Dr. Nawal Makhseed
MBBS, FAAP, FRCPC, DABMGG, FCCMG
Pediatric Metabolic Consultant
Second Jahra Pediatric conference 5-6 May/2017
What is a metabolic disease?
• Small molecule
disease
– Carbohydrate
– Protein
– Lipid
– Nucleic Acids
• Organelle disease
– Lysosomes
– Mitochondria
– Peroxisomes
– Cytoplasm
Others
Presentation
• IEM may present in the neonate is essentially
one of the three ways:
• Intoxication
• Energy insufficiency
• Problems making and breaking complex
molecules
Problems making and breaking complex
molecules
• Most of them present later in life
• Some present at birth with dysmorphism due
to defected embryogenesis:
– Zellweger syndrome
– Smith-Lemli-Opitz syndrome
– CDG Ia
– Storage problem like in I-Cell disease
Intoxication
• Usually preceded with a symptom free period
• Poor feeding period
• And usually within 72 hrs develops encephalopathy
however, intoxication may take longer like
galactosemia
• Duct dependent circulation problems and sepsis
should be excluded
– Urea cycle defects
– Organic acidemias
Energy insufficiency
• May take longer to fully decompensate as the fuel supply is
interrupted like failure to establish feeds or in the presence of
inter-current infection.
• Spectrum of severity is broad
– Energy supply
• FAOD
• Glycogen storage disease
• Gluconeogenesis defect
– Congenital lactic acidosis
• Respiratory chain defect
• Pyruvate metabolism disorders
Age of manifestation
birth
1 week
Intoxication
Reduced fasting
tolerance
Disturbed energy
metabolism/
Disorders of making of
breaking large molecules
1 year
„Long-Term Results"
Urea Cycle Defects – Central Europe
Normal development: 20/88 (23%)
Dead: 43/88 (49%)
Mortality 10 years after diagnosis: 85%
Predictors of IQ < 70: NH3  500 mol/l
Duration of coma (days) x NH3  4000/2400
Bachmann Eur J Pediatr 2003
Metabolic disorders requiring specific emergency treatment
Presentation
Disorders
Catastrophic illness
UCD
Organic acidemias
MSUD
Fatty acid oxidation defects (FAOD)
RCD
PDH
Hypoglycemia
Glycogen storage disorders
Gluconoegenesis disorders
FAOD
Disorders of ketogenesis/ketolysis
Liver failure
Galactosemia
Hereditary fructose intolerance
Tyrosinemia type I
Bile acid synthesis defects
Encephalopathy (seizures/coma)
Biotin responsive basal ganglia disorder
Folinic acid responsive seizures
Pyridoxine dependent seizures
Pyridoxal phosphate dependent seizures
Diagnostic tests
Basic investigations
Metabolic investigations
• Acute:
•
•
•
•
–
–
–
–
–
BGA
Ammonia
Glucose
Lactate
Urine ketostix
• Subacute
–
–
–
–
–
–
CBC
LFT/RFT
Electrolytes
CK
Coagulation profile
Ketostix ( urine)
Acylcarnitines profile (DBS)
Plasma amino acids
Urine organic acids /orotate
Total and free carnitine (ideally
but????)
• Reserve
–
–
–
–
–
Plasma
Serum
DNA (EDTA/filter paper)
Urine
When possible CSF
What are the typical basic laboratory constellation
NH3
Urea cycle
defects
Organic
acidurias
Glucose


Lactate
pH

 


Maple syrup
urine disease
Fatty acid
oxidation
defects
Glycogen
storage
disease I
PDH/ RC
deficiency
Ketonuria
Other

anion gap,
neutro-/
thrombocytopen
ia
DNPH-test +







CK 
High FFA
CH/TG 
uric acid 






Case
• 20 months old girl presented to the ER with
her 3rd bout of vomiting and dehydration
• First 2 episodes resolved with IV fluids
• She is now lethargic and tachypenic
What are the acute investigations to
be requested immediately?
