Metabolic emergencies
in neurology
David Dufresne, MD
R2, Child neurology
Montreal Children’s Hospital
September 1st, 2010
Presentation plan
• Objectives
• Basic theory and acute clinical
presentation of inborn errors of
metabolism
• The urea cycle and its potential defects
• Initial evaluation and management
• Quebec’s neonatal screening program
Objectives
• Recognition of acute neurological
presentations of metabolic disease
• Investigations, with focus on treatable
disorders
• Emergency management – general
principles
• Rapid overview of provincial screening
program
Clinical cases
July 1st, 8:05 am – 1st MCH rotation for a brand new R2
Ped. neurology R3 is sick, you and a very motivated M3 are alone, no
staff in sight...
You get called for two consults!
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BB Tremblay-Gagnon
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No consanguinity
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Unremarkable FMHx
Term BB boy, GDM, otherwise unremarkable
pregnancy
Prolonged labor, c-section for failure to progress
after 22 hours
APGAR 3-5-6, bag and mask ventilation by
pediatrician on call, eventually intubated
BW 5 kg
Cord gas (venous) 6.9/80/10/-17
Neurology called by NICU on DOL 2
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Profound hypotonia, no suction, lethargy
since birth, now multifocal myoclonic jerks
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Afebrile, BP 70/40, HR 145, general exam
reveals jaundice
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DOL 1:
• Venous lactate 19
• Improving metabolic acidosis
• Hypoglycemic – requires IV D10
• Elevated liver enzymes
• Poor urine output, high BUN
• Normal CBC
• Bilirubin below phototherapy level
• Cultures taken at 2 hours of life still
not growing anything
BB Smith
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Later named either Pierre-Olivier (or Louis-Philippe)
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Later named John
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No consanguinity
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Unremarkable FMHx
Term BB boy, severe gestational HTN, father talks
of platelets that were too low
Prolonged labor, c-section for profound fetal
decceleration (1-2 minutes)
APGAR 8-9-10, no resuscitation needed
BW 3.6kg
Cord gas 7.2/45/20/-3
Initially well, breastfed twice but then mother
transferred to ICU
Transferred to NICU at 36 hours of life for
progressive lethargy and hypotonia, now not
drinking at all, very poorly responsive
Neurology called for multifocal myoclonic jerks
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AVSS, general exam reveals hepatomegaly,
jaundice
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DOL 2
• Increasing liver enzymes
• Hypoglycemic, NICU nurse inserting
IV to run standard aminoacid solution
with 10% dextrose
• Normal CBC
• Bilirubin below phototherapy level
• Normal BUN and urine output
• Urine analysis unremarkable, no
ketones
• Blood, urine and CSF cultures
pending
Basic theory
• Inborn error of metabolism (IEM):
– Genetic defect precluding normal
functioning of one particular pathway
• Most commonly enzymatic defect, but sometime
problem arises from faulty transporter and such
• Normal functioning of enzymatic
pathway =>
S1± … ±Sx =Zxyz=> P1±… ±Px
Basic theory
• Inborn error of metabolism (IEM):
– Symptoms result from accumulation of
substrate, lack of product or both
S1± … ±Sx ≠>
P1±… ±Px
– Usually 2nd to enzymatic defect, but also
transporter, anomaly organelle
superstructure, etc.
