IEM_Ellefson - Approach to Inborn Errors of Metabolism of...

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Unformatted text preview: Approach to Inborn Errors of Metabolism of Andrew M. Ellefson MD Cpt, USA, MC Pgy-2 NCC Pediatrics Goals for this lecture: Goals Discuss acute/emergency management of IEMs. Review broad categories of IEMs. Focus on Board favorite zebras. Complete the Board prep. Objectives in most Complete recent 2006 edition. Integrate the “Laughing your way through Boards” Integrate tips. Have fun with this usually stressful topic. Have What we WON’T DO: What Memorize metabolic pathways. Mention, think of, or utter the enzyme αMention, ketoglutarate dehydrogenase complex. Laugh at, throw bagels or coffee at, or Laugh otherwise mock Drew. otherwise Discuss the adverse sequelae of the Eagle’s Discuss previous decision to recruit T.O. previous IEM Board/Prep Goals: IEM Recognize – – – – – – – – – – Urea Cycle defects Organic acidemias S+S of CHO disorders S+S of Galactosemia S+S of hyperinsulinism Glycogen Storage Dz Lipoprotein Disorders Gaucher + Lipid Storage Dz S+S of Tay-Sachs S+S of Fatty Acid and S+S Carnitine metabolism Inheritance patterns Indication for genetics Eval of hypoglycemia Eval of acidosis Vitamin Rx for enzyme Vitamin disorders disorders Treat Hypoglycemia Natural Hx of PKU Plan/diet for PKU Manage Glycogen storage Manage diseases- Type 1 diseases- IEM- Index of Suspicion: IEM Rapid deterioration in an otherwise well infant. Septic appearing infant or abnl sepsis such as Septic E.coli. Failure to thrive. Failure Regression in milestones. Regression Recurrent emesis or feeding difficulty, alterations Recurrent in respirations, abnl urine/body smell, changing MS/lethargy, jaundice, sz, intractable hiccups. Can masquerade like pyloric stenosis. Dietary aversion- proteins, carbs. Dietary Basic Principles: Basic Although individually rare, altogether they Although are 1:800-5000 incidence. are Broadly Defined: An inherent deficiency in a Broadly key metabolic pathway resulting in key – Cellular Intoxication – Energy deprivation – Mixture of the two History and Antecedent Events: History Catabolic state induction Catabolic (sepsis,fasting,dehydration) (sepsis,fasting,dehydration) Protein intake Change or addition of PO proteins, carbs, Change etc… in formula etc… **Gotta ask- Consanguinity FHx of SIDS Assessment: Assessment Detailed H+P – Describe sz – Fevers -Milestones -FHx -Mom’s GsPs -NAT questions **Dysmorphology does not **Dysmorphology r/o IEMs** Physical Exam: – – – – – Vitals Level of alertness Abnl activity/mvmts CV- perfusion Dysmorphology, hair, Dysmorphology, smell, eyes-cornea smell, – Abdo- HS megaly – Neuro- DTRs, tone, etc – Skin- bruise, pigment, Skincolor color Emergency Management: Emergency Can be life threatening Can event requiring rapid assessment and management. management. ABC’s ABG-acidosis BMP, Ca and LFTs NH4 Lactate, Pyruvate CBC, Blood Cx if uncertain Coags- PT/PTT UA-ketones, urine reducing UA-ketones, substances, hold for OA/AAs substances, Newborn scrn results LP- r/o Meningitis, but send lactate LPSTAT, AAs, hold tubes for future STAT, Drug tox screen if indicated. **Hold spun blood or urine sample **Hold in fridge for later if possbile. in – **ABG, Lactate are iced STAT **ABG, samples samples – ** NH4 should be free flowing, ** arterial sample arterial Emergency Management: Emergency Correct hypotension. NPO, reverse NPO, catabolism with D5catabolism D10 1-1.5 x maint. Correct hypoglycemia. Correct metabolic Correct acidosis. acidosis. Dialysis, lactulose if Dialysis, High/toxic NH4 – (nl is <35µmol/L) Search for and treat Search precipitants; ie: Infection, dehydration. Low threshold for Low Sepsis w/u + ABx if uncertain. Pyridoxine for neonatal Pyridoxine sz. if AED no-response sz. Ativan, Versed, AEDs Ativan, for status epilepticus. for Some quick supplements: Some Carnitine for elimination of Organic Acid through creation of carnitine esters. through Sodium Benzoate, Phenylacetate for Phenylacetate Hyperammonemia elimination. Stable Patient, Now what? Stable