A juvenile ALS‐like phenotype dramatically improved after high‐dose riboflavin treatment

Carreau, Christophe; Lenglet, Timothée; Mosnier, Isabelle; Lahlou, Ghizlène; Fargeot, Guillaume; Weiss, Nicolas; Demeret, Sophie; Salachas, François; Veauville-Merllié, Alice; Acquaviva, Cécile; Nadjar, Yann

doi:10.1002/acn3.50977

Cited by 19 publications

(14 citation statements)

References 10 publications

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“…Neurological abnormalities, such as ataxia and inability to stand, due to riboflavin deficiency have been reported (72). In addition, riboflavin transporter deficiency has been characterized as a cause of genetic recessive child-onset motor neuron disease with hearing loss, formerly described as Brown-Vialetto-Van-Lear syndrome (73). Thus, although serum vitamin B2 has not been researched in patients with ALS, the above evidence supports our results that low levels of vitamin B2 may be a risk factor for ALS.…”

Section: Discussionsupporting

confidence: 85%

Association Between Vitamins and Amyotrophic Lateral Sclerosis: A Center-Based Survey in Mainland China

et al. 2020

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To date, conflicting results about the role of vitamins in amyotrophic lateral sclerosis (ALS) have been reported along with a lack of systematic studies on all types of serum vitamins in patients with ALS. Moreover, extensive studies have been conducted on vitamins in other neurodegenerative diseases; however, whether serum vitamin alterations in ALS are similar to those in other neurodegenerative diseases remains unclear. Therefore, we performed a study involving a large Chinese cohort of patients with ALS to address this gap. In this study, 202 patients with ALS, 214 with a neurodegenerative disease that mimicked ALS (mimics), and 208 healthy controls were enrolled. Serum vitamins of all subjects were examined under fasting state in Clinical Laboratory. As a result, we found that higher vitamin A and E levels and lower vitamin B2, B9, and C levels were in patients with ALS compared to healthy controls, and that high vitamin A and E levels, and low vitamin B2, B9, and C levels were associated with an increased risk for ALS. In addition, serum vitamin C was lower in early-onset ALS patients compared to those in late-onset ALS patients; however, there was no significant correlation between serum vitamins and age at onset, sites at onset, disease duration, or disease severity of ALS. We also found that patients with ALS showed similar vitamin alterations to mimics, with the exception of vitamin E. In summary, our study adds information to the literature on the role of vitamins in ALS and provides support for clinical guidance regarding dietary changes and vitamin supplements in patients with ALS.

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Section: Discussionsupporting

confidence: 85%

Association Between Vitamins and Amyotrophic Lateral Sclerosis: A Center-Based Survey in Mainland China

et al. 2020

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“…To the best of our knowledge, our group was the first to have reported presence of only one mutated SLC52A3 mutated allele in BVVL diagnosed individuals . By now, finding only one mutated allele in BVVL/FL diagnosed patients has been reported several times (Allison et al, 2017;Carreau et al, 2020;Ciccolella et al, 2012;Manole et al, 2017). It appears justified to conclude that a heterozygous SLC52A3 mutation may in some cases cause BVVL or FL.…”

Section: Discussionmentioning

confidence: 87%

BVVL/ FL: features caused by SLC52A3 mutations; WDFY4 and TNFSF13B may be novel causative genes

Khani

Shamshiri

Taheri

et al. 2021

Neurobiology of Aging

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Brown-Vialetto-Van Laere(BVVL) and Fazio-Londe(FL) are disorders with ALS-like features, usually with recessive inheritance. We aimed to identify causative mutations in ten probands. Neurological examinations, genetic analysis, audiometry, MRI, biochemical and immunological testings, and/or muscle histopathology were performed. Mutations in known causative gene SLC52A3 were found in seven probands. More importantly, only one mutated allele was observed in several patients, and variable expressivity and incomplete penetrance were clearly noted. Environmental insults may contribute to variable presentations. Putative causative mutations in other genes were identified in three probands. Two of the genes, WDFY4 and TNFSF13B, have immune related functions. Inflammatory responses were implicated in the patient with the WDFY4 mutation. Malfunction of the immune system and mitochondrial anomalies were shown in the patient with the TNFSF13B mutation. Prevalence of heterozygous SLC52A3 BVVL causative mutations and notable variability in expressivity of homozygous and heterozygous genotypes are being reported for the first time.Identification of WDFY4 and TNFSF13B as candidate causative genes supports conjectures on involvement of the immune system in BVVL and ALS.

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“…RF deficiency impacts redox balance, compromising energy metabolism pathways, and antioxidant defense mechanisms [ 7 , 13 ]. Insufficient availability of the vitamin results in severe clinical conditions, particularly affecting MNs; thus, sharing traits with amyotrophic lateral sclerosis (ALS) [ 14 ]. Emphasizing the importance of RF in human physiology, and furthermore, its efficient absorption and homeostasis are RTDs caused by recessive, biallelic mutations in the genes encoding human RF transporters [ 1 ].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Abnormalities in Induced Pluripotent Stem Cells-Derived Motor Neurons from Patients with Riboflavin Transporter Deficiency

et al. 2020

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Riboflavin transporter deficiency (RTD) is a childhood-onset neurodegenerative disorder characterized by sensorineural deafness and motor neuron degeneration. Since riboflavin plays key functions in biological oxidation-reduction reactions, energy metabolism pathways involving flavoproteins are affected in RTD. We recently generated induced pluripotent stem cell (iPSC) lines from affected individuals as an in vitro model of the disease and documented mitochondrial impairment in these cells, dramatically impacting cell redox status. This work extends our study to motor neurons (MNs), i.e., the cell type most affected in patients with RTD. Altered intracellular distribution of mitochondria was detected by confocal microscopic analysis (following immunofluorescence for superoxide dismutase 2 (SOD2), as a dual mitochondrial and antioxidant marker), and βIII-Tubulin, as a neuronal marker. We demonstrate significantly lower SOD2 levels in RTD MNs, as compared to their healthy counterparts. Mitochondrial ultrastructural abnormalities were also assessed by focused ion beam/scanning electron microscopy. Moreover, we investigated the effects of combination treatment using riboflavin and N-acetylcysteine, which is a widely employed antioxidant. Overall, our findings further support the potential of patient-specific RTD models and provide evidence of mitochondrial alterations in RTD-related iPSC-derived MNs—emphasizing oxidative stress involvement in this rare disease. We also provide new clues for possible therapeutic strategies aimed at correcting mitochondrial defects, based on the use of antioxidants.

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A juvenile ALS‐like phenotype dramatically improved after high‐dose riboflavin treatment

Cited by 19 publications

References 10 publications

Association Between Vitamins and Amyotrophic Lateral Sclerosis: A Center-Based Survey in Mainland China

Association Between Vitamins and Amyotrophic Lateral Sclerosis: A Center-Based Survey in Mainland China

BVVL/ FL: features caused by SLC52A3 mutations; WDFY4 and TNFSF13B may be novel causative genes

Mitochondrial Abnormalities in Induced Pluripotent Stem Cells-Derived Motor Neurons from Patients with Riboflavin Transporter Deficiency

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