Improving long term outcomes in urea cycle disorders‐report from the Urea Cycle Disorders Consortium

Abstract

The Urea Cycle Disorders Consortium (UCDC) has conducted, beginning in 2006, a longitudinal study (LS) of 8 enzyme deficiencies/transporter defects associated with the urea cycle. These include N-acetylglutamate synthase deficiency (NAGSD); Carbamyl phosphate synthetase 1 deficiency (CPS1D); Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthetase deficiency (ASSD) (Citrullinemia); Argininosuccinate lyase deficiency (ASLD) (Argininosuccinic aciduria); Arginase deficiency (ARGD, Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome (or mitochondrial ornithine transporter 1 deficiency [ORNT1D]); and Citrullinemia type II (mitochondrial aspartate/glutamate carrier deficiency [CITRIN]). There were 678 UCD patients enrolled in 14 sites in the U.S., Canada and Europe at the writing of this paper. This review summarizes findings of the consortium related to outcome, focusing primarily on neuroimaging findings and neurocognitive function. Neuroimaging studies in late onset OTCD offered evidence that brain injury caused by biochemical dysregulation may impact functional neuroanatomy serving working memory processes, an important component of executive function and regulation. Additionally, there were alteration in white mater microstructure and functional connectivity at rest. Intellectual manifestations in OTCD and other urea cycle disorders (UCD) vary. However, when neuropsychological deficits occur, they tend to be more prominent in motor/performance areas on both intelligence tests and other measures. In some disorders, adults performed significantly less well than younger patients. Further longitudinal follow-up will reveal whether this is due to declines throughout life or to improvements in diagnostics (especially newborn screening) and treatments in the younger generation of patients.

Urea Cycle Disorders in Neonates: Six Case Reports

“…During the neonatal period mortality was found to be 50% in severe cases (4). Similar mortality rates in our patients suggest that early initiation of PD may be an alternative treatment in centers where other treatment options are not available.…”

“…PD should be applied as an alternative method to cases where hemodiafiltration is not an option. Although hemodialysis has been considered more effective, some studies have shown that PD is still an effective treatment for hyperammonemic patients (4,5). In our study, PD seemed to be effective when the level of ammonia decreased.…”

“…The UCD mostly has an early onset (<28 days) (except for OTC deficiency), and high mortality especially in the neonatal period (4). Delay may occur due to the imitation of neonatal sepsis during the newborn period.…”

Development and Psychometric Evaluation of the MetabQoL 1.0: A Quality of Life Questionnaire for Paediatric Patients with Intoxication-Type Inborn Errors of Metabolism

“…Estimated incidences are 1:35,000 for UCD (Summar et al 2014) and 1:21,000 for OA (Dionisi-Vici et al 2002). Recently, the natural course of the diseases has been described in two large samples (K€ olker et al 2015a;K€ olker et al 2015b;Waisbren et al 2016). These reports highlight that IT-IEM have a major impact on patients' lives: Strict diet, daily intake of medication, the permanent risk of severe metabolic crises, and neurological sequelae are only some of the issues that the growing number of long-term surviving patients and their families face.…”

Messenger RNA therapy for rare genetic metabolic diseases

“…Urea cycle disorders result in the accumulation of ammonia causing devastating neurological sequelae in long-term survivors 48. The liver is primarily responsible for ammonia detoxification and mitochondrial ornithine transcarbamylase (OTC, EC 2.1.3.3) catalyses the incorporation of carbamoyl phosphate, involved in ridding the body of excess nitrogen, into the urea cycle.…”