Bezafibrate in skeletal muscle fatty acid oxidation disorders

Ørngreen, Mette Cathrine; Madsen, Karen L.; Preisler, Nicolai; Andersen, Grete; Vissing, John; Laforêt, Pascal

doi:10.1212/wnl.0000000000000118

Cited by 82 publications

(56 citation statements)

References 24 publications

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“…Finally, investigation of the role of mitochondrial targeted antioxidants or compounds that increase mitochondrial biogenesis and dynamics, such as resveratrol and bezafibrate, firstly in Gcdh‐/‐ mice tissues and cells from patients affected by GA I, may represent in the future novel therapies aiming to reduce reactive species levels and improve cellular respiration in this disease. In this particular, beneficial effects of these compounds have been demonstrated in animal models and fibroblasts from patients with fatty acid oxidation and respiratory chain defects (Bonnefont et al, 2009; Aires et al, 2014; Ørngreen et al, 2014; Djouadi and Bastin, 2019). We expect that this review article may encourage additional investigations in this area.…”

Section: Discussionmentioning

confidence: 99%

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Wajner

Amaral

Leipnitz

2019

Intl J of Devlp Neuroscience

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Glutaric acidemia type I (GA I) is an inherited neurometabolic disease caused by deficient activity of the mitochondrial enzyme glutaryl‐CoA dehydrogenase (GCDH), resulting in predominant accumulation of glutaric and 3‐hydroxyglutaric acids derived from lysine (Lys), hydroxylysine, and tryptophan catabolism. GA I patients usually present progressive cortical leukodystrophy and frequently develop acute striatal degeneration during encephalopathic crises during the first three years of life. The pathophysiology of the neurodegeneration observed in GA I is still partly known, although the development of the genetic mice model of GA I (Gcdh−/−) has contributed to clarify potential underlying mechanisms involved in brain damage in this disease. In this review we will summarize the knowledge acquired from studies using this animal model indicating that disruption of redox homeostasis, glutamatergic neurotransmission and bioenergetics, as well as vascular alterations, blood‐brain barrier breakage and altered myelination underlie the cortical and striatum abnormalities and white matter changes observed in GA I patients. Elucidation of these pathomechanisms potentially offers new standpoints for the development of novel therapeutic strategies for this disease.

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Section: Discussionmentioning

confidence: 99%

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Wajner

Amaral

Leipnitz

2019

Intl J of Devlp Neuroscience

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“…Significant long-term symptoms have been reported in patients identified both symptomatically and through newborn screening. Improvement in these symptoms with the use of the investigational drug triheptanoin has been reported [10, 14], but not with bezafibrate [16]. …”

Section: Introductionmentioning

confidence: 99%

Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database

Peña

Calcar

Hansen

et al. 2016

Molecular Genetics and Metabolism

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Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency can present at various ages from the neonatal period to adulthood, and poses the greatest risk of complications during intercurrent illness or after prolonged fasting. Early diagnosis, treatment, and surveillance can reduce mortality; hence, the disorder is included in the newborn Recommended Uniform Screening Panel (RUSP) in the United States. The Inborn Errors of Metabolism Information System (IBEM-IS) was established in 2007 to collect longitudinal information on individuals with inborn errors of metabolism included in newborn screening (NBS) programs, including VLCAD deficiency. We retrospectively analyzed early outcomes for individuals who were diagnosed with VLCAD deficiency by NBS and describe initial presentations, diagnosis, clinical outcomes and treatment in a cohort of 52 individuals ages 1–18 years. Maternal prenatal symptoms were not reported, and most newborns remained asymptomatic. Cardiomyopathy was uncommon in the cohort, diagnosed in 2/52 cases. Elevations in creatine kinase were a common finding, and usually first occurred during the toddler period (1–3 years of age). Diagnostic evaluations required several testing modalities, most commonly plasma acylcarnitine profiles and molecular testing. Functional testing, including fibroblast acylcarnitine profiling and white blood cell or fibroblast enzyme assay, is a useful diagnostic adjunct if uncharacterized mutations are identified.

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“…Moreover, Yasuno et al demonstrated an increased enzymatic activity following bezafibrate treatment in human induced pluripotent stem cell-derived myocytes obtained from a Japanese patient with CPT II deficiency (8). In contrast, Ørngreen et al found no significant improvement of bezafibrate treatment in a randomized clinical trial of patients with CPT II deficiency and very long-chain acyl-CoA dehydrogenase deficiencies, which put into question the effectiveness of bezafibrate in vitro and in vivo (9). However, the general effectiveness of combination therapy similar to that applied in our case remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

First Japanese Case of Carnitine Palmitoyltransferase II Deficiency with the Homozygous Point Mutation S113L

et al. 2016

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Carnitine palmitoyltransferase II (CPT II) deficiency is a rare inherited disorder related to recurrent episodes of rhabdomyolysis. The adult myopathic form of CPT II deficiency is relatively benign and difficult to diagnose. The point mutation S113L in CPT2 is very common in Caucasian patients, whereas F383Y is the most common mutation among Japanese patients. We herein present a case of CPT II deficiency in a Japanese patient homozygous for the missense mutation S113L. The patient showed a decreased frequency of rhabdomyolysis recurrence after the administration of a diet containing medium-chain triglyceride oil and supplementation with carnitine and bezafibrate.

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Bezafibrate in skeletal muscle fatty acid oxidation disorders

Abstract: This study provides Class I evidence that bezafibrate 200 mg 3 times daily is ineffective in improving changes in FAO and HR during exercise in adults with CPT II and VLCAD deficiencies.

Cited by 82 publications

References 24 publications

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database

First Japanese Case of Carnitine Palmitoyltransferase II Deficiency with the Homozygous Point Mutation S113L

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