Isovaleric aciduria
Dr Lee Shing Yan Robert,
Pricness Margaret Hospital,
Presentation in HKSIEM, 2011
Birth and perinatal history
• 38+3 weeks. First born. Birth weight
3.35kg. Normal vaginal delivery in Kwong
Wah Hospital. Discharged on Day 3.
• Non-consanguineous marriage
• On mixed feed, but poor feeding, baby
was drowsy all along, took 1 hour to finish
one feed, no cyanosis.
Signs and symptoms
Presentation
• Day 9
• Lethargy
• Respiratory distress
with pneumonia
• Smelly feet
• Convulsion the next
day
Treament
• Intubated
• Sepsis work-up
• Start of antibiotics
Initial investigations
• CRP 300 (Day 9)→69→33 (on day 19)
• WBC : 3.2 → 1.1x 109 /Litre;
Neutrophil: 1.1 → 0.1
HB : 16.8 → 12.1 g/dl
Platelet :101 → 10 x 109 / Litre
• Hypocalcaemia: Total calciium 1.11 mmol/L
• Persistent metabolic acidosis pH 7.2. Base
excess -11 mmol/L. Anion gap up to 20.
Ammonia 214 mmol/L. Glucose 8-9 mmol/L.
Differential diagnosis and then
diagnosis
• Clinical Dx:
Metabolic disease and then isovaleric aciduria
(day 11 -12)
• Chemical diagnosis (day 13) - Urine:
↑isovalerylglycine, 3- and 4-hydroxyisovaleric
acid, methylsuccinic acid
• Genetic diagnosis on day 20:
Father: heterozygous for p.Y371C;
Mother: heterozygous for
c.1148_1151dupGCTA(p.Y355X)
Patient compound heterozygous for the above
two mutations
Other results back after discharge
•
•
•
•
•
Carnitine, free (umol/L) 8 (12 -46)
Carnitine, total
23 (19-59)
Acylcarnitine
15 (19-36)
Acyl/Free carnitine
1.96 (0.45- 0.83)
Raised C4 and C5 –acylcarnitine with
other acylcarnitine levels either below or
within the reference ranges.
Treatment, presumptive dx of
kind of metabolic disease day
11
• Intravenous arginine and oral sodium
benzoate. multivitamin: thiamine, riboflavin,
biotin
Response: ammonia 214  84 mmol/L
Arginine, Glycine
Treatment with clinical diagnosis of
Isovaleric aciduria day 12
• Double volume ET done on day 12 and 13 four
times in 24 hours
• Total parenteral nutrition with protein 0.5
g/kg/day 11th Jan
• Carnitine given, dose 400mg/kg/d started on
10th Jan
• Glycine not available in Hong Kong
PROGRESS after exchange
transfusion (ET)
• Some spontaneous limb movement noted.
• Less stuporous but still drowsy
• Ammonia: 82 mmol/L → 118→ 88 (pre-ET on day
12) → 116 (post-ET day 13) →→ 42 (day 16)
→50 (day 18).
• No more acidosis after ET. pH 7.36-7.42. BE: 8.5
• Persistent neutropenia and thrombocytopenia
• On day 17, decided to have haemofiltration
scheduled on 16th Jan
• On day 18, patient became quite active and
conscious and haemofiltration called off
Collaboration with other hospitals
• Via email to members of HKSIEM, ask for
glycine and experience
• Dozens of response – negative
• Dr Joanie Hui called up the Royal Children
Hospital, Melbourne for glycine
• Glycine got on board the plane departing at
night (day 17)
• In the early morning (day 18), glycine at the
Customs
• Joanie and I went to the Customs at the airport
• We declare to the customs as “health food”
X-leu available on day 18
• X-Leu analog added to regular milk on
Day 18, providing low leucine formula (0.9
g protein 152.3mg Glycine and 53.28g
leu/100ml) gradually increased to 2
gram/kg/day of protein and 80 mg
leucine/kg/day)
Fu in SOPD
• Drugs: Glycine 150 – 300 mg/kg/day; L-carnitine
50 – 100 mg/kg/day
Double drug during intercurrent illness
• Leu restricted to 120 mg/kg/day
• Dislikes X-leu after age of 2 years
• Some protein aversion at age of 2 years but less
so after age of 3 years
• Meticulous leucine restriction replaced by low
protein diet of 1.5 g/kg/day with X-leu stopped at
age of 28 month
Leucine content in food
Food
Leucine content
Mature human milk
Cow milk
Cow and Gate formula
Egg
Rice, 1 exchange
Fruits, 1 exchange
Veggie, 1 exchange
99 mg per 100 ml
332 mg per 100 ml
160 mg per 100 ml
533 mg per 50 gram
210 mg
100 mg
90 mg
Intercurrent illness
• Appearance of sweaty leg odour
• So far no increased ammonia, no acidosis
or coma
• Tx: double dose of glycine and Lcarnitine intravenous D10  forced tube
feeding
Outcome, CAC assessment at 2
years 3 months
• Cognitive: 1 year 9 months
• Language receptive: 2 years 3 months;
expressive 1 year
• Motor: 1 year 9 months
Outcome currently, 3 years 6
months
• Borderline delay only
• Weakest in gross motor. (not yet jumping)
Toxin removal
• Theoretically: exchange transfusion,
peritoneal dialysis, haemolysis
• Review articles, textbooks
• In the case reports in the literature:
peritoneal dialysis and exchange
transfusion were reportedly done in two
patients
• Emails to experts: Carlo Dionisi-Vici and
Jean Mari Saudubray
Expert advice on toxin removal
• Dear colleague, the indication for starting CVVHD is the
persistence of severe metabolic abnormalities
or the lack of clinical response to medical
therapy. I have a limited experience with IVA but as far
as I remember patients are usulaay easyer to be
managed compared to PA and MMAs. My suggestion is
trying to keep the child anabolic and use carnitine also at
higher dose up to 500 mg/kg.
• Kind regards
• Carlo Dionisi-Vici
Expert advice, toxin removal
• Dear Dr. Lee, if there is a too slow
neurological recovery you should start with
CVVHD
• regards
• Jean Mari Saudubray
Conclusion
• Dx: mimics sepsis; blood for ammonia and
ABG and anion gap helpful
• Tx: availability of L-glycine and L-carnitine
• Resort to toxin removal by ET or
peritoneal dialysis when response to drugs
poor
• Relatively easier in management of
intercurrent illness compared to other
organic aciduria