Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study

Libri, Vincenzo; Yandım, Cihangir; Athanasopoulos, Stavros; Loyse, Naomi; Natisvili, Theona; P, Law; Chan, Pui-Kwong; Mohammad, Tariq; Mauri, Marta; Tam, Kin Tung; Leiper, James; Piper, Sophie; Ramesh, Aravind; Parkinson, Michael; Huson, Les; Giunti, Paola; Festenstein, Richard

doi:10.1016/s0140-6736(14)60382-2

Cited by 130 publications

(102 citation statements)

References 43 publications

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“…Aberrant DNA methylation has also been reported both downstream and upstream of the expansion in frataxin [39], with hypermethylation especially in the first intron showing a direct correlation with the expansion size and the age of onset [40]. Other studies have also reported modifications on the chromatin level, including decreased histone H3K9 acetylation and increased H3K9 methylation in FRDA [41], and recently, nicotinamide, a class III histone deacetylase inhibitor, has been put to clinical trials [42]. The expansion in DMPK is located in a 3.5-kb CpG island [43] in the gene-rich DM1 locus and leads to epigenetic modifications both upstream and downstream of DMPK .…”

Section: Introductionmentioning

confidence: 99%

Elevated Global DNA Methylation Is Not Exclusive to Amyotrophic Lateral Sclerosis and Is Also Observed in Spinocerebellar Ataxia Types 1 and 2

et al. 2018

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Adult-onset neurological disorders are caused and influenced by a multitude of different factors, including epigenetic modifications. Here, using an ELISA kit selected upon careful testing, we investigated global 5-methylcytosine (5-mC) levels in sporadic and familial amyotrophic lateral sclerosis (sALS and fALS), spinocerebellar ataxia types 1 and 2 (SCA1 and SCA2), Huntington’s disease, Friedreich’s ataxia, and myotonic dystrophy type 1. We report a significant elevation in global 5-mC levels of about 2–7% on average for sALS (p < 0.01 [F(1, 243) = 9.159, p = 0.0027]) and various forms of fALS along with SCA1 (p < 0.01 [F(1, 83) = 11.285], p = 0.0012) and SCA2 (p < 0.001 [F(1, 122) = 29.996, p = 0.0001]) when compared to age- and sex-matched healthy controls. C9orf72 expansion carrier ALS patients exhibit the highest global 5-mC levels along with C9orf72 promoter hypermethylation. We failed to measure global 5-hydroxymethylcytosine (5-hmC) levels in blood, probably due to the very low levels of 5-hmC and the limitations of the commercially available ELISA kits. Our results point towards a role for epigenetics modification in ALS, SCA1, and SCA2, and help conclude a dispute on the global 5-mC levels in sALS blood.

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Section: Introductionmentioning

confidence: 99%

Elevated Global DNA Methylation Is Not Exclusive to Amyotrophic Lateral Sclerosis and Is Also Observed in Spinocerebellar Ataxia Types 1 and 2

et al. 2018

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“…Nicotinamide increased mRNA and protein levels of frataxin in the peripheral mononuclear cells of these patients when given in doses up to 200 times the recommended daily allowance. Clinical outcomes showed no significant changes [85].…”

Section: Erythropoietinmentioning

confidence: 87%

Milestones in Friedreich ataxia: more than a century and still learning

et al. 2015

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Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia worldwide. This review highlights the main clinical features, pathophysiological mechanisms, and therapeutic approaches for FRDA patients. The disease is characterized by a combination of neurological involvement (ataxia and neuropathy), cardiomyopathy, skeletal abnormalities, and glucose metabolism disturbances. FRDA is caused by expanded guanine-adenine-adenine (GAA) triplet repeats in the first intron of the frataxin gene (FXN), resulting in reduction of messenger RNA and protein levels of frataxin in different tissues. The molecular and metabolic disturbances, including iron accumulation, lead to pathological changes characterized by spinal cord and dorsal root ganglia atrophy, dentate nucleus atrophy without global cerebellar volume reduction, and hypertrophic cardiomyopathy. DNA analysis is the hallmark for the diagnosis of FRDA. There is no specific treatment to stop the disease progression in FRDA patients. However, a number of drugs are under investigation. Therapeutic approaches intend to improve mitochondrial functioning and to increase FXN expression.

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“…Adverse events were comparable in the two arms, with no reported life-threatening events. Nicotinamide was well tolerated by the 10 patients included in the Friedreich's ataxia trial [1] . Only nausea and perturbation of liver function tests were reported.…”

Section: Case Reportmentioning

confidence: 97%

“…For the last 4 days, she had been taking 4.4 g of nicotinamide daily. As an active member of the Association Suisse de l'Ataxie de Friedreich, she was informed of the results of the clinical trial previously cited [1] . DISCUSSION Administration of vitamin B3 in pharmacological doses is usually considered safe.…”

Section: Case Reportmentioning

confidence: 99%

“…No causal treatment is yet available. Recently, in an exploratory clinical trial, daily administration of nicotinamide (the amide form of vitamin B3, nicotinic acid being the acidic form) at a dose of 2-8 g increased the concentration of frataxin in patients with Friedreich's ataxia [1] . This finding suggested that nicotinamide could favourably affect the course of the disease.…”

Section: Introductionmentioning

confidence: 99%

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Life-Threatening Adverse Reaction after Self-Initiated, Off-Label Use of High Dose Nicotinamide for the Treatment of Friedreich’s Ataxia

Garin

Arnold²

2015

European Journal of Case Reports in Internal Medicine

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A 40-year old woman, previously known for Friedreich's ataxia, presented with shock, profound lactic acidosis and hepatic failure after ingestion of a high dose of nicotinamide, the amide form of vitamin B3. On her own initiative, she was taking up to 4.4 g per day of nicotinamide, after having learned the results of a phase 2 study suggesting a potential benefit in Friedreich's ataxia. The outcome was good with supportive care and withdrawal of nicotinamide. LEARNING POINTS• High-dose nicotinamide can cause life-threatening shock, lactic acidosis and hepatic failure.• Extensive use of experimental treatments can lead to unexpected, severe adverse reactions, even with apparently safe over-thecounter products.• Vulnerable patients with orphan diseases may self-initiate hazardous treatment which is still under investigation.

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Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study

Abstract: Ataxia UK, Ataxia Ireland, Association Suisse de l'Ataxie de Friedreich, Associazione Italiana per le Sindromi Atassiche, UK National Institute for Health Research, European Friedreich's Ataxia Consortium for Translational Studies, and Imperial Biomedical Research Centre.

Cited by 130 publications

References 43 publications

Elevated Global DNA Methylation Is Not Exclusive to Amyotrophic Lateral Sclerosis and Is Also Observed in Spinocerebellar Ataxia Types 1 and 2

Elevated Global DNA Methylation Is Not Exclusive to Amyotrophic Lateral Sclerosis and Is Also Observed in Spinocerebellar Ataxia Types 1 and 2

Milestones in Friedreich ataxia: more than a century and still learning

Life-Threatening Adverse Reaction after Self-Initiated, Off-Label Use of High Dose Nicotinamide for the Treatment of Friedreich’s Ataxia

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