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

Susan E Waisbren, Andrea L Gropman, Members of the Urea Cycle Disorders Consortium (UCDC), Mark L Batshaw, Susan E Waisbren, Andrea L Gropman, Members of the Urea Cycle Disorders Consortium (UCDC), Mark L Batshaw

Abstract

The Urea Cycle Disorders Consortium (UCDC) has conducted, beginning in 2006, a longitudinal study (LS) of eight 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 deficits 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.

Figures

Figure 1
Figure 1
The Urea Cycle: N-acetylglutamate synthase (NAGS), Carbamyl phosphate synthetase 1 (CPS1), Ornithine transcarbamylase (OTC), Argininosuccinate synthetase (ASS), Argininosuccinate lyase (ASL), Arginase deficiency (ARG), mitochondrial ornithine transporter 1 (ORNT 1), and mitochondrial aspartate/glutamate carrier (CITRIN).
Figure 2
Figure 2
The Urea Cycle Disorders Consortium (UCDC): Map of the 14 sites and the date the institution joined the consortium.
Figure 3a
Figure 3a
1H MRS metabolite differences in OTCD versus age matched control Reprinted with permission from Gropman AL, Fricke ST, Seltzer RR, Hailu A, et al (2008). Mol Genet Metab. 95(1-2):21-30. NAA=N acetylaspartate; Glu=glutamate; Gln= glutamine; Asp=aspartate; Cre and PCr=creatine and phosphocreatine;Cho=choline; mI=myoinosital
Figure 3b
Figure 3b
This shows the inverse relationship of Brain Gln levels and Performance IQ. From: Pacheco-Colón I, Fricke S, VanMeter J, Gropman AL. Advances in urea cycle neuroimaging: Proceedings from the 4th International Symposium on urea cycle disorders, Barcelona, Spain, September 2013. Mol Genet Metab. 2014 113(1-2):118-126. Reprinted with permission. Gln=glutamine; PIQ=performance IQ
Figure 3c
Figure 3c
this shows the relationship between Fractional anisotropy (FA), a measure of white matter integrity with brain glutamine levels in patients with symptomatic OTCD.
Figure 4
Figure 4
Diffusion tensor imaging shows evidence of white matter injury in motor tracts that connect parts of the brain important in attention and memory Reproduced with permission from Gropman et al., Metab Brain Dis. 2013 Jun; 28(2): 269–275.
Figure 5
Figure 5
Trails Test Performance in patients with OTCD by group. From: Pacheco-Colon I, Fricke S., VanMeter J, Gropman AL. Advances in urea cycle neuroimaging: Proceedings from the 4th International Symposium on urea cycle disorders, Barcelona, Spain, September 2013. Mol Genet Metab. 2014 113(1-2): 118-126. Reprinted with permission.
Figure 6
Figure 6
Stroop Performance group means. Reprinted with permission from Gropman A. Brain imaging in UCD. Mol Genet Metab. 2010;100 Suppl 1:S20-30.

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