Transcript IEMs Emergency Management

IEMs
Emergency Management
July 27, 2011
Emergency Lecture Series, AHD
Ali Alwadei, MD
R5 Peds Neuro
Outline
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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
If time permits
11.DDx of Cherry-Red Spots & RP
12.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:
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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
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CHO: Galact, Fruct, GSD [Energy Metabolism]
Lipids: [Large Mol]
– FAOD [Energy Metabolism]
– Lysosomal:
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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, Rhizo chondrodys punct
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Mitochondrial [Energy Metabolism]
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PDHC, Leigh, Wolfram, Alpers, MERRF, MELAS, KSS, NARP, LHON,CPEO.
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Transport Defects: Wilson, Menkes,
Sterol metabolism: SLOS
Purines-Pyrimidines metab: LNS
B.A. metab: CTX
CDGs
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:
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Hirsutism: MPSs
Alopecia: Biotinidase
Kinky: Menkes
Blond= PKU
– Unusual odor: all Protein IEMs
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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)
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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:
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@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:
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< 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. UCD
2. 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. Sepsis
2. HIE
3. Liver Failure
4. Cardiac Failure (LA only)
High NH3
• Defnition: in micromol/L
Neonate
NL < 110
Sick < 180
IEM > 200
Child
NL < 80
Sick < 100
IEM > 100
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
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CPS
NAGS
OTC (X-Linked)
ASS (Citrulinemia)
ASL
UCD
• Clinical:
– Neonatal:
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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 Sz
2. PLP (Pyridoxal Phosphate) Deficiency
3. Folinic-Acid responsive Sz
4. Biotinidase Deficiency
5. HXP (Hyperekplexia)
6. NKH ( Non-Ketotic Hyperglycinemia)
7. GLUT1 deficiency
8. Molybdenum Cofactor Deficiency
9. Sulfite Oxidase Deficiency
10. NCL
11. LNS
12. 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 lateonset 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.
NKH
Non-Ketotic Hyperglycinemia
• AA, AR, PHTM enz def, Glycine Cleavage Defect
• Clinical:
– Classic::
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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:
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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:
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OA
VPA
HIE
Starvation
NKH
• Rx:
– No Diet successful
1. Exp Dextromethorphan-DXM (NMDA R antagonist)
2. Benzoate (decrease Gly)
3. Carnitine (decrease Gly)
4. Folinic Acid
GLUT1
Glucose 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
HPX
Hyperekplexia
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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 + 1/3
1. 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&BS
3. Typical Muscle Bx: RRF, RBF, COX-ve fibers, AbN SDH
staining, AbN mitochondrion on EM.
• Definite:
– Molecular.
Mitoch Rx
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IVF:
– Good Hydration
– Good Calories (Low Glucose high Fat)
– + carnitine
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Treat Acidosis
Vitamins & Cofactors: justified to D/C in 6 mo if no improvement
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CoQ10,
Biotin,
Creatine.
Treat Infections (Avoid Tetra & Chlor as they – Resp chain)
Treat Sz ( Avoid VPA)
Special labs
• PAA:
– Tandem-MS
– Indications:
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Metabolic screen
High NH3
AA
UA
Mitoch
Epileptic Encephalopathy
Special labs
• UOA:
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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:
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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:
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SLOS
CDGs
Peroxisomal
ABL
• Blood Smear:
– Vacuolated Lymphocytes in Lysosomal (NCL)
– Acantho: ABL, HARP, AT, Neuroacantho, McLeod,
Wolman
Special labs
• High CK:
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MDs
FAOD
GSD
Mitoch
• High UA:
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LNS
FAOD
GSD
Mitoch
Special labs
• Peroxisomal Studies:
– VLCFA
– Phytanic Acid
– Plasmalogens
• Pyruvate:
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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 & IHC
2. Biochemical Eval
3. Enzyme Studies
4. 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
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GM1
GM2 ( Tay-Sachs)
GM2 (Sandhoff)
? MLD
Krabbe
Faber
NPD-A
Gaucher-2
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• Central Retinal Artery Occlusion
• Drugs/Toxins:
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Quinine
CO
Methanol
DDx of RP
• IEMs:
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FAOD ( Lipid)
Zellweger ( Perox)
Refsum
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NARP
( Mitoch )
KSS
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• Ataxias:
6. ABL
7. HARP
8. AVED
Causes of –ve FHx
• Non-AD inheritance:
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De Novo (Sporadic, New)
AR
XL
Maternal
Genetic Process:
5. Anticipation in Patient.
6. Incomplete Penetrance in previous Family member
7. Mosaisim in previous Family member
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Poor Hx:
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Non-Cooperation of family
Loss of contact
Adption
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