IEMs Emergency Management

July 27, 2011Emergency Lecture Series, AHD

Ali Alwadei, MDR5 Peds Neuro

Outline

1. Introduction and Definitions2. General Classification3. When to suspect IEMs4. Approach to acute IEM presentation5. Interpretation/DDx of Routine labs6. Hyperammonemia and UCD7. IEMs with Seizures/NTs8. Mitochondrial Acute Presentation9. Special labs

If time permits

11.DDx of Cherry-Red Spots & RP12.Causes of –ve FHx in genetics 13.Vitamin Rx for specific IEMs

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

General Classification

1. Protein: [Small mol]– AA: Tyr, PKU, MSUD, HC, NKH, Hartnup– OA: PPA, MMA, IVA, GA, Biotinidase Deficiency– UCD: CPS, NAGS, OTC, ASS(citru), ASL

2. CHO: Galact, Fruct, GSD [Energy Metabolism]3. 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)

4. Peroxisomal: [Large Mol]• Zellweger, XLALD, Refsum, Rhizo chondrodys punct

5. Mitochondrial [Energy Metabolism]– PDHC, Leigh, Wolfram, Alpers, MERRF, MELAS, KSS, NARP, LHON,CPEO.

1. Transport Defects: Wilson, Menkes, 2. Sterol metabolism: SLOS3. Purines-Pyrimidines metab: LNS4. B.A. metab: CTX5. CDGs6. NTs

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.

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

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

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

Approach to acute IEM presentation

• 1st line Labs:– BLOOD:

• CBC: OAs have pancyto• SMA10: protein, mitoch, perox IEMs have multi-syst involv 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

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.

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

Interpretation/DDx of Routine labs

• AbN LFTs:– AA: +++ esp Tyrosinemia I– OA: ?– UCD:?– CHO: ++ Galactosemia– Lipids: ++ FAOD– Lyso: +– Perox: ++ Zellweger (multi-systemic)– Mitoch: ++ (multi-systemic)

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)

Interpretation/DDx of Routine labs

• Hyper-NH3:1. UCD2. OA

Interpretation/DDx of Routine labs

• Acidosis:– AA: ++ MSUD– OA: ++++ all– UCD: initially Alk– CHO: ++– Lipids: ++ FAOD– Lyso: ?– Perox: ?– Mitoch: +++

Interpretation/DDx of Routine labs

• Non-IEMs DDx of AbN LFTs, Hypoglycemia, High NH3 & Acidosis:

1.Sepsis2.HIE3.Liver Failure4.Cardiac Failure (LA only)

High NH3

• Defnition: in micromol/L

High NH3

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

High NH3

• Should be in ice and immediately analyzed• False +ve is common• DDx:1. UCD ( e.g. OTC)2. OA ( e.g. PPA)• Others– Sepsis, HIE, Liver Failure– Patent ductus venosus (Transient)– Ass Ventilation, RDS, Gen Sz ( Inc Muscle Act)

High NH3

• How to differentiate b/w UCD and OA?– Send:

1.Orotic Acid: if High UCD. So, send Citrulin: if high ASS (Citrulinemia) and if low OTC

2.Acylcarnitines: if AbN OA

• One of the most common IEMs• Urea Cycle:

UCD

UCD

1. CPS2. NAGS3. OTC (X-Linked)4. ASS (Citrulinemia)5. ASL

UCD

• Clinical:– Neonatal:

• Rapidely progressive symptoms in first days of life after short Sx free interval.• Poor Feeding, Lethargy to Coma (Encephalopathy).• Sz• HV Resp Alkalosis initially• T” Changes• ICH b/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.

UCD

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

UCD

• Rx:– As in High NH3

IEMs with Seizures/NTs• DDx of Intractable Neonatal/Infantile Sz from metabolic standpoint:1. B6 (Pyridoxine) Dependent Sz2. PLP (Pyridoxal Phosphate) Deficiency3. Folinic-Acid responsive Sz4. Biotinidase Deficiency5. HXP (Hyperekplexia)6. NKH ( Non-Ketotic Hyperglycinemia)7. GLUT1 deficiency8. Molybdenum Cofactor Deficiency9. Sulfite Oxidase Deficiency10.NCL11.LNS12.CDGs

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)

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.

NKHNon-Ketotic Hyperglycinemia

• AA, AR, PHTM enz def, 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

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:1.OA2.VPA3.HIE4.Starvation

NKH

• Rx:– No Diet successful1.Exp Dextromethorphan-DXM (NMDA R antagonist)2.Benzoate (decrease Gly)3.Carnitine (decrease Gly)4.Folinic Acid

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

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

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.