Basic theory
Cellular biology 101:
obviously, photosynthesis
is not pertinent for
human pathologies, but
unfortunately the rest
is…
2003 International
Union of Biochemistry
and Molecular Biology
Clinical presentation patterns
• IEMs can be divided in groups
according to pathophysiology
– Different disorders from same group have some
phenotypical similarities
– Approach to treatment also similar within group
• Categories not totally exclusive – defect in
enzyme X can produce symptom by
accumulation of substrate AND lack of product
– Atypical presentation possible, depending on
endogenous and environmental factors
Clinical presentation patterns
• Typical presentations
– Group 1: Disorders of intoxication
– Group 2: Disorders of energy metabolism
– Group 3: Disorders involving complex molecules
– Group 4: Vitamin-responsive encephalopathy
Clinical presentation patterns
• Group 1: Disorders of intoxication
– Accumulation of metabolite to toxic level:
ammonia, AA, OA, CHO, metals, porphyrins
• Usually no interference with embryo-fetal life
• Acute, episodic or chronic presentation, usually
after symptom-free interval
– Patient presenting after exogenous intake or
endogenous release eg. catabolic state
• Varying end-organ involvement depending on
specific metabolite and end-organ susceptibility
Clinical presentation patterns
• Group 1: Disorders of intoxication
– Variable presentation (especially disorders of
metal transport and porphyrias)
– Frequent neonatal presentation after initial
‘‘honeymoon’’ phase
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Lethargy / irritability
Weak suck
Seizure
Eventual coma
± hepatic, cardiac or renal failure
– Occasionally, episodic or late catastrophic
presentation from infancy to adulthood
Clinical presentation patterns
• Group 1: Disorders of intoxication
• DDx:
– Urea cycle disorders - ammonia
• e.g. OTC deficiency, CPS deficiency
– CHO intolerance – specific sugar
• e.g. galactosemia, hereditary fructose intolerance
– Aminoacidopathies – various aminoacids
• e.g. maple sirup urine disease, PKU
– Organic acidurias – various organic acids
• e.g. propionic aciduria, methylmalonic aciduria
– Disorders of metal transport - metal
• e.g. hemochromatosis, Wilson’s, Menkes’
– Porphyrias – porphyrins and precursors
• e.g. acute intermittent porphyria
Clinical presentation patterns
• Group 2: Disorders of energy
metabolism
– Mitochondrial or cytoplasmic defect
• Often associated with prominent lactic acidosis
– Mitochondrial usually more severe than
cytoplasmic energy metabolism disorder
– Some of them interfere with embryo-fetal
development – possible dysmorphisms
Clinical presentation patterns
• Group 2: Disorders of energy
metabolism
– Mitochondrial metabolism defects:
• Especially prone to decompensating in periods of high
metabolic demand
• Some drugs are toxic to mitochondrias (eg:VPA, barbiturates)
• Frequently untreatable
– Exceptions are FAODs, ketone metabolism disorders
– Various cofactors used as mitochondrial “booster” – variable
results
• Variable presentations of mtDNA-transmitted disorders
– Heteroplasmy accounts for different severity and variable organ
involvement of mtDNA defect
– More or less random involvement of nervous system, liver,
kidneys, heart or skeletic muscle, depending of specific
disorder
• DDx:
– Congenital lactic acidemias
» Pyruvate metabolism, Krebs’ cycle
– Respiratory chain disorders
– Fatty acid oxydation defects
– Disorders of ketogenesis or ketolysis
Clinical presentation patterns
• Group 2: Disorders of energy
metabolism
– Cytoplasmic energy metabolism disorders:
• More homogenous presentation with a similar defect
than mtDNA defects
• Fasting hypoglycemia, hepatopathy vs myopathy /
exercise intolerance
• DDx:
– Glycogen storage disorders and other disorders of
glucose metabolism
» Also chronic, progressive intoxication-type
disease
– Persistent hyperinsulinism
– Creatine deficiency syndrome
Clinical presentation patterns
• Group 3: Disorders involving complex
molecules
– Chronic, progressive diseases due to disturbance in synthesis or
destruction of complex molecules
– Dysmorphism, various organ involvement
– Symptoms independents of intercurrent events or nutritional
