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IEMs Emergency Management July 27, 2011 Emergency Lecture Series, AHD

IEMs Emergency Management July 27, 2011 Emergency Lecture Series, AHD. Ali Alwadei, MD R5 Peds Neuro. Outline. Introduction and Definitions General Classification When to suspect IEMs Approach to acute IEM presentation Interpretation/DDx of Routine labs Hyperammonemia and UCD

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IEMs Emergency Management July 27, 2011 Emergency Lecture Series, AHD

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  1. IEMs Emergency ManagementJuly 27, 2011Emergency Lecture Series, AHD Ali Alwadei, MD R5 Peds Neuro

  2. Outline • Introduction and Definitions • General Classification • When to suspect IEMs • Approach to acute IEM presentation • Interpretation/DDx of Routine labs • Hyperammonemia and UCD • IEMs with Seizures/NTs • Mitochondrial Acute Presentation • Special labs

  3. If time permits • DDx of Cherry-Red Spots & RP • Causes of –ve FHx in genetics • Vitamin Rx for specific IEMs

  4. Introduction and Definitions • Inherited Biochemical Disorders • Generally AR with few exceptions: • LNS, Hunter, OTC, Fabry, PDHC are X-Linked • Affect: • Synthesis, • Metabolism, • Transport or • Storage of biochemical compounds • Many feature significant clinically apparent neurologic dysfunction

  5. General Classification • Protein: [Small mol] • AA: Tyr, PKU, MSUD, HC, NKH, Hartnup • OA: PPA, MMA, IVA, GA, Biotinidase Deficiency • UCD: CPS, NAGS, OTC, ASS(citru), ASL • CHO: Galact, Fruct, GSD [Energy Metabolism] • Lipids: [Large Mol] • FAOD [Energy Metabolism] • Lysosomal: • MPSs & Oligos(Sialid), • Sphingos ( GMs, MLD & Krabbe, Fabry & Farber, NPD A-B & Gaucher) • Mucolip & Lipidosis ( NPD C-D & ?Gaucher) • NCL & GSD II (Pompe) • Peroxisomal: [Large Mol] • Zellweger, XLALD, Refsum, Rhizochondrodyspunct • Mitochondrial [Energy Metabolism] • PDHC, Leigh, Wolfram, Alpers, MERRF, MELAS, KSS, NARP, LHON,CPEO.

  6. Transport Defects: Wilson, Menkes, • Sterol metabolism: SLOS • Purines-Pyrimidines metab: LNS • B.A. metab: CTX • CDGs • NTs

  7. When to suspect IEMs • Hx: • Age: • any age ( usually childhood) • FHx: • Consang, miscarriages, deaths (SIDS, sepsis or unexplained), MR/DD, Sz, specific ethnic group • HPI: • NL at birth • Sx free period until toxic exposure (DOL#2 usually) • Septic picture of Acute overwhelming neonatal presentation: poor feeding, lethargy to coma (encephalopathy) and Sz (myoclonic high amplitude tremors) • Continuing deterioration despite Abx and –ve full sepsis screening • Episodic stress-related post-neonatal presentation of neonatal Sx [ stress= fasting, fever/infections, high load of toxic metabolite, exercise, drugs, surgery, vaccine] + DD/DR, liver disease.

  8. When to suspect IEMs • Exam: • Encephalopathy • Dysmorphism • Coarse: MPSs • Others with typical unusual facies: Zellweger, SLOS, PPA • Hair AbN: • Hirsutism: MPSs • Alopecia: Biotinidase • Kinky: Menkes • Blond= PKU • Unusual odor: all Protein IEMs • Cabbage=Tyrosenemia I • MSU=MSUD • Mousy/Musty= PKU • Sweaty feet= IVA&GA2 • Fish=TMAuria • Cat Urine= 3-methyl-crotonyl-coA carboxylase deficiency • CNS non-specific findings: HC, Tone, Cherry-Red, RP • Organomegaly, CVS, MSK

  9. When to suspect IEMs • Why it is crucial to have early Dx? • Specific treatments that may radically alter individual outcomes averting significant neurologic sequelae • Success related to earlier timing of identification & intervention