• BGA
pH: 7.54, pCo2: 2.5, HCO3: 17
electtolytes: normal
• Ammonia
Ammonia: 315 uM
• Glucose
Glucose : 3.1
• Lactate
lactate: 2.2
• Urine analysis
pH: 5, glucose/protein : -ve
Ketones: 1+
Ammonia
•
Ammonia values
– Neonate:
• Healthy
• Sick
• Suspected metabolic disease
< 110 μmol/l
up to 180 μmol/l
> 200 μmol/l
– After the neonatal period:
• Healthy
• Suspected metabolic disease
•
50-80 μmol/l
>100 μmol/l
Blood sample collection:
–
–
–
–
–
Notify the lab
Uncuffed venous or arterial sample
Transport sample on ice
Analyze immediately
If the sample can not be collected under perfect conditions, do it any ways, and
repeat under better circumstances
Case analysis
• Blood gas
• Ammonia
• Glucose
• Lactate
• Urine ketones
Respiratory alkalosis secondary
metabolic acidosis
Elevated
low normal
Normal but???
Appropriate (not-Hypo or
hyperketosis) ? Starving
Hyperammonemias
Patient 1
Urea cycle disorders
(“classical”) Organic acidurias
Fatty acid oxidation defects
Sepsis
0
500
1000
Plasma ammonia (µmol/l)
1500
Case analysis
• Acylcarnitines profile (DBS)
• Plasma amino acids
• Urine amino acids ?
• Urine organic acids/orotate
• Total and free carnitine (ideally
but????)
Elevated C2/Very low citrulline
Elevated glutamine: 1695 (N: 360-740)
Citrullline: 0
Low essential amino acids
Not done
Urine organic acids: unremarkable
Urine orotate: elevated
Not done
Diagnosis?
•
•
•
•
OTC: ornithine transcarbamylase deficiency
X-linked disorder
What was the red flag in this case?
What is learnt from this case?
Organic acidemias (PPA, MMA) clinical
presentation
– Recurrent acute
encephalopathy
• Metabolic acidosis;
keto/lactic acidosis +
• +/-hypoglycemia
• Hyperammonemia
• Lethargy/ vomiting/
dehydration
– Chronic from
• Chronic vomiting
• FTT
• Psychomotor retardation
• Special Investigations:
• Filter paper or
acylcarnitines profile
• Urine organic acids
• Plasma amino acids
Causes of neonatal hyperammonemia
Inherited disorders
Acquired disorders
Urea cycle disorders
Organic acidurias
FAOD Mainly seen in CACT/
CPTI deficiency
PC deficiency
Hyerpammonemia,
Hyperornithinemia,
homocitrullinemia syndrome
( HHH)
Hyperinsulinism
hyeroammonemia syndrome
(HI-HA)
Any severe illness
Birth asphyxia
TPN
Herpes Simplex
THAN
Severe liver failure
Increased muscle
activity during assisted
ventilation
Pyrroline-5-carboxylate synthetase def.
(transient hyperammonemia of the newborn)
( values rarely above 180)
Pathophysiology in
relation to treatment
Pathophysiology in
relation to treatment
Pathophysiology in
relation to treatment
Pathophysiology in
relation to treatment
Goals of treatment
 Prevent brain damage , organ failure & death
 Avoidance of exogenous precursors
 Inhibition of endogenous catabolism
 Clearance of toxic metabolites
Manage the patient in PICU
Manage the patient in PICU
Manage the patient in PICU
Manage the patient in PICU
Manage the patient in PICU
Duration of coma and outcome
dictates the urgency of treating
patients with hyperammonemia
IQ scores in
12 months
old patients
Duration of coma during
hyperammonemia crises
Management of hyperammonemia
• Stop all feeds:
– For how long? And why?
– How can we resume feeds?
– When to use TPN?
• Promote anabolism
– 10%-12.5% dextrose at 1-1.5 maintenance ( use 5% dextrose if
suspecting primary lactic acidosis)
– +/- insulin infusion when glucose is >10mmol/l or there is glucosuria!
• Correct electrolytes imbalance and dehydration
• Elimination of toxic metabolites:
– Medications:
– Dialysis, when and how?