intake – some neonatal presentations, but most less acute than
other disorders
– Includes lysosomal storage disorders (sphingolipidoses,
mucopolysaccharidoses, cystinosis), peroxysomal disorders
(Zellweger, x-ALD, Refsum, etc), congenital disorders of
glycosylation and others
– Diagnosis often fastidious, involving enzyme assays and genetic
tests
– Few, if any, acute presentation – new patients usually present
with subacute or chronic symptoms
– Some amenable to treatment
• Enzyme replacement therapy
• Bone marrow transplant
• Substrate reduction occasionally gives modest (but more often
disappointing eg: Lorenzo oil) results
Clinical presentation patterns
• Group 4: Vitamin-responsive epileptic
encephalopathies
– Neonatal/infantile epileptic encephalopathies
– Usually refractory to standard therapy
• Some AEDs actually inhibit GLUT1, leading to worsening
– Pyridoxine (Vit. B6) responsive seizures
• Typically, perinatal onset, refractory seizures – but described as late
as 18 months at onset
• Defect in lysine catabolism leads to increased inactivation of
pyridoxal-phosphate
• Concomitant accumulation of alpha-aminoadipic-semialdehyde and
pipecolic acid can be detected in urine – but depends on test
availability
– Pyridoxal-phosphate responsive seizures
• Similar to Vit.B6 responsive seizures
• With microcephaly + hypotonia
• Pyridox(am)ine 5’-phosphate oxydase (PNPO) deficiency ± more
severe Vit. B6 responsive seizures
Clinical presentation patterns
• Group 4: Vitamin-responsive epileptic
encephalopathies
– Folinic acid responsive seizures
• Extremely rare, classically diagnosed with CSF markers
• One case series has found several patient to have same genetic
defect and biochemical markers as pyridoxine responsive seizures
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(Gallagher RC, Van Hove JLK, Scharer G, Hyland K, Plecko B, Waters PJ, et al.
Folinic acid-responsive seizures are identical to pyridoxine-dependent epilepsy. Ann
Neurol. 2009;65:550–6)
– Biotidinase deficiency (biotin responsive seizures)
• Waxing and waning symptoms – probably diet related
• Association of neurological symptoms (lethargy, hypotonia, seizures,
ataxia, eventual GDD, leukoencephalopathy, hearing and visual loss)
and dermatological manifestation (eczematous or erythematous rash,
alopecia, keratoconjunctivitis); eventual organic aciduria
– GLUT1 transporter deficiency
• GDD, complex motor disorder, slow and slurred speech, hypotonia
and ataxia +/- spasticity
• Hypoglycorrhachia
• Good response to ketogenic diet
• Usually improving by adulthood
• Avoid inhibitors of GLUT1 (phenobarbital, chloral hydrate, diazepam,
methylxanthines, R-OH, green tea)
– Carbamazepine or phenytoin well tolerated if additional AED
required
The urea cycle disorders
• Urea cycle: main pathway for removal of ammonia
produced during AA deamination
– Converts ammonia to urea in the liver
– NH3 production increased in period of increased catabolism eg:
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Fasting
Infection / surgery / anesthesia
Large protein load
Puerperium
Etc.
• Urea cycle disorders:
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Inability to properly detoxify ammonia
Cumulative prevalence varies according to source
• Possibly relatively common – range 1:8000 to 1:25 000 live born
Mostly autosomal recessive – OTC X-linked dominant with variable expression
due to random X inactivation
The urea cycle disorders
Glutamine
synthetase
deficiency
NAGS
deficiency
Carbamoyl PO4
synthetase
deficieny
OTC
deficiency
Citrin
deficiency
HHH syndrome
Arginosuccinate
synthetase deficiency
Arginosuccinate
lyase deficiency
Arginase
deficiency
Saudubray et al, Inborn
Metabolic Diseases, 4th
edition
The urea cycle disorders
• Clinical presentation
– As in other Group 1 disorders
• Normal antenatal development
• Initial ‘‘Honeymoon phase’’ post-natally
• Symptoms triggered by endogenous or exogenous substrate
load
• Hyperammonemia, initial respiratory alkalosis
• Catastrophic presentation in periods of catabolic stress
– High incidence of neurological impairment after severe
decompensation
• Some patients are highly sensitive to VPA - beware!