You could memorize some of these: these: The Daunting Differential List: The Transient Transient Hyperammonemia of Newborn Newborn Inborn Errors of Metab: – – – – – Organic Acidemias Organic Fatty Acid Oxidation def Urea Cycle Defects Amino Acidurias Non-ketotic Hyperglycinemia Molybdenum Cofactor Molybdenum Deficiency – Sulfite Oxidase Deficiency Metal Storage Disorders: Cholesterol Disorders: Leukodystrophies, other… – Krabbe disease Mitochondrial Disorders Glycogen Storage Glycogen Disorders Disorders Hyperinsulinism Carbohydrate Disorders Lysosomal Disorders – Mucopolysaccharidoses (Xlinked Hunter’s, Hurler’s) – Gaucher disease – Tay-Sachs Disease Peroxisomal Disorders – Zellwegger’s (CerebroHepato-renal) – X-linked X-linked Adrenoleukodystrophy Adrenoleukodystrophy Patient is stabilized. Now what: Patient Broad DDx for IEMs scares people. You can group into KEY features. You Can focus on initial labs = Hyperammonia, Can Hyperammonia, hypoglycemia, metabolic acidosis. hypoglycemia, metabolic Can focus on Prominent neurologic features. Can Can focus on Dysmorphic features. Can If these don’t exactly fit, resort back to categories If of IEMs and Neurodegenerative Disorders. Quick References: Quick MA: *metabolic *metabolic acidosis acidosis NH4: Glu: Dz: *Non-ketotic *Non-ketotic Hyperglycine Hyperglycine *Urea Cycle *Urea defects defects *Fatty Acid *Fatty Oxs Oxs *OAemia *OAemia *OAemia *OAemia *Glycogen Strg *Glycogen dfc dfc *Amino Aciduris *Carb *Carb Metabolism dfc Metabolism Transient Hyperammonemia of Newborn: Newborn: Markedly high NH4 in an infant less than 24 Markedly high HOL, or first 1-2 DOL before protein intake occurs. occurs. Often in context of large, premature infant with Often large, symptomatic pulmonary disease. symptomatic Very sick infant. Very sick Unknown precipitant, unknown etiology (possible Unknown slow delayed urea cycle initiation), with potential for severe sequelae (20-30% death, 30-40% abnl devo) if not treated. Does not recur after being treated. Does Organic Acidemias: Organic *Acidotic with high Gap with *Urine Ketones high high *High to nl Ammonia Often present first 2-7 days of life after dietary Often first protein introduced. protein Drunk appearance in infant. Drunk *May have low WBC and Plts. *May Check serum AAs/OAs, Urine AAs/OAs, CSF Check OAs/AAs. Organic Acidemias cont: Organic **Multiple Carboxylase Deficiency** **Multiple or or Defect in Biotin Utilization Defect Biotin is vital cofactor in many pathways, defect results in: Severe deterioration, dermatitis, alopecia, immune Severe deficiency- candidal skin infections. High NH4, acidemic, ketotic like the others. High Dx by enzyme assay. Dx Rx with Biotin 10mg/kg/d PO **Rocky will get this if he consumes too much Avidin, aka, **Rocky Avidin aka, raw eggs. Amino Acidurias: Amino Maple Syrup Urine Disease – – – – – – – – Sweet smell of body fluid esp Urine. Classically develops in 1st week of Life. Classically Poor feeding, emesis, lethargy and coma. Periods of Hypertonicity. Periods Hypertonicity Secondary Hypoglycemia. Possible Metabolic Acidosis, hyperammonemia **Obtain serum/urine AAs/OAs** Treatment requires rapid removal of Branched chain Treatment AAs, often through dialysis. Amino Acidurias: Amino Fresh Urine Uric acid and Sulfite Dipstick if Fresh Uric neurologic abnormalities are present, low uric acid is suggestive for molybdenum cofactor deficiency and Sulfite Oxidase Deficiency. Deficiency Don’t forget PKU. Basic on newborn scrn, Don’t PKU Basic but only does good if results followed up. For the Boards: For *Sweaty feet smell* – Isovaleric Acidemia, think ISOTONER shoes smell think ISOTONER What defect may present with Pulmonary What Embolus? Embolus? Homocystinuria- and thereafter may ask which supplement to initiate? supplement Pyridoxine- due to residual enzyme activity. Other names to know: – Methylmalonic Acidemia- Rx with large dose vitamin B12 B12 – Propionic Acidemia- RX with Biotin. Biotin. Urea Cycle Defects: Urea All but one of the disorders is autosomal recessive. All Symptom free period and then