feedings, avoid fasting, neutropenia precautions Enzyme replacement Similar to GSD1a ? transplant Avoid excess excercise

30 An infant with apparently normal development for the first 6 months begins to slow down. She was able to sit unassisted by 1 year. She was very socially interactive and could grasp objects. After one year she gradually lost her ability to sit and she could no longer grasp objects. She became less and less interactive, and lost interest in eating and became emaciated. She had splenomegaly. Ophthalmology exam revealed a cherry red spot macula: What type of disorder do you suspect? Lysosomal storage disease How would you confirm a diagnosis? Enzyme assay What is the differential diagnosis of cherry red macula? Patient with developmental regression

31 Lysosomal lipid storage disorders associated with cherry red macula: Niemann-Pick A GM1 gangliosidosis Tay-Sachs disease Sandhoff disease Farber lipogranulomatosis Sialidosis Lysosomal storage disease: ocular features

32 Mucoploysaccharides (glycosaminoglycans Bone, connective tissue, skin, cornea,joints etc Cell membranes, organelles Bacteria, viruses Lysosome Sphingolipids, glycolipids etc Food particles Glycoproteins Acid hydrolases “The cells wrecking crew” Glycogen Abnormal lysosomal storage leads to developmental regression

33 Metachromatic Leukodystrophy Rapid developmental regression starting in late infancy Lysosomal accumulation of sulfatides

34 GM1 Gangliosidosis Neonatal presentation: hypotonia, ascites

35 A 14 month old female presented with developmental delay to your clinic. She was reportedly normal at birth but at 8 months was noted to have mild kyphosis when sitting. She had a history of chronic rhinorrhea. Late in infancy, the parents noticed gradual changes in craniofacial features including thickening of the eyebrows, large tongue, prominence of forehead. The patient been pulling to stand but lost this ability and seemed to be regressing in overall development. On exam, you notice a scaphocephalic head shape, frontal bossing, relatively thick eyebrows, cloudy cornea and stiff elbows. The patient most likely has a disorder within which category of inborn error of metabolism? Lysosomal storage disease (mucopolysaccharidosis) How would you confirm a specific diagnosis? Enzyme assay

36 Mucopolysaccharidosis Hurler Syndrome: comparison with sibs

37 Hurler syndrome

38 Mucopolysaccharidosis Hurler syndrome – alpha L-iduronidase def. organomegaly

39 Sanfilipo Syndrome (MPS 3) facial features Sanfilipo (MPS III) Less severe somatic features Developmental delay Behavioral problems Neurological regression

40 Maroteaux-Lamy (MPS VI)

41

42 Morquio (MPS IV)

43

44

45 Lysosomal storage disease: laboratory diagnosis Urine mucopolysaccharides Urine oligosaccharide Enzyme assay DNA (for genetic counseling and to rule out pseudoalleles)

46 Disease Typical presentation Inheritance Developmental regression, dysosotosis multiplex, cloudy cornea, organomegaly, cardiac valve disease Hurler (MPS1) Hunter (MPS2) San Filippo (MPS3) Autosomal recessive Later onset, mild somatic features Mainly skeletal involvement Similar to Hurler but no cloudy cornea Morquio (MPS4) Maroteaux-Lamy (MPS6) Similar to Hurler but “CNS sparing” Treatment X-linked Autosomal recessive BMT/ERT ?ERT

47 PKU Adult with Mental Retardation: born before newborn screening era Severe mental retardation, microcephaly, behavioural problems Phenylalanine hydroxylase defect Autosomal recessive Normal infant at birth PheTyr Dietary protein PAH Neurotransmitters, melanin etc

48 PKU: Clinical Problems if Untreated mental retardation seizures hypopigmentation rash Tx: low phenylalanine diet *Due to newborn screening, the above problems rarely occur.

49 Heel stick: Obtain at about 48 hours If obtained too early, false negative Filter paper with blood spots and demographic information “Guthrie cards”

50 Patients with PKU: low Phe diet, frequent monitoring of Phe, dietary counseling Normal growth and development Studies have shown that NBS has virtually eliminated mental retardation due to PKU Phenylketonuria

51 HYPERCHLOREMIC METABOLIC ACIDOSIS LIVER DISEASE CATARACTS HYPERBILIRUBINEMIA REDUCING SUBSTANCES Selected Presentations/Diagnostic Considerations INFANT/CHILD WITH SUSPECTED METABOLIC DISEASE KETONES NEGATIVE ENCEPHALOPATY < 24 HRS OLD, BURST SUPPRESSION EEG METABOLIC ACIDOSIS HYPOGLYCEMIA INAPPROPRIATELY LOW KETONES RESPIRATORY ALKALOSIS HYPERAMMONEMIA FATTY ACID OXIDATION DEFECT ORGANIC ACIDEMIA UREA CYCLE DISEASE GALACTOSEMIA NON KETOTIC HYPERGLYCINEMIA HYPOGLYCEMIA HEPATOMEGALY GLYCOGEN STORAGE DISEASE (LIVER) DEVELOPMENTAL REGRESSION SKELETAL DYSPLASIA ORGANOMEGALY VARIABLE CLOUDY CORNEA Lysosomal storage (MPS) WIDE ANION GAP METABOLIC ACIDOSIS, KETONURIA, HYPERAMMONEMIA DEVELOPMENTAL REGRESSION ORGANOMEGALY CHERRY RED MACULA Lysosomal storage (glycolpids)) WEAKNESS RHABDOMYOLYSIS GLYCOGEN STORAGE DISEASE (MUSCLE)


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