Analysis of Single Nucleotide Polymorphisms in the Melanocortin-4 Receptor Promoter in Infantile Spasms

Liu, Z.-L.; He, Bo; Fang, Fude; Tang, Cheng; Zou, Lei

doi:10.1055/s-2008-1065358

Cited by 10 publications

(8 citation statements)

References 51 publications

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“…Outside the United States, tetracosactide, a synthetic ACTH compound, is frequently used; however, there are no comparative studies of tetracosactide and natural ACTH. Among randomized controlled trials, the clinical spasm and hypsarrhythmic EEG response rate to natural or synthetic ACTH has ranged from 42–87% of patients (Hrachovy et al., 1983, 1994b; Baram et al., 1996; Vigevano & Cilio, 1997; Lux et al., 2004), and associations between genetic polymorphisms of the MC2R and MC4R genes and variability in ACTH responsiveness in IS are currently being examined (Liu et al., 2007, 2008b). The ongoing, NIH‐funded Epilepsy Phenome Genome Project is collecting 250 cases of cryptogenic IS as well as cases of IS with specific errors in brain development for detailed genetic analysis and will ultimately yield important information in this area.…”

Section: Therapeutic Options For Ismentioning

confidence: 99%

Infantile spasms: A U.S. consensus report

et al. 2010

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SUMMARYThe diagnosis, evaluation, and management of infantile spasms (IS) continue to pose significant challenges to the treating physician. Although an evidence-based practice guideline with full literature review was published in 2004, diversity in IS evaluation and treatment remains and highlights the need for further consensus to optimize outcomes in IS. For this purpose, a working group committed to the diagnosis, treatment, and establishment of a continuum of care for patients with IS and their families-the Infantile Spasms Working Group (ISWG)-was convened. The ISWG participated in a workshop for which the key objectives were to review the state of our understanding of IS, assess the scientific evidence regarding efficacy of currently available therapeutic options, and arrive at a consensus on protocols for diagnostic workup and management of IS that can serve as a guide to help specialists and general pediatricians optimally manage infants with IS. The overall goal of the workshop was to improve IS outcomes by assisting treating physicians with early recognition and diagnosis of IS, initiation of short duration therapy with a first-line treatment, timely electroencephalography (EEG) evaluation of treatment to evaluate effectiveness, and, if indicated, prompt treatment modification. Differences of opinion among ISWG members occurred in areas where data were lacking; however, this article represents a consensus of the U.S. approach to the diagnostic evaluation and treatment of IS.

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Section: Therapeutic Options For Ismentioning

confidence: 99%

Infantile spasms: A U.S. consensus report

et al. 2010

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“…Mc4r, leptin and Drd2 are present in the brain and hypothalamus, which are involved in regulating food intake and energy metabolism. Studies have demonstrated that the three genes can have antiepileptic effects in the brain (41)(42)(43). Therefore, the downregulated expression levels of Mc4r, Drd2 and leptin in the RS group in the present study may be associated with seizure propagation during epileptogenesis.…”

Section: Discussionmentioning

confidence: 50%

Long-term expression of metabolism-associated genes in the rat hippocampus following recurrent neonatal seizures and its regulation by melatonin

Hóng

Sun

Tian

et al. 2015

Molecular Medicine Reports

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Despite the effective use of antiepileptic drugs (AEDs) for epilepsy, therapeutic failure occurs in 30% of patients. Novel approaches are targeting the inhibition of epileptogenesis. N-acetyl-5-methoxytryptamine (melatonin) is an indoleamine produced mainly by the pineal gland, and has been observed to exhibit antiepileptic and neuroprotective effects in experimental and clinical investigations. In the present study, the underlying protective mechanism of melatonin on neonatal seizure-induced long-term excitotoxicity was examined in the hippocampus of rats, predominantly on the metabolism-associated genes. Sprague Dawley rats (6-day-old; P6) were randomly divided into four groups, the control (Cont), melatonin-treated control (Mel), recurrent neonatal seizure (RS) and treatment with melatonin and RS combined (Mel+RS). At P35, mossy fiber sprouting and changes in gene expression in hippocampus were assessed using Timm staining, reverse transcription-quantitative polymerase chain reaction and use of the 2(-ΔCT) methods, respectively. The aberrant mossy fiber sprouting in the supra granular region of the dentate gyrus and CA3 subfield of the hippocampus was suppressed by pretreatment with melatonin. In addition, among the nineteen genes identified, four energy metabolism-associated genes (Kcnj11, leptin receptor, dopamine receptor D2 and melanocortin 4 receptor), four lipid metabolism-associated genes (apolipoprotein A-I, opioid receptor κ 1, pyruvate dehydrogenase kinase, isozyme 4 and cytochrome P450, family 46, subfamily a, polypeptide 1) and zinc transporter 1 (ZnT1), sphingomyelinase (nSMase) and Cathepsin-E, were markedly downregulated by melatonin treatment in the Mel group or in the developmental seizure RS and Mel + RS groups, compared with that in the Cont group. Furthermore, the melatonin-pretreated seizure rats (Mel + RS) exhibited a significantly upregulated expression of calcium/calmodulin-dependent protein kinase II α (CaMKIIα), acetyl-Coenzyme A acetyltransferase 1 (ACAT1), ZnT-1, metallothionein 1 (MT-1), nSMase and Cathepsin-E, compared with the RS rats. Thus, the present study investigated changes in the expression of metabolic genes in the hippocampus following pretreatment with melatonin. Fluorthyl-induced decreases in the expression levels of ACAT1/nSMase/Cathepsin-E, ZnT-1/MT-1 and CaMKIIα in the hippocampus, and the reversal by melatonin may be associated with a decrease in neonatal seizure-induced aberrant mossy fiber sprouting, which requires further investigation.