emesis->lethargy-->>COMA Key features: – – – – High Ammonia, low BUN Possible Lactic acidosis *Absence of ketonuria* Nl to mild low Glucose **Treat high ammonia, infuse glucose, send plasma **Treat AAs/OAs, urine orotic acid, and plasma citrulline. AAs/OAs, Infusion of 6ml/kg 10% Arginine HCl over 90 min may help. Infusion Milder forms may show episodic emesis, confusion, ataxia, Milder and combativeness after high protein meals. high For the Boards: For Most common Urea cycle defect and also Most only X-linked: only Ornithine Transcarbamylase Deficiency Fatty Acid Oxidation Defects: Fatty **Autosomal recessive inheritance** Examples are MCAD, LCAD, VLCAD Defect in acyl-CoA Dehydrogenase, a mitochondrial duty, Defect acyl-CoA and important in fasting state. KEY features: Acute attack of life-threatening coma with Hypoglycemia Acute Hypoglycemia Absence of urine ketones, and reducing substances, nl urine serum AAs. +/- mild acidosis, or hyperammonemia, elevated LFTs, abnl +/coags. +/-Hepatomegaly-/+ +/-Hepatomegaly-/+ Dx with serum Acylcarnitine Profile or fibroblast enzyme Dx or assay assay For the Boards: For Fetal Defect in LCHAD may result in Fetal Prenatal course complicated by : Prenatal Maternal HELLP syndrome Non-ketotic Hyperglycinemia: Non-ketotic Unique entity in that Glucose, NH4, pH are all Unique normal. 4 types with varying ages of onset, however, types classic form is Neonatal with onset in 1st week of Neonatal life. life Will present just like the other devastating IEMs. Will Lethargy, emesis, hypotonia, seizures, etc… Lethargy, Uncontrolled hiccups. Dx with no urine ketones, and Elevated Glycine. Dx No effective Rx. Will require diet restriction. No Long term is a devastating disease. Carbohydrate related Disorders: Carbohydrate Galactosemia: Galactosemia: First 1-2 wks of Life: Presents with hypoglycemia, jaundice, First hypoglycemia jaundice emesis. Secondary to intolerance of Galactose. Will be in baby’s first Secondary meals of breast milk or lactose containing formulas. Also index of suspicion for GramNeg or E.coli sepsis. Also GramNeg E.coli Dx assisted by Non-glucose reducing substances in urine. Dx Non-glucose reducing substances urine Confirmation by Galactose-1-PO uridyl transferase activity in RBCs. Confirmation Adverse sequelae include Cataracts, MR, persistent liver Adverse disease. disease. For the Boards: For Which is worse? – Essential Fructosuria – Inherited Fructose Intolerance Inherited Fructose Intolerance – Occurs after ingestion of Fructose (sucrose= glucose + Occurs fructose) fructose) – Severe and life threatening intoxication of F-1-PO4. – Presents with emesis, seizures and profound illness Presents after ingestion of fructose. – May also present similar to Galactosemia. – Life long avoidance of fructose. Life Glycogen Storage Disorders: Glycogen Type 1= Von Gierke’s: – – – – – – Shortly after birth: Severe lifethreatening Hypoglycemia Shortly Hypoglycemia Lactic acidosis –due to isolated glycolysis of G6Po Hyper-uricemia, hyper lipidemia Increased association with epistaxis Increased *Hepatomegaly **Adverse response to Glucagon with worsening Lactic acidosis Management requires IV glucose, and then as outpt, close Management NG corn-starch or glucose solution administration to achieve close to nl glucose homeostasis. Frequent snacks and meals. Continuous nighttime glucose Frequent infusions up to the age of 2. Glycogen Storage Disorders: Glycogen Type 2- Pompe’s disease: Normal Glucose Do to an accumulation of glycogen in lysosomes. Do **Ancient city of Pompeii was destroyed by Mt. Vesuvius- 79 AD** Manifested by massive Cardiomegaly, Manifested Cardiomegaly Hepatomegaly, Macroglossia. Hepatomegaly Macroglossia Fatal If results in CHF. Fatal Limited therapies in Neonatal Variant. – Attempts at enzyme replacement ongoing. Mitochondrial Disorders: Mitochondrial Emerging spectrum of diseases with life-time Emerging variation of presentation. Infantile/Neonatal: may present with Infantile/Neonatal: encephalopathic picture, regressed milestones, cerebral cortical atrophy. Generally lab findings