– Thought to be related to close relationship between urea cycle and TCA
cycle
The urea cycle disorders
• Clinical presentation
– Severity of disease related to degree of enzymatic impairment
• Typically presents neonatally, in late infancy, puberty and
sometime adulthood
– Neonatal presentation: poor feeding and vomiting,
irritability/lethargy, tachypnea followed by eventual central
hypoventilation, seizures, autonomic instability, hypotonia, loss
of normal reflexes, eventual cerebral or pulmonary hemorrhage
– Infantile presentation: Usually less acute, with anorexia, NoVo,
lethargy, failure to thrive and poor development; progression to
encephalopathy with intercurrent illness
– Adolescence/adulthood: Precipitated by illness, fasting,
puerperium, anorexia, malaise, NoVo, H/A, ataxia, followed by
fluctuating LOC, occasionnal focal deficits and resolution or
death by cerebral oedema if not corrected
• Arginase deficiency associated with more indolent course of
progressive spastic diplegia, dystonia ataxia and seizures, not always
presenting episodes of acute encephalopathy
Initial investigations
• Basics – ABCs, then H&P
– History
• Past medical history – especially NYD syndromes
– Good antenatal / perinatal history is essential
» LCHAD associated with maternal HELLP or acute fatty
liver of pregnancy
» Infantile E.Coli sepsis associated with galactosemia
• Family history
– Origin
– Consanguinity
– SIDS, other perinatal death (eg: neonatal sepsis), unexplained
infantile/childhood death
– Neurological impairment, especially if unexplained
• HPI
– Circumstances leading to presentation
» Fasting, injury/illness, surgery, weaning of
breastmilk/introduction of new foods
– Physical
• As usual, plus special attention to
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Vitals and general status, height, weight, head circumference
Dysmorphisms, skin/hair anomalies, dysraphism
Organomegaly
Smell (patient, urine)
Initial investigations
• Basic investigations
– ‘‘Shotgun’’ approach
• Many disorders progress rapidly and leave deficits
• Need to exclude treatable disorders rapidly
• If within neonatal period, obtain provincial screening results
(CHUS/CHUL)
• Some tests are run in reference centers – can call for stats
Plasma
Urine
- Blood gas, including
- Analysis with ketones
lactate, glucose, lytes, AG
- Liver enzymes
- Organic acids
- BUN, Creat
- Culture
- CBC
- Blood culture
- Amino acids
- Ammonia
Sample needs to be put drawn
from free flowing vessel (no
capillary sample), w/o tourniquet,
put in chilled tube, on ice and
processed ASAP
- ±Pyruvate
Also needs special processing,
check w/ lab
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± Acylcarnitine profile
- FAOD and others
In doubt, draw more and
freeze to use later, samples
are more valuable during
acute episode
Initial investigations
• Additional investigations
– According to clinical suspicion
– Genetics consult highly recommended
Plasma
Urine
- Orotic acid
- Reducing substances
- VLCFA
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- Peroxysomal disorders
Carnitine
Uric acid
Homocysteine
Insulin
CK
Liver synthetic function
- Coags, albumin
Inflammatory markers
- ESR, CRP
CSF
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Cell count
Biochemistry
Cultures
Amino acids
Lactate, pyruvate
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Process sample
adequately, draw
serum, call lab
- Neurotransmitters and
metabolites
Initial investigations
• Additional investigations
– As clinically warranted
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EEG
Neuroimaging
ECG
CXR
Echocardiogram
Initial management
• ABCs first
• Strongly consider ICU setting
• Consult genetics if available – this is their field
• Eliminate the insulting agent – in case of new patient,
need to eliminate as much as possible
– NPO
– Promote anabolism - High parenteral caloric intake
• Low lipids (fatty acid oxydation defects, ketone body metabolism, etc)
• Low proteins (UCD, aminoacidopathies, organic acidurias)
• Low complex sugar (galactosemia, hereditary fructose intolerance, etc.)
– D10% infusion, initial rate 150% maintenance
» However, risk of worsening in congenital lactic acidemias
• If not worsening with dextrose, control hyperglycemia with insulin
– Eliminate offending drugs, control fever, infection, etc.
