Premium
Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency
Author(s) -
Huemer Martina,
Carvalho Daniel R.,
Brum Jaime M.,
Ünal Özlem,
Coskun Turgay,
WeisfeldAdams James D.,
Schrager Nina L.,
SchollBürgi Sabine,
Schlune Andrea,
Donner Markus G.,
Hersberger Martin,
Gemperle Claudio,
Riesner Brunhilde,
Ulmer Hanno,
Häberle Johannes,
Karall Daniela
Publication year - 2016
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-016-9928-y
Subject(s) - asymmetric dimethylarginine , arginase , pathophysiology , medicine , urea cycle , oxidative stress , arginine , enos , endocrinology , nitric oxide , biomarker , nitric oxide synthase , chemistry , biochemistry , amino acid
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.