We collected data on 48 patients from 38 families with guanidinoacetate methyltransferase (GAMT) deficiency. Global developmental delay/intellectual disability (DD/ID) with speech/language delay and behavioral problems as the most affected domains was present in 44 participants, with additional epilepsy present in 35 and movement disorder in 13. Treatment regimens included various combinations/dosages of creatine-monohydrate, l-ornithine, sodium benzoate and protein/arginine restricted diets. The median age at treatment initiation was 25.5 and 39 months in patients with mild and moderate DD/ID, respectively, and 11 years in patients with severe DD/ID. Increase of cerebral creatine and decrease of plasma/CSF guanidinoacetate levels were achieved by supplementation with creatine-monohydrate combined with high dosages of l-ornithine and/or an arginine-restricted diet (250 mg/kg/d l-arginine). Therapy was associated with improvement or stabilization of symptoms in all of the symptomatic cases. The 4 patients treated younger than 9 months had normal or almost normal developmental outcomes. One with inconsistent compliance had a borderline IQ at age 8.6 years. An observational GAMT database will be essential to identify the best treatment to reduce plasma guanidinoacetate levels and improve long-term outcomes.
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.
Hyperargininemia is caused by deficiency of arginase 1, which catalyzes the hydrolysis of L-arginine to urea as the final enzyme in the urea cycle. In contrast to other urea cycle defects, arginase 1 deficiency usually does not cause catastrophic neonatal hyperammonemia but rather presents with progressive neurological symptoms including seizures and spastic paraplegia in the first years of life and hepatic pathology, such as neonatal cholestasis, acute liver failure, or liver fibrosis. Some patients have developed hepatocellular carcinoma. A usually mild or moderate hyperammonemia may occur at any age. The pathogenesis of arginase I deficiency is yet not fully understood. However, the accumulation of L-arginine and the resulting abnormalities in the metabolism of guanidine compounds and nitric oxide have been proposed to play a major pathophysiological role. This article provides an update on the first patients ever described, gives an overview of the distinct clinical characteristics, biochemical as well as genetical background and discusses treatment options.
NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3cyclohexanedione) is the mainstay of treatment in tyrosinemia type 1 (HT 1). The current recommendation is to divide the total daily dose of NTBC into two doses. We monitored the plasma NTBC concentrations in a series of seven patients who were changed from multiple divided doses to a single daily dose of NTBC. Two additional patients were started on a single daily dose of NTBC after the diagnosis of HT 1 was established. In three patients, NTBC kinetics were performed over 6 and 24 hours, respectively. The use of multiple divided doses or a single daily dose did not significantly affect plasma NTBC concentrations or the mean daily dose needed to attain therapeutic plasma NTBC concentrations. Moreover, kinetic studies demonstrated that plasma NTBC concentrations were completely stable over a period of 24 hours with a single dose regimen, as expected given the known NTBC plasma half life of 54 hours. Although these preliminary results need to be confirmed in more patients, our findings show that administration of NTBC in a single daily dose may be as effective as a multiple-dose regimen in reaching therapeutic plasma NTBC concentrations and suppressing succinylacetone formation in patients with HT 1. In fact, single dose treatment may increase patients' compliance with the drug treatment and improve metabolic control.
Introduction: Progress in diagnosis and treatment of patients with intoxication-type inborn errors of metabolism (IT-IEM) such as urea cycle disorders, organic acidurias or maple syrup urine disease is resulting in a growing number of long-term survivors. Consequently, health-related quality of life (HrQoL) of patients is increasingly regarded as a meaningful outcome parameter. To develop the first validated, disease-specific HrQoL questionnaire for IT-IEM, patients and parents were interviewed as content experts to identify major physical and psychosocial constraints and resources.Methods: Focus group interviews with 19 paediatric IT-IEM patients and 26 parents were conducted in four metabolic centres in Austria, Germany and Switzerland. Disease-specific HrQoL categories were established by qualitative content analysis.Results: Fourteen disease-specific topics related to the three well-established generic HrQoL dimensions of physi-
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