Medications and Diet
• Meds eliminating ammonia:
•
•
•
•
•
•
–
–
–
–
–
Sodium benzoate IV
Arginine hydrochloride
Na-phenylacetate IV
Na-phenylbutyrate (Ammonaps) oral
New medicine is Ammonul, what is it?
Carbaglu ( N-acetylglutamate analogue)
Carnitine
Vitamin B12
Biotin
Glycine
Special formula according to the underlying diagnosis
Phenylbutyrate
(Ammonaps)
Phenylacetate
Ammunol IV
Phenylactoglutamate
FAO
AcetylCoA
Glutamine
Benzoate
carbaglu
Glycine
Hipuric acid
NAG
OA
Inhibit
Arginine
supplementation
Use of Carbaglu in Organic acidemia
Protocols of treatment of hyperammonemia before the final diagnosis
carbaglu
Guideline for the management of
hyperammonemia
• European guidelines on Orphanet
• Guideline for Acute Management of
Hyperammonemia in the Middle East Region
• Most important point
– Do not delay investigations
– Do not delay treatment initiation
– Make yourself familiar with the medications, how
to get them and how they are used
Emergency management of MSUD and
Glutaric aciduria type I
• Both can present with catastrophic neurological
presentation
• MSUD caused by a deficiency of Branched chain
ketoacids dehydrogenase Leucine encephalopathy
• GAI caused by a deficiency of glutaryl CoAdehydrogenase causing a defect in lysine/tryptophan
catabolism  basal ganglia disorder
• In both disorders during crisis
– Patients needs to be on adequate amount of protein which
is depleted of the offending amino acids
– Without which  patient will develop further neurological
damage.
Causes of acute liver failure
•
•
•
•
•
•
•
•
•
Galactosemia
Fructose intolerance
Tyrosinemia type I
Alph-1-antitrypsin
Respiratory chain disorders (mitochondrial)
LCHAD (Fatty acid oxidation disorders)
Dihydrolipoamide dehydrogenase deficiency
Neonatal hemochromatosis
Urea cycle disorders when patient present with
multiorgan failure
• Smith-Lemli-Opitz Syndrome
Liver failure and metabolic disorders
• Two of them we are screening for:
– Tyrosinemia type I (Succinylacetone is
pathognomonic for tyrosinemia type I)
– Galactosemia
• One newly defined to exist in Kuwait with
most likely a founder mutation
– Dihydrolipoamide dehydrogenase deficiency
Galactosemia
• Screening uses filter
paper
• Confirming the diagnosis
uses erythrocytes,
Transfusion can give a
false negative results
• It is essential to do
Galactose-1-Phosphate.
The patient has to be on
regular milk
Biochemistry
• Why is it important to know biochemical
pathways ?
• What is DLD: dihydrolipoamide
dehydrogenase
• E3 subunit of three complexes:
– PDH, alph-KGD, BCKAD
– L- subunit in glycine cleavage system
Pyruvate dehydrogenase complex
E1
E2
E3
citrulline
Aspartate
TCA cycle
Pyruvate
KGDc composed of
E1 subunit (PDHA1)
E2 subunit (DLST)
E3 subunit (DLD)
Branched chain ketoacids
dehydrogenase
Elevated
BCAA
BCKA
There is no formal diagnostic criteria
• The diagnosis of DLD deficiency is suspected in
individuals with the following presentations:
– Early onset Neurologic manifestations (early-onset
hypotonia, lethargy and emesis)
– Isolated liver disease: as early as neonatal period, and as
late as third decade
– Most recently identified presentations
•
•
•
•
•
•
Myopathic presentation
Leigh’s disease
Cardiomyopathy
Optic nerve atrophy
Hyperammonemia
Pancreatitis
Liver disease
• Evidence of liver injury or failure preceded by nausea and vomiting
• Frequently associated with encephalopathy, raised liver enzyme, synthetic
failure (coagulopathy)
• Hepatomegaly
• Usually associated with lactic acidosis
• With resolution of the acute episodes patients frequently return to
baseline with no residual neurologic deficits
• Liver failure can result in death even in those with late onset disease
• Brassier et al 2013, Quinonez et al 2013, these patients are additionally
are more susceptible to hepatotropic viruses e.g. EBV
• Liver biopsy:
– Increased glycogen content, mild fibrosis, acute necrosis as seen in Reye-like
episode
– EM showed lipid droplets
Pediatric case 1-Kuwait
14 yrs old girl, Kuwaiti, far relatives parents., healthy siblings
Onset of symptoms at 6-7 yrs
Recurrent episodes of acute onset of vomiting with abdominal pain
associated with lethargy.
