Hyperammonemia-Hyperornithinemia-Homocitrullinemia (HHH Syndrome)

Prakash C Vaghela

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Prakash C Vaghela.

Kalarav Children Hospital, Kushal Neonatal Nursery, Bhavnagar, Gujarat, India.

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Dr Prakash C Vaghela. Kalarav Children hospital, Kushal Neonatal Nursery, Akar complex, Bhavnagar, 364001, Gujarat, India.
Email: prakash_vghl@yahoo.co.in

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Inborn errors of metabolism (IEM) are of concern in India, the spectrum being wide, varied and poorly diagnosed. Population based studies indicate tyrosinemia, maple syrup urine disease and phenylketonuria to be the commonest inborn errors of amino acid metabolism among newborns in India. HHH Syndrome is rare inherited autosomal recessive disorder resulting from deficiency of N-acetylglutamate synthetase leading to defect in transport of ornithine from cytosol into mitochondria characterized by hyperornithinemia ,hyperammonemia and homocitrullinemia. A two months old male child, first in birth order born of non-consanguineous marriage presented with recurrent vomiting, lethargy and failure to thrive. He was born at 35weeks of gestation with birth weight of 1.8kg. At the age of one month, he was hospitalized for septic shock. He was on breast feed and dairy milk without dilution and sugar. On examination, weight was 2kg, length was 47 cm and head circumference was 32cm. There was no dysmorphism, hepatosplenomegaly or specific odor in urine. Fundus was normal. His hemogram, sepsis screen, serum electrolytes, BUN, creatinine, serum acetone were normal. Urine for reducing substance was absent. Serum ammonia was 193micromol/liter. Blood gases showed pH of 7.29 bicarbonate of 5.6 mmol/l. Plasma aminoacid (micromole per liter) by Tandem mass spectrometry showed arginine 146 (Normal - 12-130), Leucine 389 (Normal - 50-150), Ornithine 470 (Normal - 20-100) and Ornithine/citrulline 7.3 (Normal <1.7). He was treated with low protein diet (1.2gm/kg/day). To provide adeqate calories, MCT oil and sugar were added in expressed breast milk. Sodium bezoate 250mg/kg/day was given for hyperammonemia. On follow up, baby has gained 600 gm in last twenty days.

HHH is a genetic/metabolic disorder caused by a defect in the mitochondrial ornithine transporter, ORNT1 that has been mapped to band 13q14. Hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome varies widely in age of presentation and long-term prognosis. Internationally only about 50 cases have been reported. Growth and developmental delays, learning disabilities (especially speech delay), periodic confusion and ataxia are typical presenting symptoms. Coagulation factors VII and X may be deficient. The amount of 14 C Ornithine incorporated into fibroblasts from patients with HHH syndrome typically is only 15% of that incorporated into control fibroblasts. This test has been extremely useful in the diagnosis of HHH syndrome. Ornithine and citrulline supplementation reduces ammonia levels in some patients. Sodium benzoate and sodium phenyl acetate and sodium phenyl butyrate may reduce ammonia levels by providing an alternative pathway. Hyperammonemic crisis might be managed with short-term protein restriction and IV fluids containing large amounts of glucose followed by slow reintroduction of small amounts of protein. First-trimester diagnosis of HHH syndrome may be achieved by study of the incorporation of [14 C] ornithine into proteins of chorionic villi cells, amniocytes.

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