of: – – – – Lactic Acidosis Nl to low serum pyruvate, incomparison to Lactate Nl organic acids. *** Important to check CSF values of the above*** Leigh’s Disease Leigh’s AKA- Subacute necrosing encephalopathy AKA- Subacute Due to defects in the mitochondrial electron Due transport chain. transport May have devastating presentation with significant May developmental regression. developmental Unfavorable natural history. May respond to host of supplements. **Other Mitochondrial disorders for completion **Other sake** sake** – MELAS, MERRF, Leber’s HON Leukodystrophies: Leukodystrophies: Krabbe disease: – Type 1- “Infantile”= irritability, hypertonia, Type hyperesthesia, and psychomotor arrest, followed by rapid deterioration, optic atrophy, and early death – Type 2- Late infantile Type Late – Type 3- Juvenile Type Juvenile – Type 4- Adult Type Adult A demyelination disorder due to CNS demyelination accumulation of galactosylceramide. Diagnosis: supported by cortical atrophy on Diagnosis: CT/MRI, High CSF protein and definite evidence of High deficient GALC assay in WBCs or skin fibroblasts. deficient in Lysosomal Disorders Lysosomal Focus on key differences: Gaucher Disease: – Infantile vs chronic Infantile juvenile juvenile – Organomegaly – Bone pain – Easy bruisability – **low Plts, **low osteosclerosis, and lytic bone lesions bone – MNEUNOMIC= MNEUNOMIC= “Clumsy Gaucho cowboy” cowboy” Tay-Sachs Disease: – Progressive neurologic Progressive degeneration in first YOL and death by age 4-5 yo 4-5 – AR inheritance with AR classic Jewish Ashkenazi relationship. Ashkenazi – Increased startle reflex – Cherry red macula – Macrocephaly Peroxisomal Disorders Peroxisomal Zellweger Syndrome aka: Cerebro-hepato-renal aka: syndrome syndrome Typical and easily Typical recognized dysmorphic facies. Progressive degeneration Progressive of Brain/Liver/Kidney, with death ~6 mo after onset. death When screening for PDs. When obtain serum Very Long Chain Fatty AcidsChain VLCFAs VLCFAs Further Evaluation in IEMs: Further ** Head CT, MRI, Ophtho, Audio, EKG, ** EEG** Genetics consultation. Genetics Peds Neuro consultation. Random Questions for the Boards: Random Amino Acids responsible for MSUD? Valine, Leucine, Isoleucine Name 1 of the 3 classic Metal Storage disorders? Name Metal Menke’s Kinky Hair Syndrome (X-link recessive) Wilson’s Disease Neonatal Hemachromatosis Lysosomal storage disease associated with Adrenal Gland Lysosomal calcifications? calcifications? Wolman Disease – Fatty acid deposits, nl lipid panel – **Mneumo= Wool Man Disease white wool deposits. **Mneumo= Recognize that Smell: Recognize Musty or Mousy: PKU Boiled Cabbage Tyrosinemia or Tyrosinemia hypermethioninemia hypermethioninemia Maple Syrup maple syrup urine disease Sweaty feet: iisovaleric acidemia or glutaric sovaleric acidemia type II Cat urine multiple carboxylase multiple deficiencies (Biotin deficiency) deficiencies Follow up Questions ? Follow Name some classic Mucopolysaccharidosis? Hunter’s (X-linked, no corneal clouding) Hurler’s (presence of Corneal clouding) Morquio Syndrome (nl IQ, short, cloudy cornea) *tattoo on FI *tattoo Morquio -How are mucopolysaccharidoses Diagnosed? -How Urine MPSs, definite with Skin Fibroblast Bx How to treat Neonatal Hyperinsulinism? How Neonatal Hyperinsulinism Diazoxide- inhibits pancreatic B-cell insulin secretion. DiazoxideChild Dx with PKU, now diet restricted, but with progressive Child neuro deterioration. What else might be deficient? neuro Tetrahydrobiopterin (BH4) Finally and to wet your appetite for Sat: Sat: Name this syndrome and the associated metabolic Name defect. Smith-Lemli-Opitz Syndrome: due to defect in cholesterol synthesis. cholesterol For Reference: For AAP Guidelines to IEMs. 1998;102;69- Barbara K. Burton DOI: 10.1542/peds.102.6.e69 Pediatrics Quick Algorithms: Quick ...
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This note was uploaded on 12/24/2011 for the course STEP 1 taught by Professor Dr.aslam during the Fall '11 term at Montgomery College.

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