A double‐blind, parallel, multicenter comparison of <scp>L</scp>‐acetylcarnitine with placebo on the attention deficit hyperactivity disorder in fragile X syndrome boys

Torrioli, Maria Giulia; Vernacotola, Silvia; Peruzzi, L.; Tabolacci, Elisabetta; Milá, Montserrat; Militerni, Roberto; Musumeci, S; Ramos, Feliciano J.; Frontera, María; Sorge, Giovanni; Marzullo, E; Romeo, G; Vallée, Louis; Veneselli, Edvige; Cocchi, Elena; Garbarino, Eleonora; Moscato, Umberto; Chiurazzi, Pietro; D'Iddio, S; Calvani, Menotti; Neri, Giovanni

doi:10.1002/ajmg.a.32268

Cited by 94 publications

(67 citation statements)

References 39 publications

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“…78,79,80 A doubleblind, parallel, multicentre comparison of L-acetylcarnitine with placebo in patients with attention-deficit/hyperactivity disorder and in boys with fragile X syndrome indicated that L-actylcarnitine significantly improved social behaviour. 81 The alteration in these serum biomarkers could partly contribute to the variety of clinical manifestations of autism. The significant changes in serum pregnanetriol between children with autism and controls indicated perturbations in estrogen metabolism in children with autism.…”

Section: Discussionmentioning

confidence: 99%

Potential serum biomarkers from a metabolomics study of autism

Wang

Liang

Wang

et al. 2016

jpn

104

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Section: Discussionmentioning

confidence: 99%

Potential serum biomarkers from a metabolomics study of autism

Wang

Liang

Wang

et al. 2016

jpn

104

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“…Acetyl-l-carnitine (Nicetile, a natural compound improving cell metabolism), shown to inhibit cytogenetic expression of the fragile X site in patient-derived cultured lymphocytes (98), was administered to boys with FXS (99). A significant amelioration of the hyperactivity and adaptive behavior of drug-treated boys (compared with those treated with placebo) was observed; however, the methylation state of FMR1 did not change, and the expression of the gene did not increase (100). The third tested compound is valproic acid (101), which is already known as a reactivator of silenced genes (102) that appeared to be a weak reactivator of FM (103).…”

Section: Therapeutic Approaches To Fxsmentioning

confidence: 99%

Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics

Bagni¹,

Tassone²,

Neri³

et al. 2012

J. Clin. Invest.

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290

289

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Genetics of fragile XFragile X syndrome (FXS), an X-linked condition first described by Martin and Bell (1), is the leading cause of inherited intellectual disability (ID). Estimates report that FXS affects approximately 1 in 2,500 to 5,000 men and 1 in 4,000 to 6,000 women (2, 3). FXS is caused by mutations in the FMR1 gene, which is located on the X chromosome and whose locus at Xq27.3 coincides with the folate-sensitive fragile site (4, 5). Cytogenetic methods (6) used in the past to diagnose FXS have been replaced by molecular diagnostic of FMR1 DNA using Southern blot analysis and, more recently, PCR.Affected men display varying degrees of symptoms ranging from mild to severe. Due to compensation by the unaffected X chromosome, only one-third of female carriers with a full mutation (FM) have ID; the majority have normal IQ, although learning difficulties and emotional problems are common (7).Identified in 1991 by positional cloning (8), the FMR1 gene is characterized by the presence of a polymorphic CGG triplet sequence in the 5′ UTR (8, 9). Expansion in this triplet sequence gives rise to FXS, which is the prototype of unstable triplet expansion disorders. The triplet variability defines four types of alleles (Figure 1). Normal alleles have a number of CGG repeats, ranging from 5 to 54, with a mode of 30. Premutation (PM) alleles have a number of CGG repeats, ranging from 55 to 200. PM alleles are unstable and have a strong tendency to expand to FM alleles upon maternal transmission. Expansion from a PM to FM can occur with alleles as small as 56 CGGs (10). Alleles possessing between 45 and 54 CGG repeats, referred to as gray-zone or intermediate alleles, are proposed to be precursors of PM alleles, potentially due to paternal and maternal meiotic instability (11). The risk of a PM to FM transition depends on the CGG repeat size, such that the expansion risk is nearly 100% for alleles of >99 CGG repeats (11). A recent study (12) showed that the number of AGG interruptions present in the CGG repeats correlates inversely with the risk of expansion to a FM in the next generation. The presence of AGG interruptions, in addition to the CGG length, may thus better define the risk for transmission from a maternal PM to FM in the offspring.FMR1 silencing is the consequence of rather complex epigenetic modifications (13). In FXS, cytosines located approximately up to 1-kb upstream of the CGG repeat sequences, including the FMR1 promoter, are methylated (14, 15). Normal alleles are also methylated in the FMR1 promoter region but not in close proximity to the CGG repeat, which seems to be a "boundary" in the normal allele that prevents methylation from spreading. This boundary is missing in FM alleles, and the cytosines upstream of the CGG repeat become methylated around the thirteenth week of embryonic development (16). As a consequence, gene transcription is inhibited, leading to the absence of its protein product FMRP (17). Of note, some alleles remain partially or even fully unmethylated (UFM), despite containing ...