Few episodes of hypoglycemic encephalopathy
no H/O muscle weakness, or impaired cardiac function
systemic review was unremarkable. She has normal developmental
milestones, and normal growth
she had several admissions with similar presentation
Almost all attacks were identical
Mild elevation of liver enzymes
Hypoglycemia
Basic metabolic workup was unremarkable (PAA,
UOA, acylcarnitine profile)
She was suspected to have
Fatty acid oxidation defect
Mitochondrial disorder
Pediatric case 1- Kuwait
• Boarded to UK
• Suspected to have ACAD9 defect
• Functional analysis of fatty acid oxidation defect
in fibroblasts was normal
• Upon return to Kuwait, she had less episodes, no
follow up and no acute episodes.
• And showed up at OPD at 14 years of age with
new episodes of similar pattern
• urgent DLD mutation analysis  c.685G>T
(p.Gly229Cys)
Pediatric case 2 Kuwait
8 yrs old girl, Kuwaiti, far relatives parents. 5 siblings.
Onset of symptoms at 6 yrs
Recurrent episodes of acute onset of vomiting with abdominal pain
associated with lethargy, no H/O muscle weakness, or impaired
cardiac function
systemic review was unremarkable. She has normal developmental
milestones.
she had several admissions with similar presentation
Almost all attacks were identical
Raised liver enzymes
Acidosis
Hypoglycemia
Coagulation abnormalities if there is a delay in seeking medical advice
She consumes large amount of junk food especially sugary
food
Has five siblings, one brother was admitted with
hypoglycemic seizures , found to have hepatomegaly
Clues to the diagnosis of DLD
• Signs and symptoms
– Hypoglycemia
– Metabolic Lactic acidosis
– Raised liver enzymes
• If prolonged episode
– Coagulation abnormality
– Hyperammonemia
• Special investigations:
– In some cases Elevated branched chain amino acids /+ alloisoleucine
– Alpha-ketoglutarate in urine organic acids
DLD deficiency
• If not recognized early fatal outcome
• When recognized early normal and
unremarkable recovery
Recommendations for the acute
management
• Goals:
– Promote anabolism and reduce catabolism
• Glucose infusion with careful monitoring
• May consider intralipids to increase caloric intake as well an attempt to reduce acidosis
• Hold protein intake for about 24 hours and reintroduce slowly with the monitoring of
BCAA especially leucine
• Introduce BCAA free formula
• May be at risk of leucine encephalopathy during acute crisis
– Maintain normal blood glucose
– Treat any precipitating factors
– Correct metabolic acidosis
• Treat with Na bicarbonate if HCO3 <14, and pH <7.2
• If acidosis as well as encephalopathy persists, may consider dialysis. Has
been successful in some patients with DLD and BCKD complex deficiency
(Schaefer et al 1999, Quinones et al 2013)
• Consider:
–
–
–
–
Thiamine
Riboflavin ( the only one tested to be effective at tissue level)
Lipoic acid
Carnitine
Others
• Hypoglycemia
– Collect critical samples on time
– Most missed sample is urine
• Acute neonatal seizures
• Treatable causes
– Pyridoxine dependent seizures
– Pyridoxal phosphate dependent seizures
– Folinic acid responsive seizures
Take home message
• Managing acute metabolic emergencies is not
a one man show!!!
• Needs extra efforts to arrange for proper
management in a timely fashion
• Taking investigations on time is as essential as
the acute management