Abstract:
BACKGROUND:Arginase 1 (ARG1) deficiency is a rare urea cycle disorder (UCD). This hypothesis-generating study explored clinical phenotypes, metabolic profiles, molecular genetics, and treatment approaches in a cohort of children and adults with ARG1 deficiency to add to our understanding of the underlying pathophysiology. METHODS:Clinical data were retrieved retrospectively from physicians using a questionnaire survey. Plasma aminoacids, guanidinoacetate (GAA), parameters indicating oxidative stress and nitric oxide (NO) synthesis as well as asymmetric dimethylarginine (ADMA) were measured at a single study site. RESULTS:Nineteen individuals with ARG1 deficiency and 19 matched controls were included in the study. In patients, paraparesis, cognitive impairment, and seizures were significantly associated suggesting a shared underlying pathophysiology. In patients plasma GAA exceeded normal ranges and plasma ADMA was significantly elevated. Compared to controls, nitrate was significantly higher, and the nitrite:nitrate ratio significantly lower in subjects with ARG1 deficiency suggesting an advantage for NO synthesis by inducible NO synthase (iNOS) over endothelial NOS (eNOS). Logistic regression revealed no significant impact of any of the biochemical parameters (including arginine, nitrates, ADMA, GAA, oxidative stress) or protein restriction on long-term outcome. CONCLUSION:Three main hypotheses which must be evaluated in a hypothesis driven confirmatory study are delineated from this study: 1) clinical manifestations in ARG1 deficiency are not correlated with arginine, protein intake, ADMA, nitrates or oxidative stress. 2) GAA is elevated and may be a marker or an active part of the pathophysiology of ARG1 deficiency. 3) Perturbations of NO metabolism merit future attention in ARG1 deficiency.
journal_name
J Inherit Metab Disjournal_title
Journal of inherited metabolic diseaseauthors
Huemer M,Carvalho DR,Brum JM,Ünal Ö,Coskun T,Weisfeld-Adams JD,Schrager NL,Scholl-Bürgi S,Schlune A,Donner MG,Hersberger M,Gemperle C,Riesner B,Ulmer H,Häberle J,Karall Ddoi
10.1007/s10545-016-9928-ysubject
Has Abstractpub_date
2016-05-01 00:00:00pages
331-340issue
3eissn
0141-8955issn
1573-2665pii
10.1007/s10545-016-9928-yjournal_volume
39pub_type
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