Transcript Glutaric Aciduria type II

Glutaric Aciduria type II
a Fatty acid oxidation defect
NORAH A A KHATHLAN MD
Consultant Pediatric Intensivist
Director PICU
04/ 2007
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Glutaric Aciduria type II
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Glutaric Acid
 It
is an intermediate in three major metabolic
pathways:
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-Fatty acid metabolism
-Lysine metabolism
-Tryptophan metabolism
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Fatty acid oxidation defects
Short chain acyl-CoA dehydrogenase def.
(SCAD)
 Medium chain acyl-Co A dehydrogenase def. (MCAD)
 Long chain acyl-CoA dehydrogenase def.
(LCAD)
 Multiple acyl-CoA dehydrogenase def.
(MAD)
 Riboflavin responsive defects of ß-oxidation (RR-MAD)
 3-Hydroxy-3-methylgtutaryl CoA lyase def. (HMG-CoA)

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MAD deficiencies

Defects in electron transfer flavoprotein ( ETF ) & its
dehydrogenase (ETF-DH).
Impairs transfer of electrons into mitochondria electron
transfer chain.

1.
2 Types:
(MAD-S) severe neonatal form or.
GLUTARIC ACIDURIA type II.
2.
( MAD- M) mild “late onset” variant.
ethyl-malonic-adipic aciduria.
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Glutaric aciduria II ( MAD-S )

Severe neonatal form:
acidosis, hypoglycemia, coma, hypotonia & cardiomyopathies.

Two subgroups:
1.
With congenital anomalies.
2. Without congenital anomalies.
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Clinical picture
Growth retardation.
 Special odor.
 Metabolic acidosis.
 Hypoglycemia.
 Dysmorphism.
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Early neonatal death.
Def of electron transport chain flavoprotein or its oxidoreductase.
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( MAD- S )
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Abnormal liver (including function)
Biliary atresia & stenosis
Macrocephaly
Large kidneys & Multiple renal cysts
Organic aciduria
Pancreas (exocrine), general abnormalities
Undermineralization of skull
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( MAD- S )
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Macrocephaly.
Brain, general abnormalities.
Club foot/hindfoot, varus.
Rocker-bottom feet / hindfeet.
Fontanelles, delayed closure/large.
Hamartoma of brain.
Hypoglycaemia.
Hypospadias.
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Diagnosis
 Urinary organic acid profile.
Shows - Ethyl-malonic acid
- Dicarboxylic acid
- Lysine
- Branched chain amino acid

GCMS
Blood metabolic screening : Tandem MS
- Glutaric acid
- Lysine
- Leucine
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Glutaric aciduria type II
Differentiate from GA type I.
-
Def. Of glutaryl CoA dehydrogenase.
Progressive dystonia & dyskinesia.
Vomiting , seizures, coma & Reye-like presentation.
Ketosis, hypoglycemia, hyperammonemia & hepatitis picture.
High conc of glutaric acid in serum & urine.
 3- Hydroxyglutaric acid.
C.F. 2- Hydroxyglutaric acid in GA II.
N.B. Glutaric aciduria type III is a peroxisomal disorder.Very long chain fatty acids
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Treatment

Acute illnesses :
1.
2.
Prompt treatment with D10% to suppress lipolysis.
Correct acidosis.

Chronic:
1.
Avoid starvation.
Special formula. (low protein-low fat).
Carnitine & riboflavin supplements.
2.
3.
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Sick days plan for patients with G.A. II

Problems that may lead to significant metabolic illnesses in children
with organic acidemias:
1.
Fever - increases metabolic rate, increases rate of protein breakdown
and dehydration.
Painful infections - Pain increases metabolic rate, infections of the
mouth and throat often decrease appetite and fluid intake.
2.
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Sick days plan for patients with G.A. II
3. Vomiting - prevents calorie and fluid intake and may be a sign of
metabolic illness.
4. Diarrhea - causes dehydration, sodium and bicarbonate loss, and
acidemia - all of which decrease the ability of the liver and kidney
to remove pathological metabolites from the blood.
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Sick days plan for patients with G.A. II
5. Poor appetite - when calorie intake falls below 45 Cal/kg-day,
then protein from muscle is broken down for energy .
6.
When a sustained increase in protein catabolism is combined with
dehydration and acidemia , then the catabolic state is associated
with brain intoxication and injury.
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Goals of treatment during illnesses:
Metabolic illnesses usually evolve over a 12-48 hour
period. Early recognition of illness or the problems listed
above and careful attention to specific goals of treatment
will usually keep the metabolic disorder under control.
 If the goals are not met and signs of illness develop then
evaluation at hospitalization for emergency management
may be necessary.

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Goals of treatment during illnesses:
1.
2.
Minimum daily caloric intake 60 Cal/kg-day.
If eating is poor then give small amounts
regularly every 2 hours.
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Goals of treatment during illnesses:
3. If fever is high and diarrhea is frequent then weigh twice
daily, A weight loss of more than 3-5% is significant in an
infant with such disorders.
4. Treat fever and pain with high doses of Tylenol 130 mg
every 4 hours as needed to keep fever under 38°C.
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In-hospital management of acute
illnesses

Successful therapy in part depends upon :
1.
continued infusion of glucose at a rate of approximately
twice the basal metabolic rate of the patient.
2.
an initial insulin response to rapid glucose
administration.
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In-hospital management of acute
illnesses cont.
3.
If hyperglycemia (>200 mg/dl) persists beyond the first
120 minutes of therapy then regular insulin should be
administered by IV bolus starting at 0.1 units/kg.
4.
Insulin should be used to maintain the blood glucose
between 100-150 mg/dl and should be discontinued
when the blood glucose falls below 100 mg/dl.
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In-hospital management of acute
illnesses
“Hyperglycemia should not be considered an
indication for lowering the rate of glucose
infusion, to do so defeats the purpose of the
therapy.”
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In-hospital management of acute
illnesses
Acidemia also must be managed aggressively.
1.
2.
3.
Recovery may depend in part upon the renal clearance of nonvolatile dicarboxylic acids.
correction of acidemia, intravascular volume expansion to
establish vigorous urine output (initial bolus 20 ml/kg), and a
urine pH greater than 7.5.
During correction of acidemia blood potassium may decrease,
to allow urine alkalization potassium should be maintained 3.5
- 4.5 mEq/L, which can usually be accomplished with 10-20
mEq/L KCL in the IV fluid.
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Pitfalls
 If
a metabolic disorder is still suspected with a
negative screening  repeat Tandem MS &
request GCMS.
 Do not lower the glucose infusion rate due to
hyperglycemia….! Give insulin.
 Minimal protein “TPN” helps to control
catabolism.
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THANK YOU
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