Questionnaire survey on the current status of ketogenic diet therapy in patients with glucose transporter 1 deficiency syndrome (GLUT1DS) in Japan

Objectives

We conducted a questionnaire survey on the efficacy and side effects of ketogenic diet (KD) therapy in patients with glucose transporter 1 deficiency syndrome (GLUT1DS) as well as issues associated with long-term KD therapy from the viewpoint of patients' families.

葡萄糖转运子1缺乏综合征的临床特点与基因突变分析

目的 探讨葡萄糖转运子1缺乏综合征(GLUT1-DS)的临床与SLC2A1基因突变特点.方法 对6例GLUT1-DS患儿的临床表现、脑脊液、脑电图、头颅影像学、治疗与转归等临床资料进行总结;应用聚合酶链式反应与测序、多重连接探针扩增技术对SLC2A1基因进行突变分析.结果 本组6例,3例患儿为经典型GLUT1-DS,以早发惊厥为主要临床表现,3例患儿为非经典型GLUT1-DS,表现为发作性精神行为异常、意识障碍、共济失调等.5例患儿伴智力运动发育落后.6例患儿血糖均正常,脑脊液糖在1.10 ～2.45 mmoL/L之间,均降低,平均值1.68 mmol/L,脑脊液糖与血糖比值为0.16 ～0.51:1,均降低,平均值0.34.4例患儿脑电图正常,2例有局灶性或弥漫性(癎)样放电,其中一例同时有大量弥漫性慢波.3例头颅MRI正常,3例呈非特异性改变,其中1例呈轻度脑萎缩,1例双侧脑室饱满,1例左侧额、枕叶白质发育迟缓.6例患儿均存在SLC2A1基因突变,例1于第2外显子存在大片段缺失,例2至例6分别为c.741 G＞A(E247K)、599delA、761delA、c.1148 C＞A(P383H)、c.1198 C＞T(R400C).2例患儿行生酮饮食治疗,3例予增加饮食次数,疗效显著,1例放弃治疗.结论 GLUT1-DS临床症状多样,以癫(癎)及多种发作性的临床症状为主要表现,饥饿与疲劳可诱发临床症状的出现或加重,此特点为本病重要的临床诊断线索,而脑脊液糖与血糖比值的降低是本病最为重要的临床诊断依据.GLUT1-DS是可治性的神经系统疾病,早诊断、早治疗可显著改善患儿的预后.     

Seizures, ataxia, developmental delay and the general paediatrician: glucose transporter 1 deficiency syndrome

AIM: Glucose transporter 1 deficiency syndrome (GLUT1-DS) is an important condition for the general paediatrician's differential armamentarium. We describe a case series of eight patients in order to raise awareness of this treatable neurometabolic condition. The diagnosis of GLUT1-DS is suggested by a decreased absolute cerebrospinal fluid (CSF) glucose value (<2.2 mmol/L) or lowered CSF: plasma glucose ratio (<0.4). METHODS: This is a review of eight Queensland patients with GLUT1-DS. The clinical presentation, clinical course, laboratory investigations and treatment outcomes are discussed. RESULTS: The clinical features noted in our patient cohort include combinations of ataxia, developmental delay and a severe seizure disorder that is refractory to anticonvulsant medications. Seizures are the most common clinical manifestation and may be exacerbated by phenobarbitone. The paired CSF: plasma glucose results ranged from 0.2 to 0.39 (normal <0.6) with an average of 0.33. 3-O-Methyl-D-Glucose uptake and GLUT1 Genotyping analysis have been performed on five patients thus far. Rapid and impressive seizure control was observed in 100% of our patients once the ketogenic diet was instituted, with half of the cohort being able to wean completely from anticonvulsants. CONCLUSION: Children presenting with a clinical phenotype consisting of a refractory seizure disorder, ataxia and developmental delay should prompt the consideration of Glucose transporter 1 deficiency syndrome. While the diagnostic test of lumbar puncture is an invasive manoeuvre, the diagnosis provides a viable treatment option, the ketogenic diet. GLUT1-DS displays clinical heterogeneity, but the value of early diagnosis and treatment is demonstrated by our patient cohort.     

