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Indian Pediatr 2014;51:
755-756 |
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Low Dose of Carglumic Acid for Treatment of
Hyperammonemia due to N-Acetylglutamate Synthase Deficiency
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Ertugrul Kiykim and Tanyel Zubarioglu
Istanbul University Cerrahpasa Medical Faculty,
Department of Pediatrics, Division of Nutrition and Metabolism,
Istanbul, Turkey.
Email:
[email protected]
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N-acetylglutamate synthase (NAGS) deficiency is an autosomal recessive
disorder of the urea cycle. N-carbamylglutamate (NCG) is a structural
analogue of human N-acetylglutamate and is licensed for the treatment of
hyperammonemia due to NAGS deficiency [1,2].
A 5-day-old boy – first child of a consanguineous
Turkish couple – had an elevated ammonia level of 328 mmol/L. Treatment
with intravenous glucose, oral sodium benzoate (200 mg/kg/day) and
arginine (200 mg/kg/day) was started and enteral feeding was stopped.
Despite this, his ammonia level remained elevated. Carglumic acid was
started with a dose of 100 mg/kg/day, and the ammonia level was
normalized. His clinical and laboratory findings were consistent with
NAGS deficiency. Mutation analysis revealed classical mutation of the
NAGS gene (Exon6: c.1450T>C (p. Trp484Arg)). The patient was discharged
with carglumic acid (100 mg/kg/day) and a protein-restricted,
high-calorie diet.
The patient was not brought to our outpatient clinic
for the following 6 months. At 8 months of age, he was not using
protein-restricted diet, and carglumic acid dose was reduced to 12.5
mg/kg/day as the child was now heavier. Carglumic acid dose was raised
to 25 mg/kg/day. The patient did not attend to our clinic for another 7
months, and he was taking carglumic acid at the dose of 10 mg/kg/day
when he was 15 months of age. Carglumic acid dose was again raised to 20
mg/kg/day, and a protein-restricted diet was continued. At 27 months,
reported to emergency unit with an elevated ammonia level of 228 mmol/L
along with an upper respiratory tract infection. The carglumic acid dose
was raised to 50 mg/kg/day, and ammonia level returned to normal within
6 hours. After hyper-ammonemia resolved, carglumic acid dosage was
reduced to 30 mg/kg/day and protein-restricted diet was discontinued.
The patient’s ammonia levels remained within normal limits. At 3 years
of age, the patient has no neurodevelopmental abnormalities.
The initial NCG dosage for treatment of acute
hyperammonemia ranges between 100 to 250 mg/kg/day [2,3]. After the
acute episode, the lowest reported effective daily dosage is 15
mg/kg/day [4]. Our patient had no hyperammonemia episodes under NCG
treatment with a dose of 10 mg/kg/day. However, it seems that a lower
dose is not enough during illness, as he was using a dose of 20
mg/kg/day when he developed hyper-ammonemia along with an infection. NCG
therapy appears to correct the metabolic defect; therefore, dietary
protein can be increased to 2-3 g/kg/day in some patients [2,5]. In our
child – after the NCG dosage was raised to 30 mg/kg/day – protein
restriction was totally removed but the ammonia levels remained normal.
We conclude that NCG is effective for controlling hyperammonemia in NAGS
deficiency; at a much lower dose, except during acute infections.
References
1. Elpeleg O, Shaag A, Ben-Shalom E, Schmid T,
Bachmann C. N-acetylglutamate synthase deficiency and the treatment of
hyperammonemic encephalopathy. Ann Neurol. 2002;52:845-9.
2. Häberle J. Role of carglumic acid in the treatment
of acute hyperammonemia due to N-acetylglutamate synthase deficiency.
Ther Clin Risk Manag. 2011;7:327-32.
3. Ah Mew N, Caldovic L. N-acetylglutamate synthase
deficiency: an insight into the genetics, epidemiology, pathophysiology,
and treatment. Appl Clin Genet. 2011;4:127-35.
4. Gessler P, Buchal P, Schwenk HU, Wermuth B.
Favourable long-term outcome after immediate treatment of neonatal
hyperammonemia due to N-acetylglutamate synthase deficiency. Eur J
Pediatr. 2010;169:197-9.
5. Caldovic L, Morizono H, Daikhin Y, Nissim I,
McCarter RJ, Yudkoff M, et al. Restoration of ureagenesis in N-acetylglutamate
synthase deficiency by N-carbamyl-glutamate. J Pediatr. 2004;145:552-4.
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