A possible association of responsiveness to adrenocorticotropic hormone with specific GRIN1 haplotypes in infantile spasms

Abstract

AIM Adrenocorticotropic hormone (ACTH) has been used as the major therapy for infantile spasms since 1958 because it effectively suppresses seizures; it also normalizes the electroencephalogram in the short-term treatment of infantile spasms. G protein-regulated inducer of neurite outgrowth 1 (GRIN1, also known as N-methyl-D-aspartate receptor 1, NMDAR1), a glutamate receptor, is the main component of functional N-methyl-D-aspartic acid receptors that are involved in the glucocorticoid-induced neuronal damage. Thus, it may be a candidate gene to be tested for responsiveness to ACTH in infantile spasms. In the present study, polymorphisms in the GRIN1 gene in infantile spasms were investigated using a case-control design.METHOD Twelve single nucleotide polymorphisms in the GRIN1 gene were genotyped in a Chinese case-control set consisting of 97 unrelated patients with infantile spasms (60 males, 37 females; mean age 6.4mo, SD 2.7) and 96 healthy individuals (63 males, 33 females; mean age 7.3mo, SD 3.8). Association analysis was performed on the genotyped data.RESULTS Five estimated haplotypes with a frequency of more than 3% were detected. Results of the study showed that responsiveness to treatment with ACTH in homozygous carriers of the CTA haplotype was higher than that in heterozygous carriers and non-carriers (p=0.022). Furthermore, CTG, a rare haplotype, was strongly associated with infantile spasms (p=0.013). INTERPRETATIONThe results suggest that haplotypes of GRIN1 may influence responsiveness to ACTH. The findings necessitate further study for confirmation.Infantile spasms is an age-specific epileptic encephalopathy that occurs in infancy and is considered refractory to conventional antiepileptic drugs. Adrenocorticotropic hormone (ACTH) has been identified as a drug that is effective in the treatment of infantile spasms.1 However, some patients are clinically resistant to ACTH therapy, and the exact molecular mechanism remains to be explained. Data from pharmacogenetic studies of epilepsy have shown that the variations in some receptor genes can contribute to the pathogenesis and mechanisms of antiepileptic drug resistance towards infantile spasms.Several models and hypotheses have been proposed to explain the pathogenesis of infantile spasms and its unique sensitivity to ACTH.2 However, none of them has been accepted as a satisfactory model for drug testing. Recently, the clinical features of flexion seizures induced by N-methyl-Daspartic acid (NMDA) in rat pups have been shown to be correlated with human infantile spasms. For instance, flexion spasms and electroencephalogram (EEG) in the rat model correlate with ictal electrodecrement, or after discharges in infantile spasms.3 Interestingly, this model, which is based on the prenatally 'stressed' brain, also shows an acute and partial response to ACTH treatment. In addition, an expression peak of the NMDA receptor was observed in the cortex and hippocampus of children aged 1 to 3 years old. In contrast, the axon and dendrite are mostly developed in ...

NR3C1 gene polymorphism for genetic susceptibility to infantile spasms in a Chinese population

“…Further, experiments were conducted to evaluate the TCCT in vitro, demonstrating that the TCCT leads to an increased expression of MC2R and a strong response to ACTH (Ding et al, 2010b). Ding et al (2010a) report that the CTA haplotype of GRIN1 in homozygous-carriers was higher than that in heterozygous-carriers and non-carriers in the response to the ACTH treatment.…”

“…Data from pharmacogenetic studies of epilepsy have shown that variations in some receptor genes could take part in the pathogenesis and mechanisms of antiepileptic drug resistance towards IS (Ding et al, 2010a). In the current study, an association analysis of polymorphisms in the NR3C1 gene with ACTH efficacy was performed, and a TG genotype of rs6877893 was found to be associated with decreased ACTH responsiveness (P = 0.047, OR = 2.56, 95% CI = 1.01-6.50).…”

Massive expansion of SCA2 with autonomic dysfunction, retinitis pigmentosa, and infantile spasms

“…As ISS can be associated with mutations in genes with roles in forebrain development, specifically synaptic function, 29,[32][33][34][35] we focused our bioinformatics analysis on discovery of further interactions between the ATXN2 network and proteins important in synapse biology. Previous work on the ATXN2 network 18,26 supported this approach, and we report additional possible interactions between ATXN2 and proteins involved in synaptic vesicle endocytosis, including SH3KBP1, SYNJ1, DNM1, and AMPH.…”

Regional Changes in Gene Expression after Limbic Kindling

“…In addition, the relations between mutations in the postnatally expressed NR2A and epilepsy have been recently described (Endele et al 2010). Risk haplotypes of the common NR1 subunit have been associated with infantile spasms, further implicating functional NMDA receptors in epileptogenesis (Ding et al 2010). Thus, the association of kindling with changes in the expression of individual NMDA subunits is particularly compelling.…”