Transcript Approach to Inborn Errors of Metabolism - Pediatrics

Dr Yaser A. Mohammad
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2 Cases
 2 yrs old boy KCO Ethylmalonic Aciduria.
 Presenting with bronchopneumonia & Metabolic
crisis.
 Drowsy, acidotic breathing, tachycardic , BP & SPo2
maintained with O2.
 BGA PH: 7.15 CO2: 2 HCO3: 12 BE: -15
RBS : 8 Lactate: 6.5 Ammonia : 40
 5 yrs old boy KCO Arginosuccinic Aciduria.
 Presenting sleepy & vomiting after taking an overdose
of his antiepileptics(phenobarbitone & Keppra) &
missing 2-3 doses of his metabolic medicine.
 Drowsy GCS 11-12 , HR 70, BP & SPo2 maintained in
R.A.
 BGA PH 7.43 PC02: 5 HCO3: 23 BE : -1.5
K : 1.9 RBS : 8 Ammonia 246
Outline
 Brief description of types of IEM that have an acute
presentation.
 Approach to metabolic emergencies.
 Diagnostic clues
 Quiz
Organic Acid Disorders
- Results from enzyme deficiencies in the pathway of
Amino acids degradation.
- Presentation with acidosis, hypoglycaemia lactic
acidosis & hyperammonaemia. Ketosis may also occur.
- Analysis of the urine for Organic Acids is the mainsty
of the Dx.
- E.g. Methylmalonic, Ethylmalonic & propionic
Acidaemia.
- Rx low protein diet, avoid catabolic state; high carbs
feeds during illness & carnitine.
Urea Cycle Defect
 Defect in the metabolism of Ammonia in the Urea Cycle, so
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high Ammonia.
Presentation : poor feeding, lethargy, convulsion, coma &
Resp. alkalosis.
Difficult to Dx due to lack of biochemical abnormality
apart of hyperammonaemia.
Treated as sepsis initially.
Dx with raised Plasma Amino Acids.
E.g. Ornithine transcarbomylase, Arginosuccinic aciduria.
Rx low protein diet, Na benzoate, phenylbutyrate &
arginine. Avoid catabolic state.
Fatty acid oxidation defect
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FA oxidised in skeletal muscle, heart & liver.
4 enzymes inolved (Chain Acyl-CoA Dehydrogenase).
SCAD, MCAD, LCAD & VLCAD.
Presentation: Non-ketotic hypoglycaemia, lethargy,
siezures, myoglubiuria, mucsle weakness &
cardiomyopathy.
 Dx: Reye like illness ( hypoglycaemia, raised ALT & AST ,
no ketosis). Hyperammonaemia.
 Dx: Acylcarnitine profile by tandem mass spectrometry.
Urine O.A & skin fibroblasts enzyme assay.
 Rx prevention of fasting stress & carnitine.
Mitochondrial DO
 Have their own DNA & are derived from the ovum, so
all mtDNA DO are mternally inherited.
 Presentation: weakness, abnormal tone,
opthalmoplegia, seizures, cadiomyopathy, liver failure.
Lactic acidosis with normal glucose.
 Dx enzyme analysis of fibroblast, muscle or liver
biopsy.
 E.g MELAS ( Mitochondrial Encephalopathy, Lactic
acidosis & Stroke like episodes).
MERRF ( Myoclonic Epilepsy with ragged red
fibres)
Carbohydrate metabolism DO
 Galactosaemia; GAL-1-PUT. Accumulatiom of GAL-1
phosphate damages liver , brain & kidney
 Presentation: vomiting, hypoglycaemia, irritibility
siezures, jaundice, hepatomegaly & cataracts.E.coli
sepsis.
 Dx enzyme assay in RBC. Urine: non-glucose reducing
substance.
 Rx Lactose & galactose free diet.
Carbohydrate metabolism DO
 Glycogen Storage disease
- Threre are several enzyme deficiencies that leads to
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glycogen accumulation.
Primarly affect liver, muscle or both.
Presentation : hypoglycaemia, hepatomegaly, lactic
acidosis, weakness & cardiomyopathy.
Dx : enzyme assay of blood, liver or muscle biopsy.
Rx : avoidance of fasting, continuous overnight feeds &
uncooked corn starch.
How IEM present?
 Non-specific symptoms
 Attributed to infection or sepsis
 Routine blood tests could be normal
 Suspect when lack of improvement with standard
therapy.
 Neontal screening.
Metabolic crisis
 Metabolic crisis occur when there is build up of toxic
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metabolites. Triggers factors that increase catabolism:
Infection
Fasting
trauma
Surgery
Increase consumption of protein.
Clinical presentation
 An acute presentation with multisystem involvement
is strongly suggestive of an IEM. It can include:
- Vomiting and anorexia or failure to feed.
- Lethargy that can progress to coma.
- Seizures, particularly intractable.
- Rapid, deep breathing that can progress to apnea.
- Hypothermia (related to illness, not specific to a
particular metabolic pathway).
 In one review of 53 patients who presented to an
emergency department and were subsequently
diagnosed with an IEM:- 85 % had neurologic signs or symptoms.
- 58 % had gastrointestinal signs or symptoms.
- 51 % had both neurologic and gastrointestinal signs
and/or symptoms.
investigations
 Glucose
 ABG
 CBC, U &E, LFT
 Urine: color, odor, dipstick & ketones
 Ammonia
 Lactate
Diagnostic clues
Diagnostic clues
Diagnostic clues
Immediate Mx
 Fluid resuscitation
 Treatment of hypogycaemia
 Ventilation support
 HCO3 for correction of acidosis ( rapid correction have
adverse effect on CNS).
 Empiric IV antibiotic
 Stop oral feeding pending Dx.
 Avoid catabolism by administration of IV D10% with
electrolyte. 8-10mg/kg/min.
Provision of co-factors:
- Pyridoxine: 100mg iv for uncontrolled seizures.
- Cobalmine: (Vit B 12 1mg im) metabolic acidosis &
suspected organic acidaemia.
- Carnitine: (100 mg/kg per day in three divided doses
either orally or IV) may be useful in patients with
organic acidemias, fatty acid oxidation disordersor
carnitine defeciency.
- Biotin: 10 mg for neonate with recurrent seizures
Quiz
Summary
 Optimal outcome of IEM depends on early
recognition, diagnosis, treatment of metabolic
decompensation.
 Symptoms are non-specific
 Initial investigation could give a clue to diagnosis
pending more detailed ones.
 management of metabolic decompensation must be
initiated promptly to avoid long term sequele.
References
 Inborn Errors of Metabolism overview & specific
disorders by Paul Levy. Pediatrics in review vol 30. No.
4 April 2009.
 Inborn errors of metabolism : metabolic emergencies.
Uptodate, pediatrics. Reid Sutton.