• Ondansetron might be useful – pathology itself as
well as drugs used make patient nauseous
Initial management
• Substrate removal
– Ammonia
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Na-phenylacetate (phenylbutyrate if n/a), Na-benzoate
L-arginine – promotes continuation of urea cycle
Extracorporeal detoxification if NH3 >500
Carbaglu if OTC or CPS suspected
– Organic acids
• Carnitine helps restore CoA and excrete organic acid as acylcarnitine
– Also, secondary carnitine loss in many other disorders, and
might improve status in congenital lactic acidemia
• Vitamin cocktail for various disorders (Q10, biotin,
thyamine, riboflavin, etc.)
• Electrolytic and acid-base imbalance managed as
usual
Specific treatments
– Initial protein restriction usually last 24-48 hours
• Group 1: Disorders of intoxication
– Initial management with IV dextrose +/- insulin
– Lipids to be started after FAOD ruled-out
– MCTs in long-chain fatty acid oxydation defect
– Strict Ins and Outs, daily weight
– Specific formulas or synthetic essential AA
mixtures for aminoacidopathies
» Synthetic essential AA also useful in UCD
• Group 2
– Requires only normal glucose intake
» Except hyperinsulinism
» Too much can exacerbate congenital lactic
acidosis – start lipids when feasible
» Avoid additional mitochondrial toxicity
• Group 4
– Consider trial of pyridoxine, pyridoxal-phosphate, folinic
acid or biotin if seizures are prominent
– Ketogenic diet for GLUT1 deficiency
Quebec’s neonatal
screening program
• 2 arms:
– blood (CHUQ - Quebec)
• Dried bloodspot from heelprick, before initial
departure from hospital
• PKU, congenital hypothyroidism, tyrosinemia
– Urine (CHUS - Sherbrooke)
• Dried urine sent on filter paper, around 21 days
of postnatal life
• Disorders of amino acid metabolism, organic
acidurias, amino acid transport disorders, urea
cycle disorders
• Research done in detection of some other
disorders (eg: Fabry’s disease)
• Many more disorders (eg: FAOD) could be tested
relatively easily using tandem MS technology; in this
respect, most of Canada is lagging behind most
industrialized countries
Summary
• Individual IEMs are quite rare in general population
– Combined prevalence, however, is much more significant
– By the time neurology is consulted, much has been done to
rule-out frequent pathologies – or the patient is critically ill
• Suspect neurological manifestation of IEM in
– Critically ill neonate without clear evidence in favor of HIE
or sepsis, or other evident cause
– Any other patient with recurrent episodes of acute
encephalopathy, ataxia, vomiting, seizure, LOC
– Suspicious familial history (consanguinity, most infantile
death, unexplained death later in childhood or adulthood)
• Act fast to rule-in/out treatable disorders, while
trying for an effective empirical treatment
• Involve genetics early, and keep on reading!
Tidbits
• Good references
– Fernandes, Saudubray, Van den Berghe, Walter, Inborn
Metabolic Diseases: Diagnosis and Treatment, 2006,
ISBN 3540287833
• Good reference, nice revision of involved pathway at the
beginning of each chapter, greatest problem is its cost…
– Joe T. R. Clarke, A Clinical Guide to Inherited
Metabolic Diseases, 2006, ISBN 0521614996
• Like the Fenichel for Child Neurology, provides good
approach to differential diagnosis according to clinical picture,
but not the reference to learn in depth about a particular
disease.
• How to contact…
– Shebrooke (CHUS):
• urine screening program, some standard tests (urine organic
acids for example) are also done there and can be done faster if
you have a reasonnable reason
• 819-346-1110, dial 0 for operator and ask for genetic lab
– Quebec (CHUQ)
• If you think your patient might have PKU, tyrosinemia or
congenital hypothyroidism and is still in the window period where
the results might not be in yet
• 418-654-2103 (Medical genetic) or 418-525-4444 (general #)
Questions or comments?