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?1.Several mitochondrial enzyme complexes

which share producing some proteins.2. accumulating metabolites may have

inhibitory effect on other enzymes.

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.

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

Mitoch DX

• Probable:– Clinical + 1/31.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.

2.Typical MRI: High T2 signal BG&BS3.Typical Muscle Bx: RRF, RBF, COX-ve fibers, AbN SDH

staining, AbN mitochondrion on EM.• Definite: – Molecular.

Mitoch Rx1. IVF:

– Good Hydration– Good Calories (Low Glucose high Fat)– + carnitine

2. Treat Acidosis3. Vitamins & Cofactors: justified to D/C in 6 mo if no improvement

1. CoQ10, 2. Biotin, 3. Creatine.

4. Treat Infections (Avoid Tetra & Chlor as they – Resp chain)5. Treat Sz ( Avoid VPA)

Special labs

• PAA:– Tandem-MS– Indications:• Metabolic screen• High NH3• AA• UA• Mitoch• Epileptic Encephalopathy

Special labs• UOA:

– GCMS– Metabolic Screen– Hypoglycemia, Acidosis.– OA– AA– FAOD– Mitoch– Epileptic Encephalopathies

• Acylcarnitines:– Tandem-MS– FAOD– OA ( characteristic Profile)

Special labs

• Glycosylation Studies:– PAA/Tandem-MS

• Lysosomal Studies:– Urine GAGs, oligos

• UCD:– Orotic Acid (PAA)

Special labs• High AFP:– Tyr I– Hepatoblastoma– Hemochromatosis – AT

• High Urine and Liver Copper:– Wilson– Peroxisomal

• Low serum Copper and Ceruplasmin:– Wilson– Menkes

Special labs

• Lipid profile:– Low in:• SLOS• CDGs• Peroxisomal• ABL

• Blood Smear:– Vacuolated Lymphocytes in Lysosomal (NCL)– Acantho: ABL, HARP, AT, Neuroacantho, McLeod,

Wolman

Special labs

• High CK:– MDs– FAOD– GSD– Mitoch

• High UA:– LNS– FAOD– GSD– Mitoch

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

Special labs

• Urine RS:– Galactosemia– Fructose intol.– Fanconi’s– Tyrosenemia

Special labs• CSF:– Glu:

• NL (CSF/P) ratio > 0.65• Low ( < 0.35) in GLUT1 def

– AA• Gly:

– NL < 0.04, ( in Neon , 0.08)– High in NKH

• Ala and Thr:– High in Mitoch

• GABA:– Low in HXP– Low in B6

Special labs

• CSF Lactate/Pyruvate:– High in Mitoch– High Pyr in PDHC with NL La/Pyr ratio

• CSF NTs:– Biogenic amines for Folinic Acid-responsive Sz– Pterins for Segawa

Special labs

• Skin Bx:– Don’t Freeze– In Cx medium Fibroblast for Enz Studies– In Formalin For Histopath– NCL: Finger-print sign

Special labs

• Muscle Bx:– Mitoch– For:1.Histochem & IHC2.Biochemical Eval3.Enzyme Studies4.Mutation Analysis ( Molecular Testing)5.Mitochondia Isolation and Eval

Special labs

• Molecular Genetic Testing:– Gene Mutation Analysis (screening & Scanning)– DNA (GS) & Genomic (Super GS) Analysis

DDx of Cherry-Red Spots• Oligo

– Sialidosis• Sphingos

1. GM12. GM2 ( Tay-Sachs)3. GM2 (Sandhoff)4. ? MLD5. Krabbe6. Faber7. NPD-A8. Gaucher-2-----------------------------------------------------------------------------------------------------------------------------------

• Central Retinal Artery Occlusion• Drugs/Toxins:

1. Quinine2. CO3. Methanol

DDx of RP

• IEMs:1. FAOD ( Lipid)2. Zellweger ( Perox)3. Refsum “4. NARP ( Mitoch )5. KSS “

• Ataxias:6. ABL7. HARP8. AVED

Causes of –ve FHx• Non-AD inheritance:

1. De Novo (Sporadic, New)2. AR3. XL4. Maternal

• Genetic Process:5. Anticipation in Patient.6. Incomplete Penetrance in previous Family member7. Mosaisim in previous Family member

• Poor Hx:8. Non-Cooperation of family9. Loss of contact10. Adption11. Unfortunately False Paternity (Non-Paternity)

Helpful Vitamin Rx for AA&OA• MSUD & PDHC: – Thiamin

• HC: – B12, Folate, B6, Betain, Vit C

• NKH:– Folinic Acid

• Hartnup:– Nicotinamide

-----------------------------------------------------------------• MMA:– B12

THANK YOU