Compliance to Clinical Guidelines Determines Outcome in Glutaric Aciduria Type I in the Era of Newborn Screening

Höliner, Isabella; Simma, B; Reiter, Alfred; Sass, Jörn Oliver; Zschocke, Johannes; Huemer, Martina

doi:10.1055/s-0029-1239525

Cited by 6 publications

(3 citation statements)

References 4 publications

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“…Defects in pericyte migration during early and post-natal development in GA-I patients could therefore disrupt pericyte coverage of vessels and induce vascular dysfunction. In this regard, increased GA levels could affect brain structure, not only during early infancy, but also prenatally [39]. The link between blood flow alterations in GA-I patients and pericyte dysfunction or loss requires further study.…”

Section: Discussionmentioning

confidence: 99%

Glutaric Acid Affects Pericyte Contractility and Migration: Possible Implications for GA-I Pathogenesis

et al. 2019

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Glutaric Acidemia I (GA-I) is an inherited neurometabolic childhood disease characterized by bilateral striatal neurodegeneration upon brain accumulation of millimolar concentrations of glutaric acid (GA) and related metabolites. Vascular dysfunction, including abnormal cerebral blood flow and blood-brain barrier damage, is an early pathological feature in GA-I, although the affected cellular targets and underlying mechanisms remain unknown. In the present study, we have assessed the effects of GA on capillary pericyte contractility in cerebral cortical slices and pericyte cultures, as well as on the survival, proliferation and migration of cultured pericytes. GA induced a significant reduction in capillary diameter at distances up to ~10 µm from the center of pericyte somata. However, GA did not affect the contractility of cultured pericytes, suggesting that the response elicited in slices may involve GA evoking pericyte contraction by acting on other cellular components of the neurovascular unit. Moreover, GA indirectly inhibited migration of cultured pericytes, an effect that was dependent on soluble glial factors since it was observed upon application of conditioned media from GA-treated astrocytes (CM-GA), but not upon direct GA addition to the medium. Remarkably, CM-GA showed increased expression of cytokines and growth factors that might mediate the effects of increased GA levels not only on pericyte migration but also on vascular permeability and angiogenesis. These data suggest that some effects elicited by GA might be produced by altering astrocyte-pericyte communication, rather than directly acting on pericytes. Importantly, GA-evoked alteration of capillary pericyte contractility may account for the reduced cerebral blood flow observed in GA-I patients.

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Section: Discussionmentioning

confidence: 99%

Glutaric Acid Affects Pericyte Contractility and Migration: Possible Implications for GA-I Pathogenesis

et al. 2019

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“…While the first guideline mostly included grade D and a few grade C recommendations, reflecting significant uncertainty (59), the level of evidence and grade of recommendations have been improved continuously, demonstrated by the first (60) and second revision (61). This progress was much accelerated by careful long-term follow-up of national and international cohorts (38,56,57,59,(61)(62)(63)(64)(65)(66)(67)(68)(69), demonstrating that (i) newborn screening is the prerequisite of favorable neurological outcome and survival and (ii) is highly cost-effective, and that (iii) adherence to recommended maintenance and emergency treatment is associated with the most favorable neurological outcome and (iv) normal growth. Furthermore, these studies described a so far unknown renal disease manifestation, unraveled similarities (risk of striatal necrosis with concomitant complex movement disorder with predominant dystonia) and discrepancies (cognitive function, white matter changes, subdural hematoma) between biochemically delineated subgroups (high versus low excreter phenotype), and evaluated which part of the complex clinical spectrum can be specifically targeted and changed by current therapy, highlighting the need for safer and more effective medicines.…”

Section: Guideline Developmentmentioning

confidence: 99%

Rare Disease Registries Are Key to Evidence-Based Personalized Medicine: Highlighting the European Experience

et al. 2022

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Rare diseases, such as inherited metabolic diseases, have been identified as a health priority within the European Union more than 20 years ago and have become an integral part of EU health programs and European Reference Networks. Having the potential to pool data, to achieve sufficient sample size, to overcome the knowledge gap on rare diseases and to foster epidemiological and clinical research, patient registries are recognized as key instruments to evidence-based medicine for individuals with rare diseases. Patient registries can be used for multiple purposes, such as (1) describing the natural history and phenotypic diversity of rare diseases, (2) improving case definition and indication to treat, (3) identifying strategies for risk stratification and early prediction of disease severity (4), evaluating the impact of preventive, diagnostic, and therapeutic strategies on individual health, health economics, and the society, and (5) informing guideline development and policy makers. In contrast to clinical trials, patient registries aim to gather real-world evidence and to achieve generalizable results based on patient cohorts with a broad phenotypic spectrum. In order to develop a consistent and sustained framework for rare disease registries, uniform core principles have been formulated and have been formalized through the European Rare Disease Registration Infrastructure. Adherence to these core principles and compliance with the European general data protection regulations ensures that data collected and stored in patient registries can be exchanged and pooled in a protected environment. To illustrate the benefits and limitations of patient registries on rare disease research this review focuses on inherited metabolic diseases.

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“…Observational studies have demonstrated the importance of aggressive management, especially in an asymptomatic infant [ 6 , 27 , 28 ], although the implementation of dietary recommendations is often not clear. Herein we present results from an international empiric study on the nutritional management of patients with GA-1.…”

Section: Introductionmentioning

confidence: 99%

Inconsistencies in the Nutrition Management of Glutaric Aciduria Type 1: An International Survey

et al. 2020

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Glutaric aciduria type 1 (GA-1) is a cerebral organic aciduria characterized by striatal injury and progressive movement disorder. Nutrition management shifted from a general restriction of intact protein to targeted restriction of lysine and tryptophan. Recent guidelines advocate for a low-lysine diet using lysine-free, tryptophan-reduced medical foods. GA-1 guideline recommendations for dietary management of patients over the age of six are unclear, ranging from avoiding excessive intake of intact protein to counting milligrams of lysine intake. A 22–question survey on the nutrition management of GA-1 was developed with the goal of understanding approaches to diet management for patients identified by newborn screening under age six years compared to management after diet liberalization, as well as to gain insight into how clinicians define diet liberalization. Seventy-six responses (25% of possible responses) to the survey were received. Nutrition management with GA-1 is divergent among surveyed clinicians. There was congruency among survey responses to the guidelines, but there is still uncertainty about how to counsel patients on diet optimization and when diet liberalization should occur. Ongoing clinical research and better understanding of the natural history of this disease will help establish stronger recommendations from which clinicians can best counsel families.

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Compliance to Clinical Guidelines Determines Outcome in Glutaric Aciduria Type I in the Era of Newborn Screening

Cited by 6 publications

References 4 publications

Glutaric Acid Affects Pericyte Contractility and Migration: Possible Implications for GA-I Pathogenesis

Glutaric Acid Affects Pericyte Contractility and Migration: Possible Implications for GA-I Pathogenesis

Rare Disease Registries Are Key to Evidence-Based Personalized Medicine: Highlighting the European Experience

Inconsistencies in the Nutrition Management of Glutaric Aciduria Type 1: An International Survey

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