14. Paeds Flashcards
Common clinical features of IEM in infancy + childhood
Acidosis CNS dysfunction; irritability, coma, hypotonia, seizures, etc Failure to thrive Frequent vomiting + other GI probs Hypoglycemia Unusual odour
Essential basic lab tests for 1st line investigation of IEM
FBC
ABG - acid-base status
Serum;
- U&E: electrolytes, urea, creatinine, bicarbonate
- LFTs
- CK
- uric acid
Plasma;
- glucose
- ammonia
- lactate
Urine;
- ketones
Second line investigations for investigation/diagnosis of IEM
Bloodspot/plasma acylcarnitines
Galactose 1-phosphate uridyl transferase (RBCs)
Plasma;
- amino acids
- very long chain fatty acids (VLCFAs)
Urine;
- amino acids
- organic acids
- orotic acid
- reducing substances/sugar TLC
- glycosaminoglycans (GAGs)
Give example of cofactor supplementation as treatment of IEM
E.g. Classical Homocystinuria
Conversion: homocysteine > cystathionine reqs cystathionine B-synthase
- peroxidase = co factor of cystathionine B-synthase
Homocystinuria sufferers divided into pyroxidine responsive/unresponsive;
- supplementation in responsive = reduced homocysteine in plasma = improved symptoms
List the individual IEM disorders examined
Amino acid disorders;
- phenylketonuria (PKU)
- maple syrup urine disease (MSUD)
Urea cycle defects
Organic acid disorders
Fatty acid oxidation defects;
- medium chain acyl-CoA dehydrogenase deficiency (MCADD)
Galactose metabolism defects;
- galactosemia
List the 3 deficiencies of galactose metabolism
- galactokinase
- galactose-1 phosphate uridyl transferase (gal-1 PUT)
- UDP-galactose 4’ epimerase
Clinical features of untreated PKU
Appear normal to 6 months;
- microcephaly
- severe mental retardation
- agitation + regression
- seizures
- other neuro abn
- blond hair, blue eyes
- ‘mousy’ odour
Clinical presentation of MSUD
Lethargy
Feeding difficulties/vomiting
Progressive CNS dysfunction-poor tone, seizures, coma, apnoea
May be fatal/ lead to permanent neuro abn + severely impaired mental development
Biochemical abn of MSUD
Metabolic ketoacidosis (not major feature)
Ketosis
Hypoglycemia (uncommon)
Urine + sweat may have distinct sweet odour of maple syrup
3 methods of diagnosis for MSUD
- Positive dinitrophenylhydrazine screen test for ketoacids in urine (old blood spot)
- Increased branched chain aa in plasma (val/leu/isoleu) + alloisoleu presence;
- ion exchange HPLC - Increased branched chain ketoacids + hydroxyacids in urine (e.g. 2 ketoisocaproic acid (toxic) + 2-OH-isovaleric acid);
- urine org acid analysis by GC-MS
6 enzyme deficiencies in UC disorders
Carbamylphosphate synthetase I (CPS1) Ornithine transcarbamylase (OTC) Argininosuccinate synthetase Argininosuccinate lyase Arginase N-acetylglutamate synthetase
Clinical features of neonate with UC defect
Well at birth - onset within 48 hours
Lethargy
Poor feeding
Hyperventilation (NH3 = resp stimulant = resp alkalosis)
Seizures
Progressive encephalopathy with deepening coma
Clinical features of infant/child with UC defect
FTT Feeding problems, esp avoidance of protein containing food Vomiting Chronic neuro symptoms Episodic encephalopathy Ataxia + seizures
Clinical features of adolescents/adults with UC defect
Chronic neuro/psychiatric problems
Recurrent encephalopathy associated with high protein intake, catabolism or stress
Diagnosis of UCD
Plasma + urine analyses Urine orotic acid analysis; - direct spectrophotometric - part of urine org acid analysis GC-MS Definitive: DNA/enzyme analysis in app tissue
Treatment in acute UCD
Stop protein intake Remove ammonia (drugs/extracorporeal detox) Replenish UC intermediates with arganine + citrulline (depends on enzyme def in) Fluid replacement
Treatment in long term UCD
Maintain anabolic state Limit protein intake Arginine/citrulline supp as app Remove ammonia; - sodium benzoate - sodium phenylbutyrate Vitamins + trace elements Consider liver TP
Clinical presentation of fatty acid ox disorders
Ppted by fasting
Varies with individual condition
Hypoketotic hypoglycemic coma
Liver disease
Muscle weakness + rhabdomyolysis (increased plasma CK)
Cardiac: arrhythmias, cardiomyop, cardiac failure
Neuro: lethargy, coma, hypotonia, seizures
SIDs
Abn biochemical findings in fatty acid ox disorders
Hypoglycemia
Inapp low plasma + urine ketones
Metabolic acidosis (lactic acidosis)
Increased ratio FFAs:3-hydroxybutyrate in plasma (lipolysis working but not ketogenesis)
Diagnosis fatty acid ox disorders
Blood/urine collected during illness (when hypoglycemia)
Analysis of;
- acylcarnitine in blood spot/plasma by MS/MS
- organic acids in urine by GC/MS
Confirmation: mutation/enzyme assays
MCADD diagnosis
Bloodspot/plasma acylcarnitine profile MS/MS;
- increased hexanoylcarn C6 + octanoylcarn C8
- increased ratio C8:C10
- increased C8 = screening blood spot newborns
Urine org acids GC/MS;
- increased C6-C10 dicarboxylic acids (adipic, suberic, sebacic acids)
- presence suberylglycine + hexanoglycine
Clinical features classical galactosemia
1st week of life when milk feeding established
Vomiting + diarrhea FTT Jaundice/disturbed liver function Sepsis>death from liver/renal failure Bilateral cataracts
Diagnosis of classical galactosemia
Positive urinary reducing substances (clinitest) spot test
Increased galactose in urine sugar thin layer chromatography (TLC);
- false neg if lactose free diet/severe vom
Definitive: measure gal-1-PUT RBC activity;
- false neg e.g. blood tfn
Screening type assays for RBC gal-1-PUT e.g. Beutler test = rapid results
