Double‐blind, placebo‐controlled study of L‐acetylcarnitine for the treatment of hyperactive behavior in fragile X syndrome

Torrioli, Maria Giulia; Vernacotola, Silvia; Mariotti, Paolo; Bianchi, Estelle N.; Calvani, Menotti; Gaetano, Andrea De; Chiurazzi, Pietro; Neri, Giovanni

doi:10.1002/(sici)1096-8628(19991203)87:4<366::aid-ajmg18>3.3.co;2-6

Cited by 14 publications

(17 citation statements)

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“…ADHD comorbidity includes disorders of fatty acid metabolism (Richardson et al 2000), their plasma concentration being decreased in ADHD patients (Stevens et al 1995). ALC administration has been shown to modulate positively aggressive behaviour and attentional problems of ADHD children (Van Oudheusden and Scholte 2002), to reduce hyperactivity in fragile-X boys (Torrioli et al 1999), and to improve cognitive performance in rats (Caprioli et al 1990(Caprioli et al , 1995Ghirardi et al 1992).…”

Section: Introductionsupporting

confidence: 92%

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Acetyl-l-carnitine reduces impulsive behaviour in adolescent rats

et al. 2004

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The attention deficit/hyperactivity disorder (ADHD) can affect human infants and adolescents. One important feature of this disorder is behavioural impulsivity. This study assessed the ability of chronic acetyl-L-carnitine (ALC, saline or 100 mg/kg SC, plus 50 mg/kg orally) to reduce impulsivity in a validated animal model for ADHD. Food-restricted rats were tested during adolescence (postnatal days, pnd, 30-45) in operant chambers with two nose-poking holes, one delivering one food pellet immediately, and the other five pellets after a delay. Delay length was increased over days (from 0 to 80 s). Individual differences in the preference-delay curve emerged, with the identification of two distinct subpopulations, i.e. one with a nearly horizontal curve and another with a very steep ("impulsive") slope. The impulsivity profile was slightly but consistently reduced by chronic ALC administration. Consistent results were also obtained with methylphenidate (MPH, saline or 3 mg/kg IP twice daily). Impulsive rats exhibited a lower metabolite/serotonin (5HIAA/5HT) ratio in the medial frontal cortex (MFC) and lower noradrenaline (NA) levels in the MFC and cingulate cortex (CC) when compared with the other subgroup. The ALC treatment increased NA levels in the CC and the 5HIAA/5HT ratio in both CC and MFC. Present data suggest that ALC, a drug devoid of psychostimulant properties, may have some beneficial effects in the treatment of ADHD children.

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Section: Introductionsupporting

confidence: 92%

“…However, when a linear regression and slope analysis were performed, drug effects were statistically significant. This profile is consistent with recent clinical data, reporting some beneficial effects of ALC on ADHD children (Torrioli et al 1999;Van Oudheusdem and Scholte 2002).…”

Section: Discussionmentioning

confidence: 99%

Acetyl-l-carnitine reduces impulsive behaviour in adolescent rats

et al. 2004

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“…Moreover, it is presumed to be effective only on dividing cells, which excludes postmitotic neurons. 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).…”

Section: Therapeutic Approaches To Fxsmentioning

confidence: 99%

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

Bagni¹,

Tassone²,

Neri³

et al. 2012

J. Clin. Invest.

297

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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“…20 It also proved effective in ameliorating the hyperactive behavior, when administered to children with the fragile X syndrome. 23 However, Pascale et al 24 showed that long-term ALC treatment did not cause DNA demethylation of the mutant FMR1 promoter, nor reactivation of the gene. We now show that treatment with ALC of three fragile X cell lines results in significant acetylation of FMR1-associated H3 and H4 histones, especially in the promoter and exon 1 region.…”

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confidence: 93%

Differential epigenetic modifications in the FMR1 gene of the fragile X syndrome after reactivating pharmacological treatments

et al. 2005

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The fragile X syndrome is caused by a 4200 CGG repeat expansion within the FMR1 gene promoter, with consequent DNA hypermethylation and inactivation of its expression. To further clarify the mechanisms that suppress the activity of the mutant gene and the conditions that may permit its reactivation, we investigated the acetylation and methylation status of three different regions of the FMR1 gene (promoter, exon 1 and exon 16) of three fragile X cell lines, using a chromatin immunoprecipitation (ChIP) assay with antibodies against acetylated-H3/H4 histones and against dimethylated lysine residues K4 and K9 of histone H3 (H3-K4 and H3-K9). We then coupled the ChIP assay with real-time PCR, obtaining absolute quantification of immunoprecipitated chromatin. Basal levels of histone acetylation and H3-K4 methylation were much higher in transcriptionally active wild-type controls than in inactive fragile X cell lines. Treatment of fragile X cell lines with the DNA demethylating drug 5-aza-2-deoxycytidine (5-azadC), known to reactivate the FMR1 gene, induced a decrease of H3-K9 methylation, an increase of H3 and H4 acetylation and an increase of H3-K4 methylation. Treatment with acetyl-L-carnitine (ALC), a compound that reduces the in vitro expression of the FRAXA fragile site without affecting DNA methylation, caused an increase of H3 and H4 acetylation. However, H3-K4 methylation remained extremely low, in accordance with the observation that ALC alone does not reactivate the FMR1 gene. Our experiments indicate that H3-K4 methylation and DNA demethylation are the main epigenetic switches activating the expression of the FMR1 gene, with histone acetylation playing an ancillary role.

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Double‐blind, placebo‐controlled study of L‐acetylcarnitine for the treatment of hyperactive behavior in fragile X syndrome

Cited by 14 publications

References 0 publications

Acetyl-l-carnitine reduces impulsive behaviour in adolescent rats

Acetyl-l-carnitine reduces impulsive behaviour in adolescent rats

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

Differential epigenetic modifications in the FMR1 gene of the fragile X syndrome after reactivating pharmacological treatments

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