SLC2A1 gene analysis of Japanese patients with glucose transporter 1 deficiency syndrome

Abstract

Glucose transporter 1 deficiency syndrome (Glut1-DS) is a congenital metabolic disorder characterized by refractory seizures with early infantile onset, developmental delay, movement disorders and acquired microcephaly. Glut1-DS is caused by heterozygous abnormalities of the SLC2A1 (Glut1) gene, whose product acts to transport glucose into the brain across the blood-brain barrier. We analyzed the SLC2A1 gene in 12 Japanese Glut1-DS patients who were diagnosed by characteristic clinical symptoms and hypoglycorrhachia as follows: all patients had infantile-onset seizures and mild to severe developmental delay, and ataxia was detected in 11 patients. For the 12 patients, we identified seven different mutations (three missense, one nonsense, two frameshift and one splice-site) in exons and exon-intron boundaries of the SLC2A1 gene by direct sequencing, of which six were novel mutations. Of the remaining five patients who had no point mutations and underwent investigation by multiplex ligation-dependent probe amplification, a complex abnormality with deletion and duplication was identified in one patient: this is the first case of such recombination of the SLC2A1 gene. Changes in regulatory sequences in the promoter region or genes other than SLC2A1 might be responsible for onset of Glut1-DS in the other four patients (33%) without SLC2A1 mutation.

Nationwide survey of glucose transporter-1 deficiency syndrome (GLUT-1DS) in Japan

“…Since we reported the first case of GLUT-1DS in Japan in 2004, the number of cases has gradually accumulated [18,20,24]. This study is a first nation-wide The total number of patient showing focal and generalized epileptiform discharges exceeded those having epileptiform EEG discharges because some patients had both focal and generalized EEG discharges.…”

“…Familial cases with autosomal dominant and recessive transmission have recently been described and included a parent or siblings having the same SLC2A1 mutation to a proband who exhibited the typical clinical characteristics, but almost no clinical symptoms or mild symptoms [9,20,30,32]. Hashimoto et al already reported the details of the two families included in the present study, in which both families included an affected parent and sibling and mild clinical symptoms in the mother were undiagnosed until the proband was diagnosed [20].…”

“…If direct sequencing yielded normal results, large rearrangements of SCL2A1 were examined using the Multiple Ligation Probe Amplification (MLPA) method. The details of these methods were described elsewhere [20,21].…”

“…Arg333 and Arg330 mutations, which were detected in multiple nonconsanguineous family lines, were thought to be prevalent mutation sites. Familial cases were identified in two family lines (cases 1 and 7, cases 31 and 32), with the details of one being described elsewhere [20]. Three cases of GLUT-1DS with SLC2A1 mutations (case 18, 31, 32) did not exhibit the low uptake of 3-O-methyl-D-glucose by erythrocytes.…”

“…Approximately 200 cases of GLUT-1DS have been reported to date, mainly in the US and Europe [17]. There have also been sporadic reports in Japan since 1991 [18][19][20][21]. Although epileptic seizures in GLUT-1DS patients are often refractory to antiepileptic drug treatments, ketogenic diet therapy (KD) is an effective and causal therapeutic method that can supply ketone bodies instead of glucose as a source of brain energy [22][23][24].…”