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“…The X chromosome-linked disorder is caused by loss of function of a single gene, fragile X mental retardation 1 (FMR1), most frequently by expansion of CGG repeats (>200 repeats) in the 5Ј regulatory region causing hypermethylation that results in transcriptional silencing (Heitz et al, 1992;Oberle et al, 1991;Pieretti et al, 1991). In addition to mental impairment, FXS patients also display a wide range of social interaction problems characterized by poor eye contact, hyperactivity, attention deficit and obsessive-compulsive behaviors (Boccia and Roberts, 2000;Cornish et al, 2001;Fryns et al, 1984;Torrioli et al, 2008), and hypersensitivity to sensory stimuli (Fryns, 1984;Hessl et al, 2001). Other physical anomalies include elongated face, prominent ears and enlarged male testes (Chudley and Hagerman, 1987;Giangreco et al, 1996;Moore et al, 1982).…”

Section: Introductionmentioning

confidence: 99%

Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

Coffee

Tessier

Woodruff

et al. 2010

Disease Models &Amp; Mechanisms

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SUMMARYFragile X syndrome (FXS), resulting solely from the loss of function of the human fragile X mental retardation 1 (hFMR1) gene, is the most common heritable cause of mental retardation and autism disorders, with syndromic defects also in non-neuronal tissues. In addition, the human genome encodes two closely related hFMR1 paralogs: hFXR1 and hFXR2. The Drosophila genome, by contrast, encodes a single dFMR1 gene with close sequence homology to all three human genes. Drosophila that lack the dFMR1 gene (dfmr1 null mutants) recapitulate FXS-associated molecular, cellular and behavioral phenotypes, suggesting that FMR1 function has been conserved, albeit with specific functions possibly sub-served by the expanded human gene family. To test evolutionary conservation, we used tissue-targeted transgenic expression of all three human genes in the Drosophila disease model to investigate function at (1) molecular, (2) neuronal and (3) non-neuronal levels. In neurons, dfmr1 null mutants exhibit elevated protein levels that alter the central brain and neuromuscular junction (NMJ) synaptic architecture, including an increase in synapse area, branching and bouton numbers. Importantly, hFMR1 can, comparably to dFMR1, fully rescue both the molecular and cellular defects in neurons, whereas hFXR1 and hFXR2 provide absolutely no rescue. For non-neuronal requirements, we assayed male fecundity and testes function. dfmr1 null mutants are effectively sterile owing to disruption of the 9+2 microtubule organization in the sperm tail. Importantly, all three human genes fully and equally rescue mutant fecundity and spermatogenesis defects. These results indicate that FMR1 gene function is evolutionarily conserved in neural mechanisms and cannot be compensated by either FXR1 or FXR2, but that all three proteins can substitute for each other in non-neuronal requirements. We conclude that FMR1 has a neural-specific function that is distinct from its paralogs, and that the unique FMR1 function is responsible for regulating neuronal protein expression and synaptic connectivity.Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

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A double‐blind, parallel, multicenter comparison of L‐acetylcarnitine with placebo on the attention deficit hyperactivity disorder in fragile X syndrome boys

Cited by 94 publications

References 39 publications

Potential serum biomarkers from a metabolomics study of autism

Potential serum biomarkers from a metabolomics study of autism

Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics

Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

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