基金：
A defect of glucose transport across the blood-brain barrier and into the brain cells significantly impairs brain growth and development. Since the first report of defective glucose transport in 1991, a few hundred patients have been diagnosed worldwide. The phenotype has expanded significantly. Nonclassic phenotypes have been reported that include allelic variants such as intermittent ataxia, choreoathetosis, dystonia, spasticity, confusion, lethargy or somnolence, Parkinsonism, myoclonus, dyspraxia, nonkinesogenic dyskinesias, recurrent headaches, and alternating hemiplegia of childhood with or without epilepsy [2-7] . The spectrum of clinical severity has also expanded. Some patients demonstrate minimal clinical findings and appear relatively normal between episodes. Others are severely disabled with fixed neurologic deficits, and often never learn to walk or talk. Unfortunately, many patients remain undiagnosed because of a lack of awareness of the syndrome or a reluctance to perform a diagnostic lumbar puncture. Furthermore, the clinical diagnosis of Glut-1 deficiency syndrome is even more challenging if the signs are subtle or intermittent. To the best of our knowledge, this report is the first to describe Glut-1 deficiency syndrome allelic variants in mainland China. Paroxysmal movement disorders causing weakness and ataxia comprised the dominant features of these patients. Fasting and fatigue were the major triggers of paroxysmal episodes. The paroxysmal behavior abnormalities, including fluctuating mood, episodic unprovoked crying, and babbling without seizures in patients 1 and 2, comprise remarkable clinical features for Glut-1 deficiency syndrome. These episodes could represent complex partial seizures. However, no epileptiform discharges were evident during these episodes. Microcephaly was present only in patient 3. The development of patient 1 involved an intelligence quotient of 81, i.e., within the normal range, but this performance may not have reflected his initial potential. Patients 2 and 3 manifested mild developmental delay, with intelligence quotients of 71 and 65. Epilepsy comprises one of the more common presentations in Glut-1 deficiency syndrome, accounting for 82.45% of the 57 patients reported by Pons et al. [12] . The symptomatic epilepsies accompanying Glut-1 deficiency syndrome are usually refractory to antiepileptic drugs. In this series, only patient 3 experienced a clinical seizure, i.e., a single simple partial seizure. The electroencephalographic findings were normal in patients 2 and 3. Patient 1 exhibited focal and generalized epileptiform discharges, but he never manifested a clinical seizure. The epileptiform discharges and slow waves decreased significantly after food intake in patient 1, consistent with the reported electroencephalogram features in patients with Glut-1 deficiency syndrome [13] . Cranial magnetic resonance images were normal in patients 1 and 3, and only mildly abnormal in the frontal and occipital subcortical white matter in patient 2. Similar findings were reported in the literature [8,9] . The diagnosis of Glut-1 deficiency syndrome in these patients was confirmed by SLC2A1 gene mutation analysis. Patient 1 carried the novel missense mutation P383H. Patient 3 carried the missense mutation R400C. Neither of these had been reported previously. However, both amino acids P383 and H400 in human Glut-1 protein are conserved among other species such as rats, bovines, mice, and zebrafish. No mutation was evident in the parents. Accordingly, the mutations were presumed to be disease-causing. However, further studies are necessary to verify the pathogenicity of these two missense mutations (P383H and R400C). We identified a 1-base pair deletion, 761delA, in patient 2, which introduced a frameshift at amino acid position 254, resulting in a premature termination at position 339. Previous in vitro studies indicated that the deletion of the last 25-27 carboxy-terminal amino acids of GLUT1 was sufficient to abolish transport activity completely. Although the phenotypes have expanded significantly in the past few years, no specific correlation between different phenotypes and specific mutations has been demonstrated. As a general rule, missense mutations are associated with milder and intermittent phenotypes, whereas nonsense mutations and microdeletions are associated with more fixed, severe phenotypes [2] . Ketone bodies readily penetrate the blood-brain barrier and serve as an alternative fuel for the brain. The ketogenic diet is effective at controlling seizures in the majority of patients with Glut-1 deficiency syndrome and at improving gait in some patients [9,12,14] . The effects of the ketogenic diet on other paroxysmal events have not yet been confirmed [12] , but to anticipate such therapeutic effects is reasonable. Two other patients presenting with the classic phenotype and diagnosed at our hospital (unpublished data) demonstrated a very good response to the ketogenic diet. Both of them were treated with a ketogenic diet at age 3 months. They have been seizure-free and have developed normally since their diagnosis and early treatment. However, compliance with a ketogenic diet is more difficult in older patients, particularly when the signs are mild or intermittent. All three patients in this report failed their ketogenic diet regimen. Patients 1 and 3, with the missense mutations, responded well to a frequent meal plan supplemented with snacks. These two patients are similar to the patient described by Brockmann as manifesting a “carbohydrate-responsive” phenotype, in which ataxia, dystonia, and seizures significantly improved after carbohydrate intake [15] , and they are also similar to the patients of Akman et al., who responded to transient hyperglycemia [16] . In conclusion, the Glut-1 deficiency syndrome phenotype has recently expanded. This syndrome should be considered in all patients with unexplained epilepsy, movement disorders, and episodic behavioral disturbances. Signs that fluctuate with fasting, fatigue, or meals constitute additional diagnostic clues. Early diagnosis is important because this condition is treatable. Earlier treatment appears to correlate with better outcomes. This work was supported by the Key Project of Clinical Disciplines from the Chinese Ministry of Public Health (grant 2010-12 ). The authors thank the patients and their parents for participating in our research.
APA：
Liu, Y,Bao, X,Wang, D,Fu, N,Zhang, X...&Wu, X.(2012).Allelic variations of glut-1 deficiency syndrome: The Chinese experience.Pediatric neurology,47,(1)
