Favorable Long-Term Outcome Following Severe Neonatal Hyperammonemic Coma in a Patient with Argininosuccinate Synthetase Deficiency

Abstract

This chapter reports on the sequelae-free 8-year follow-up with normal growth, intellectual development, and schooling of a boy with argininosuccinate synthetase deficiency (citrullinemia type I) who was rescued from severe neonatal hyperammonemic coma at 8 days of life (peak ammonia level of 1,058 μmol/L). Important clinical management aspects were: rapidity of response to emergency therapeutic measures that included specific drug regimen, protein restriction, optimal caloric intake and hemodialysis, short coma duration (14 h), possible neuroprotective effect of mild systemic hypothermia during the acute episode, long-term metabolic control with strict compliance to standard of care therapeutic and dietary regimens, active prevention of subsequent hyperammonemic episodes, and early neurodevelopmental evaluations and interventions. We conclude that good long-term neurological outcome following rescue from neonatal hyperammonemic coma is rarely reported but attainable. Prospective registries and interventional studies regrouping clinical data from urea cycle disorders patients will assist clinicians in instituting the appropriate therapeutic measures to provide the best prospect of positive long-term outcome for these children.

Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision

“…Single patients with a normal outcome despite initial ammonia >1000 μmol/L have been reported. 16,132…”

“…However, very high ammonia concentrations are not an absolute criterion, they always have to be evaluated in association with the clinical situation and the duration of hyperammonemia. Single patients with a normal outcome despite initial ammonia >1000 μmol/L have been reported …”

Neuropsychological attributes of urea cycle disorders: A systematic review of the literature

“…An 8‐year‐old boy who presented with HA coma at 8 days of age was treated with protein restriction, arginine, and sodium benzoate. He achieved average cognitive abilities and high‐average scores on gross motor skills, personal‐social, and performance domains of the Griffiths Mental Developmental Stage assessment . His language score was average, although some vocabulary and fluency difficulties and fine motor weaknesses were noted.…”

“…Abbreviations: ARGD, arginase deficiency; ASLD, argininosuccinate lyase deficiency; ASSD, argininosuccinate synthetase deficiency; CPS1D, carbamoyl phosphate synthetase 1 deficiency; HHH, hyperornithinemia-hyperammonemia-homocitrullinuria; NAGSD, N-acetylglutamate synthase deficiency; OTCD, ornithine transcarbamylase deficiency HHH syndrome, 109 citrullinemia type I, 66 and probably in all the other UCDs, as well. Earlier treatment initiation (diet in less severe cases and ammonia scavengers or liver transplantation in severe cases) led to better outcomes in most studies, 7,8,45,47,61,84,110 whereas lack of treatment or noncompliance with treatment resulted in poorer cognitive outcomes. 56,67,68 Recent studies provide evidence for other variables that explain diversity of outcomes, including number of HA episodes, cumulative exposure to moderately abnormal biochemical levels, 65 and other epigenetic factors or environmental stressors, such as alcohol consumption, 111 menses, 25 or pregnancy in women.…”

“…While genotype was sometimes associated with neonatal vs later onset of symptoms, it did not reliably predict occurrence of intellectual disabilities in OTCD, CPS1, HHH syndrome, citrullinemia type I, and probably in all the other UCDs, as well. Earlier treatment initiation (diet in less severe cases and ammonia scavengers or liver transplantation in severe cases) led to better outcomes in most studies, whereas lack of treatment or noncompliance with treatment resulted in poorer cognitive outcomes …”