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“…In addition, the following mechanisms are hypothesized to explain the effect of corticosteroids in the treatment of IS and LGS: immune regulation or inhibition, anti-inflammatory effect, increase of enzyme activity, regulating protein metabolism, regulating intracellular and extracellular electrolyte ratios, and regulating the intracellular glucose level [ 35 – 38 ]. In addition, the hypothalamic–pituitary–adrenal axis may also play an important role [ 39 ]. However, it is worth mentioning that the 35 individuals who responded to DEX treatment did not respond to an equivalent dose of prednisone in our study, suggesting that different corticosteroids have different therapeutic effect on IS and IS-related LGS and that there may be different mechanisms involved in the treatment of the diseases.…”

Section: Discussionmentioning

confidence: 99%

Efficacy analysis of oral dexamethasone in the treatment of infantile spasms and infantile spasms related Lennox–Gastaut syndrome

Gao

Cao

et al. 2023

BMC Pediatr

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Objective Treatment with adrenocorticotropic hormone (ACTH) or a corticosteroid is the first choice for infantile spasms (IS), and vigabatrin is the first choice for children with tuberous sclerosis. Although corticosteroids may be also effective against IS and IS-related Lennox–Gastaut syndrome (LGS), the use of dexamethasone (DEX), a kind of corticosteroid, for these diseases has been rarely reported. This retrospective study aimed to evaluate the efficacy and tolerability of DEX for the treatment of IS and IS-related LGS. Methods Patients diagnosed as having IS (including patients whose condition evolved to LGS after the failure of early treatment) in our hospital between May 2009 and June 2019 were treated with dexamethasone after failure of prednisone treatment. The oral dose of DEX was 0.15–0.3 mg/kg/d. Thereafter, the clinical efficacy, electroencephalogram (EEG) findings, and adverse effects were observed every 4–12 weeks depending on the individual patient’s response. Then, the efficacy and safety of DEX in the treatment of IS and IS-related LGS were retrospectively evaluated. Results Among 51 patients (35 cases of IS; 16 cases of IS-related LGS), 35 cases (68.63%) were identified as responders to DEX treatment, comprising 20 cases (39.22%) and 15 cases (29.41%) with complete control and obvious control, respectively. To discuss the syndromes individually, complete control and obvious control were achieved in 14/35 and 9/35 IS cases and in 6/16 and 6/16 IS-related LGS cases, respectively. During DEX withdrawal, 11 of the 20 patients with complete control relapsed (9/14 IS; 2/6 LGS). The duration of dexamethasone treatment (including weaning) in most of the 35 responders was less than 1 year. However, 5 patients were treated with prolonged, low-dose maintenance therapy, which continued for more than 1.5 years. These 5 patients showed complete control, and 3 patients had no recurrence. Except for one child who died of recurrent asthma and epileptic status 3 months after stopping DEX, there were no serious or life-threatening adverse effects during DEX treatment. Conclusion Oral DEX is effective and tolerable for IS and IS-related LGS. all LGS patients were evolved from IS in this study. The conclusion may not apply to patients with other etiology and courses of LGS. Even when prednisone or ACTH is failed, DEX may still be considered as a treatment option. For children who respond to DEX but do not show complete control after 6 months of treatment, prolonged treatment with low-dose DEX administered in the morning might be considered.

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Analysis of Single Nucleotide Polymorphisms in the Melanocortin-4 Receptor Promoter in Infantile Spasms

Abstract: The present study shows that genetic variants in the MC4R promoter are associated with the development of infantile spasms. The rs11872992 polymorphism influences ACTH treatment responses in patients with infantile spasms.

Cited by 10 publications

References 51 publications

Infantile spasms: A U.S. consensus report

Infantile spasms: A U.S. consensus report

Long-term expression of metabolism-associated genes in the rat hippocampus following recurrent neonatal seizures and its regulation by melatonin

Efficacy analysis of oral dexamethasone in the treatment of infantile spasms and infantile spasms related Lennox–Gastaut syndrome

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