  10. Approach to acute IEM presentation • ABCD, IV line, Glucose, NPO (D/C toxic substance), send all labs [extremely important: Glucocheck] • Quick targeted Hx: • FHx (important) • Exam: (Targeted) • V/S • Establish LOC • Search Dysmorphism ( Cranium, skin, MSK ) • Don’t forget to smell them! • CNS: Coma limited exam, don’t forget HC • Organomegaly • CVS

  11. Approach to acute IEM presentation • 1st line Labs: • BLOOD: • CBC: OAs have pancyto • SMA10: protein, mitoch, perox IEMs have multi-systinvolv and Renal impairment • Full LFT including: enz, coags, NH3, Glucose + ketones in blood and urine • If Glu is low: send critical sample of Insulin, GH, Cortisol, FFA & Ketones • B. Gas with Lactate and pyruvate (ratio) • PAA/Acylcarnitines • URINE: • UOA and ketones • CSF: (After stabilization) • AA: NKH w high Gly, B6 def w low GABA • Lactate for mitoch • EEG if Sz • MRI/MRS when stable

  12. Fluid Mx principles in IEMs • ICU setting, Central Art and venous lines • High Rate @ 150ml/kg/day • High Glucose intake at: • @10mg/kg/min ( NL hepatic Glu production) • @~ 60 kcal/kg/day • May need more if OA, so, increase and add insulin • Maybe dangerous if PDHC (Mitich) b/o LA • Avoid quick drop in Na+ to avoid cerebral edema • Intra-Lipids @ 0.5-1 to 3 gm/kg/day only after excluding FAOD.

  13. High NH3 • If UCD is suspected ( High NH3) then: • Arginine • Benzoate • Carnitine • Zofran (Ondansetron) for V’ • Lactulose • Dialysis if > 500 • Hemofiltration or HD, PD not sufficient • Exchange Tx is C/I as increase Protein and NH3 load

  14. Interpretation/DDx of Routine labs • AbN LFTs: • AA: +++ espTyrosinemia I • OA: ? • UCD:? • CHO: ++ Galactosemia • Lipids: ++ FAOD • Lyso: + • Perox: ++ Zellweger (multi-systemic) • Mitoch: ++ (multi-systemic)

  15. Interpretation/DDx of Routine labs • Hypog-Glycemia: • < 2.6 mmol/L or < 45 mg/dL • Hyperinsulinemia and Hypopit ( most common cause) • AA: ? • OA: +++ • UCD: ? • CHO: ++ GSD I&III • Lipids: ++ FAOD • Lyso: ? • Perox: ? • Mitoch: +++ ( Liver DysFx)

  16. Interpretation/DDx of Routine labs • Hyper-NH3: • UCD • OA

  17. Interpretation/DDx of Routine labs • Acidosis: • AA: ++ MSUD • OA: ++++ all • UCD: initially Alk • CHO: ++ • Lipids: ++ FAOD • Lyso: ? • Perox: ? • Mitoch: +++

  18. Interpretation/DDx of Routine labs • Non-IEMs DDx of AbN LFTs, Hypoglycemia, High NH3 & Acidosis: • Sepsis • HIE • Liver Failure • Cardiac Failure (LA only)

  19. High NH3 • Defnition: in micromol/L

  20. High NH3 • Causes irreversible Brain damage if not treated urgently. Therefore, Rapid & efficient Mx is of utmost importance.