1型葡萄糖转运体缺陷综合征临床特征并文献复习

目的 探讨1型葡萄糖转运体缺陷综合征(glucose transporter 1 deficiency syndrome,GLUT1-DS)的临床特征并进行文献复习.方法 对1例GLUT1-DS患儿的临床资料、脑脊液葡萄糖、脑电图、MRI和基因突变特点进行分析,并进行文献复习.结果 患儿,男,6岁1个月,9个月起晨起空腹时出现全面强直阵挛发作,共发作7次,头围47.5cm.辅助检查:脑脊液葡萄糖1.87mmol/L,脑脊液葡萄糖/血糖比值0.36,头颅MRI正常,发作间期脑电图示广泛性棘慢波发放.SLC2A1基因检查:第4外显子c.350_385del(编码区第350_385号核苷酸缺失)杂合核苷酸变异,该变异为新发现的突变位点.文献复习共219例GLUT1-DS患儿,其中159例(72％)有癫痫发作,105例(47％)有运动障碍,61例(27％)有智力发育落后.脑脊液葡萄糖(1.92±0.31) mmol/L,脑脊液葡萄糖/血糖比值0.36±0.07.183例(96％)患儿存在SLC2A1基因突变,错义突变最多见.结论 GLUT1-DS临床症状谱广,脑脊液葡萄糖、脑脊液葡萄糖/血糖比值明显降低,且排除脑膜炎者可诊断GLUT1-DS,可行SLC2A1突变检查.     

The ketogenic diet in children with Glut1 deficiency syndrome and epilepsy

The effects of a long-term ketogenic diet in children with Glut1 deficiency syndrome on metabolism are unknown. Our results indicate a characteristic effect of a long-term ketogenic diet on glucose and lipid homeostasis in Glut1 deficiency syndrome. Although serum lipids and apolipoproteins reflect a proatherogenic lipoprotein profile, adipocytokine constellation is not indicative of enhanced cardiovascular risk.     

Prevalence of selective immunoglobulin A deficiency in Greek children and adolescents with type 1 diabetes

Background

The association of selective immunoglobulin A (IgA) deficiency with type 1 diabetes (T1D) remains unclear. This study was to evaluate serum IgA concentrations in Greek children and adolescents with T1D.

Methods

In two hundred individuals with T1D, serum IgA concentrations were quantitatively determined using nephelometry.

Results

Immunoglobulin A deficiency was detected in 6 (3.0%) of 200 patients who were subjected to immunological evaluation. Recurrent infections were not recorded, but human papilloma virus infection was clinically suspected and confirmed by laboratory examination in a 5-year-old girl. In regard to coincidence of selective IgA deficiency with autoimmune diseases, celiac disease was detected in a girl and juvenile idiopathic arthritis in a boy. Serum IgA concentrations differed significantly when patients were grouped according to age at the beginning of the study (P<0.001), age at diagnosis of T1D (P=0.015) and coincidence of celiac disease (CD) (P=0.038). However, when the age of the patients was adjusted, difference in serum IgA concentrations was not statistically significant despite CD was present or not. Moreover, serum IgA concentrations were positively correlated with serum IgG (P<0.001) and IgE (P=0.001) concentrations and negatively correlated with serum antigliadin antibody IgG (P=0.035) concentrations. There was no association or correlation of serum IgA concentrations with glycemic control.

Conclusion

The prevalence of selective IgA deficiency in Greek children and adolescents with T1D is high (3.0%). The correlation of serum IgA concentrations with serum IgG, IgE and anti-gliadin antibody IgG concentrations needs further investigation.

