Intellectual, Adaptive, and Behavioral Functioning in Children With Urea Cycle Disorders

Abstract

Inborn errors of urea synthesis lead to an accumulation of ammonia in blood and brain and result in high rates of mortality and neurodevelopmental disability. This study seeks to characterize the cognitive, adaptive, and emotional/behavioral functioning of children with urea cycle disorders (UCDs). These domains were measured through testing and parent questionnaires in 92 children with UCDs [33 neonatal onset (NO), 59 late onset (LO)]. Results indicate that children who present with NO have poorer outcome than those who present later in childhood. Approximately half of the children with NO performed in the range of intellectual disability (ID), including a substantial number (ϳ30%) who were severely impaired. In comparison, only a quarter of the LO group was in the range of ID. There is also evidence that the UCD group has difficulties in aspects of emotional/behavioral and executive skills domains. In conclusion, children with UCDs present with a wide spectrum of cognitive outcomes. Children with NO disease have a much higher likelihood of having an ID, which becomes even more evident with increasing age. However, even children with LO UCDs demonstrate evidence of neurocognitive and behavioral impairment, particularly in aspects of attention and executive functioning. of the six enzymes and two transport proteins involved in urea biosynthesis. The specific disorders are: N-acetylglutamate synthase deficiency, carbamyl phosphate synthetase I deficiency, ornithine transcarbamylase (OTC) deficiency, argininosuccinate synthetase (AS) deficiency (citrullinemia), argininosuccinate lyase (AL) deficiency (argininosuccinic aciduria), arginase deficiency (argininemia), hyperornithinemia, hyperammonemia, homocitrullinuria syndrome (or mitochondrial ornithine carrier deficiency-ORNT), and citrullinemia type II (mitochondrial aspartate/glutamate carrier deficiency-CITR). UCDs are inherited as autosomal recessive traits, except for OTC deficiency, which is X-linked. Because of the absence of nationwide newborn screening for these disorders, the true incidence of UCD is unknown. Based on case reports and data from referred patients, the estimated combined incidence for all UCDs has ranged from 1 in 8,200 to 1 in 30,000 (1,2).Inborn errors of urea synthesis lead to an accumulation of ammonia in blood and brain and clinically present as recurrent episodes of hyperammonemia manifested by vomiting, lethargy, and coma. Infants with complete enzyme deficiencies (other than argininemia) commonly present in the newborn period with hyperammonemic coma. Despite aggressive treatment with hemodialysis, the mortality in the newborn period for proximal urea cycle defects (OTC deficiency and CPSI deficiency) has been reported to approach 50% (3). As reported in our previous studies, virtually all survivors have developmental disabilities that correlate with the number, severity, and duration of hyperammonemic episodes (4,5). Studies of children with neonatal UCDs have shown variable intellectual outcomes, based broadly on develop...

Assessing Psychological Functioning in Metabolic Disorders: Validation of the Adaptive Behavior Assessment System, Second Edition (ABAS-II), and the Behavior Rating Inventory of Executive Function (BRIEF) for Identification of Individuals at Risk

“…Parents of children with urea cycle disorders or adults with urea cycle disorders participating in a longitudinal study completed the ABAS-II and BRIEF as part of comprehensive neuropsychological evaluations (Seminara et al 2010;Krivitzky et al 2009;Ah Mew et al 2013). Additional reports on results from this study are forthcoming.…”

“…The clinical symptoms related to these disorders are variable, ranging from neonatal death due to complications of hyperammonemia to normal cognitive and developmental outcomes throughout life (Krivitzky et al 2009). Newborn screening has recently become available for several of the urea cycle disorders (Beck et al 2011), and while early diagnosis and treatment may reduce the frequency and severity of hyperammonemic episodes (Summar 2001), they do not eliminate risks of reduced cognitive abilities, maladaptive behaviors, and poor executive functioning (Krivitzky et al 2009;Ah Mew et al 2013). …”

The Measurement of Ammonia in Human Breath and its Potential in Clinical Diagnostics

“…Liver disease together with abnormal pH balance are likely to cause respiratory alkalosis. Altered consciousness along with respiratory alkalosis/acidosis should prompt the determination of blood ammonia (Krivitzky et al, 2009;Msall et al, 1984). Blood ammonia with transaminases should also be considered for perinatal asphyxia markers (Esque-Ruiz et al, 2003).…”

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

“…Complete enzymatic deficiency results in classic or type I citrullinemia (CTLN1), which is typically associated with citrulline elevations above 1,500 mmol/L. Most citrullinemia type I patients who suffered their first hyperammonemic episode as neonates are recounted to have died or to face long-term developmental or neurological disabilities (Maestri et al 1995;Tokatli et al 1998;Uchino et al 1998;Bachmann 2003a;Tuchman et al 2008;Krivitzky et al 2009;Seminara et al 2010). Only two cases of ASS-deficient patients are reported with good outcome 2 years following rescue from neonatal hyperammonemic coma (Walter et al 1992;Vilaseca et al 2001).…”

“…Children who survive the initial hyperammonemic crisis are at significant risk of disabling neurological sequelae (Msall et al 1984;Saudubray et al 1999;Bachmann 2003a;Gropman and Batshaw 2004;Nassogne et al 2005;Krivitzky et al 2009;Seminara et al 2010).…”