  21. High NH3 • Should be in ice and immediately analyzed • False +ve is common • DDx: • UCD ( e.g. OTC) • OA ( e.g. PPA) • Others • Sepsis, HIE, Liver Failure • Patent ductusvenosus (Transient) • Ass Ventilation, RDS, Gen Sz ( Inc Muscle Act)

  22. High NH3 • How to differentiate b/w UCD and OA? • Send: • Orotic Acid: if High  UCD. So, send Citrulin: if high ASS (Citrulinemia) and if low  OTC • Acylcarnitines: if AbN  OA

  23. One of the most common IEMs • Urea Cycle:

  24. UCD

  25. UCD • CPS • NAGS • OTC (X-Linked) • ASS (Citrulinemia) • ASL

  26. UCD • Clinical: • Neonatal: • Rapidely progressive symptoms in first days of life after short Sx free interval. • Poor Feeding, Lethargyto Coma (Encephalopathy). • Sz • HV  Resp Alkalosis initially • T” Changes • ICHb/o AbN Coags • Infantile: • FTT, Feeding Problem, V” • Paroxysms of Sz, Ataxia, Encephalopathy with increased Catabolism • Adol: • Chronic Neuro and Psych/Behav Problem • Paroxysms of Sz, Ataxia, Encephalopathy with increased Catabolism.

  27. UCD • Dx: • Clinical • PAA: all show high Alanin and Glutmate • High citrulin in Citrulinemia • UOA: High Orotic Acid in OTC • Enzyme studies

  28. UCD • Rx: • As in High NH3

  29. IEMs with Seizures/NTs • DDx of Intractable Neonatal/Infantile Sz from metabolic standpoint: • B6 (Pyridoxine) Dependent Sz • PLP (Pyridoxal Phosphate) Deficiency • Folinic-Acid responsive Sz • Biotinidase Deficiency • HXP (Hyperekplexia) • NKH ( Non-KetoticHyperglycinemia) • GLUT1 deficiency • Molybdenum Cofactor Deficiency • Sulfite Oxidase Deficiency • NCL • LNS • CDGs

  30. B6-Responsive Sz • AR • Unclear Etiology • High CSF Glutamate and Low GABA • Glut DC enzyme is B6-dep to convert to GABA • Dx: • Typical form intractable Neonatal Sz on DOL#1 or #2 ( within 28 days) but variants exist with atypical late-onset presentation. • Typical good response to B6 with Atypical Forms • Low CSF GABA and High Glutamate • High Urine (Amino-Adipic semi-aldehyde)

  31. B6-Responsive Sz • Rx: • No Universal Protocol for B6 challenge. • High Doses needed initially. • Suggested Protocol: • IV single dose of 100 mg, if no response  • IV additional dose of 100mg Q 10min for total of 500mg, if no response  D/C and try PLP. • if responsive  • Good Response: PO maintenance 5-15 mg/kg/day • Partial Response: PO maintenance 30 mg/kg/day for minimum of 7 days before any conclusion.

  32. NKHNon-KetoticHyperglycinemia • AA, AR, PHTM enzdef, Glycine Cleavage Defect • Clinical: • Classic:: • Onset: 6 hrs – 8 days • Early and Continuous HICUPPING • Severe Neonatal Epilep Encephalopathy (Myoclonic) • Resp Problems • Later spasticity and MR • Variant: • Later onset , few weeks only ( infantile) • Episodic Sx • Mod MR

  33. NKH • Dx: • PAA: High Gly • CSF AA: High CSF Gly/P. Gly ratio > 0.06 (NL<0.04) • MRI: Ageneis of CC • EEG: BS  HA • DDx of high Gly: • OA • VPA • HIE • Starvation

  34. NKH • Rx: • No Diet successful • Exp Dextromethorphan-DXM (NMDA R antagonist) • Benzoate (decrease Gly) • Carnitine (decrease Gly) • Folinic Acid

  35. GLUT1Glucose Transporter Deficiency • AD, NT disorder, GLUT1 • Clinical: • Neon/Infan Epilep Encephalop • Microcephaly • DD/MR • Dx: • Low CSF Glu/ S. Glu ratio < 0.35 ( NL >0.65) • Low CSF Lactate • Molecular (GLUT1) • Rx: • KD • Px: • Good w early Dx & Rx

  36. HPXHyperekplexia • AD & AR exist, rarely de novo • Chrom 5 & others ( 4, 11, 14, X) • GLRA1& other 5 identified genes • Glycine transporter mut • aka Stiff baby Sx & Exaggerated startle reaction

  37. HPX • Clinical: • Exaggerated startle reaction. • Hypertonia ( decrease in sleep). • violent flexor spasms of limbs and neck muscles. elicited by tapping the tip of the nose. • SIDS has been reported. • Intellect is usually normal. • Dx: Low CFS GABA confirmed by Molecular. • Rx: Rivotril is the DOC, Keppra may work.