     

Association between HLA-A1, B8 in children with extrinsic asthma and IgA deficiency

The tissue types, immunoglobulin levels, and the presence of circulating autoantibodies were investigated in 57 children. Fifteen of these children suffered from bronchial asthma and, in addition, had no or very little IgA in their serum and saliva (Group 1 patients). Another fifteen children with asthma but normal immunoglobulin levels in serum and saliva (Group 2 patients), seven patients with selective IgA deficiency but without allergic diseases (Group 3 patients), and twenty healthy children served as controls. Sixty per cent of the Group 1 patients had the phenotype HLA-A1, B8, whereas this tissue type was found only in 27, 14 and 15 per cent, respectively, of the Group 2 and Group 3 patients and the healthy children. Furthermore, high IgM- and IgE levels were observed in most Group 1 patients, and in five of these patients (33 per cent) autoantibodies were present in the serum. In addition, eczema and glomerulonephritis occurred rather frequently in this group of patients. Conversely, normal immunoglobulin levels and absence of circulating autoantibodies were found in the remaining three groups of children. The results emphasize the heterogeneity of the IgA deficiency syndrome, and the question is raised as to whether the tissue type HLA-A1, B8 observed in most Group 1 patients reflects the abnormal immune reactivity of these patients.     

Impact of exercise on overnight glycemic control in children with type 1 diabetes mellitus

OBJECTIVE: To examine the effect of exercise on overnight hypoglycemia in children with type 1 diabetes mellitus (T1DM). STUDY DESIGN: At 5 clinical sites, 50 subjects with T1DM (age 11 to 17 years) were studied in a clinical research center on 2 separate days. One day included an afternoon exercise session on a treadmill. On both days, frequently sampled blood glucose levels were measured at the DirecNet central laboratory. Insulin doses were similar on both days. RESULTS: During exercise, plasma glucose levels fell in almost all subjects; 11 (22%) developed hypoglycemia. Mean glucose level from 10 pm to 6 am was lower on the exercise day than on the sedentary day (131 vs 154 mg/dL; P=.003). Hypoglycemia developed overnight more often on the exercise nights than on the sedentary nights (P=.009), occurring on the exercise night only in 13 (26%), on the sedentary night only in 3 (6%), on both nights in 11 (22%), and on neither night in 23 (46%). Hypoglycemia was unusual on the sedentary night if the pre-bedtime snack glucose level was>130 mg/dL. CONCLUSIONS: These findings indicate that overnight hypoglycemia after exercise is common in children with T1DM and support the importance of modifying diabetes management after afternoon exercise to reduce the risk of hypoglycemia.     

Effect of environmental and clinical factors on lung function and respiratory symptoms in adolescents with α1-antitrypsin deficiency

Individuals identified in the Swedish neonatal α₁-antitrypsin (AAT) screening study were followed prospectively from their first to their eighteenth year of life. The aim of this study was to analyse the effect of environmental factors, i.e. active and passive smoking, and of clinical factors on lung function and the occurrence of respiratory symptoms in AAT-deficient adolescents. The study group consisted of 88 protease inhibitor (Pi)ZZ and 40 PiSZ adolescents. Medical history including respiratory symptoms, and active and passive smoking were recorded at each follow-up up to the age of 18 y. Lung function tests were performed at the present check-up. At the age of 18 y, both forced expiratory volume in one second (FEV₁) and FEV₁/vital capacity (VC) were significantly lower in the smoking than in the non-smoking subgroup, and significantly more smokers than non-smokers reported the presence of phlegm. The mean FEV₁/VC ratio was lower for those presently exposed to parental smoking. Multiple linear regression analysis indicated that clinical liver disease in early life, active smoking and parental smoking were independent determinants of FEV₁/VC. The results suggest that marginal deviations in lung function and the symptom of phlegm among AAT-deficient adolescents occur characteristically early in the subgroup of smokers. Parental smoking may contribute to decreased lung function