  38. Mitochondrial • Why Childhood presentation is more severe? • Involve both brain and muscle, whereas adults usually affect muscles and present with myopathy only. • Why the overlap in Mitochondrial disorders? • Several mitochondrial enzyme complexes which share producing some proteins. • accumulating metabolites may have inhibitory effect on other enzymes.

  39. Mitochondrial • AR, AD, XL, Maternal if mtDNA (5-10%) • Multisystem involve organs w high energy requirement: MEB+ heart&Kid • Brain: Diffuse, Cortex (Sz&MR), BG(EP Sx), WM(P Sx), BS (Bulbar Sx: Ds+Apnea&Ataxia), Arteries (Strokes&Migraine), PNS(Neuropathy). • GI: Ch Diarrhea, Pseudo-obstruction. • Blood: Pancytopenia.

  40. Mitoch Emergencies • Peds: • Neonatal Encephalopathy & Lactic Acidosis (PDHC), • Neonatal Apneas (Leigh), • Neonatal Sz (PDHC, Alpers) • Adult: • Stroke (MELAS) • Ataxia (Progressive , NOT acute) : NARP & KSS • Encephalopathy + Dementia: MERRF

  41. Mitoch DX • Probable: • Clinical + 1/3 • Typical Labs: e.g. pancytopenia, AbN LFTs, high NH3, Fanconi, high CK, AbN B. Gas and high Lactate&Pyruvate, PAA &CSF AA w high Ala and Thr. • Typical MRI: High T2 signal BG&BS • Typical Muscle Bx: RRF, RBF, COX-ve fibers, AbN SDH staining, AbN mitochondrion on EM. • Definite: • Molecular.

  42. Mitoch Rx • IVF: • Good Hydration • Good Calories (Low Glucose high Fat) • + carnitine • Treat Acidosis • Vitamins & Cofactors: justified to D/C in 6 mo if no improvement • CoQ10, • Biotin, • Creatine. • Treat Infections (Avoid Tetra & Chlor as they – Resp chain) • Treat Sz ( Avoid VPA)

  43. Special labs • PAA: • Tandem-MS • Indications: • Metabolic screen • High NH3 • AA • UA • Mitoch • Epileptic Encephalopathy

  44. Special labs • UOA: • GCMS • Metabolic Screen • Hypoglycemia, Acidosis. • OA • AA • FAOD • Mitoch • Epileptic Encephalopathies • Acylcarnitines: • Tandem-MS • FAOD • OA ( characteristic Profile)

  45. Special labs • Glycosylation Studies: • PAA/Tandem-MS • Lysosomal Studies: • Urine GAGs, oligos • UCD: • Orotic Acid (PAA)

  46. Special labs • High AFP: • Tyr I • Hepatoblastoma • Hemochromatosis • AT • High Urine and Liver Copper: • Wilson • Peroxisomal • Low serum Copper and Ceruplasmin: • Wilson • Menkes

  47. Special labs • Lipid profile: • Low in: • SLOS • CDGs • Peroxisomal • ABL • Blood Smear: • Vacuolated Lymphocytes in Lysosomal (NCL) • Acantho: ABL, HARP, AT, Neuroacantho, McLeod, Wolman

  48. Special labs • High CK: • MDs • FAOD • GSD • Mitoch • High UA: • LNS • FAOD • GSD • Mitoch

  49. Special labs • Peroxisomal Studies: • VLCFA • Phytanic Acid • Plasmalogens • Pyruvate: • Mitoch (PDHC & Resp chain disorders) • Shouldn’t usually be measured • Lactate more relevant • Don’t do it without Lactate for ratio (more helpful) • NL ratio < 20

  50. Special labs • Urine RS: • Galactosemia • Fructose intol. • Fanconi’s • Tyrosenemia

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