INSERM U845, Université Paris Descartes, Sorbonne Paris Cité, Department of Paediatric Endocrinology, Gynaecology, and Diabetology, Necker-Enfants Malades Teaching Hospital, Assistance Publique-Hôpitaux de Paris, IMAGINE affiliate, Paris, France.
Department of Genetics, Robert-Debré Teaching Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
Lancet Diabetes Endocrinol. 2013 Nov;1(3):199-207. doi: 10.1016/S2213-8587(13)70059-7. Epub 2013 Sep 6.
Neonatal diabetes mellitus is a rare genetic form of pancreatic β-cell dysfunction. We compared phenotypic features and clinical outcomes according to genetic subtypes in a cohort of patients diagnosed with neonatal diabetes mellitus before age 1 year, without β-cell autoimmunity and with normal pancreas morphology.
We prospectively investigated patients from 20 countries referred to the French Neonatal Diabetes Mellitus Study Group from 1995 to 2010. Patients with hyperglycaemia requiring treatment with insulin before age 1 year were eligible, provided that they had normal pancreatic morphology as assessed by ultrasonography and negative tests for β-cell autoimmunity. We assessed changes in the 6q24 locus, KATP-channel subunit genes (ABCC8 and KCNJ11), and preproinsulin gene (INS) and investigated associations between genotype and phenotype, with special attention to extra-pancreatic abnormalities.
We tested 174 index patients, of whom 47 (27%) had no detectable genetic defect. Of the remaining 127 index patients, 40 (31%) had 6q24 abnormalities, 43 (34%) had mutations in KCNJ11, 31 (24%) had mutations in ABCC8, and 13 (10%) had mutations in INS. We reported developmental delay with or without epilepsy in 13 index patients (18% of participants with mutations in genes encoding KATP channel subunits). In-depth neuropsychomotor investigations were done at median age 7 years (IQR 1-15) in 27 index patients with mutations in KATP channel subunit genes who did not have developmental delay or epilepsy. Developmental coordination disorder (particularly visual-spatial dyspraxia) or attention deficits were recorded in all index patients who had this testing. Compared with index patients who had mutations in KATP channel subunit genes, those with 6q24 abnormalities had specific features: developmental defects involving the heart, kidneys, or urinary tract (8/36 [22%] vs 2/71 [3%]; p=0·002), intrauterine growth restriction (34/37 [92%] vs 34/70 [48%]; p<0·0001), and early diagnosis (median age 5·0 days, IQR 1·0-14·5 vs 45·5 days, IQR 27·2-95·0; p<0·0001). Remission of neonatal diabetes mellitus occurred in 89 (51%) index patients at a median age of 17 weeks (IQR 9·5-39·0; median follow-up 4·7 years, IQR 1·5-12·8). Recurrence was common, with no difference between the groups who had 6q24 abnormalities versus mutations in KATP channel subunit genes (82% vs 86%; p=0·36).
Neonatal diabetes mellitus is often associated with neuropsychological dysfunction and developmental defects that are specific to the underlying genetic abnormality. A multidisciplinary assessment is therefore essential when patients are diagnosed. Features of neuropsychological dysfunction and developmental defects should be tested for in adults with a history of neonatal diabetes mellitus.
Agence Nationale de la Recherche-Maladies Rares Research Program Grant, the Transnational European Research Grant on Rare Diseases, the Société Francophone du Diabète-Association Française du Diabète, the Association Française du Diabète, Aide aux Jeunes Diabétiques, a CIFRE grant from the French Government, HRA-Pharma, the French Ministry of Education and Research, and the Société Française de Pédiatrie.
新生儿糖尿病是一种罕见的胰腺β细胞功能障碍的遗传性疾病。我们比较了在没有β细胞自身免疫和正常胰腺形态的情况下，在 1 岁前被诊断为新生儿糖尿病的患者中，根据遗传亚型的表型特征和临床结局。
我们前瞻性地研究了自 1995 年至 2010 年期间，由法国新生儿糖尿病研究组从 20 个国家转介而来的患者。符合条件的患者为需要胰岛素治疗的高血糖患儿，前提是他们通过超声检查评估胰腺形态正常，β细胞自身免疫检测为阴性。我们评估了 6q24 基因座、KATP 通道亚基基因（ABCC8 和 KCNJ11）和前胰岛素基因（INS）的变化，并研究了基因型与表型之间的关系，特别关注胰腺外异常。
我们共检测了 174 名指数患者，其中 47 名（27%）没有检测到遗传缺陷。在其余的 127 名指数患者中，40 名（31%）有 6q24 异常，43 名（34%）有 KCNJ11 突变，31 名（24%）有 ABCC8 突变，13 名（10%）有 INS 突变。我们报告了在编码 KATP 通道亚基的基因突变的 13 名指数患者（基因突变患者的 18%）中出现发育迟缓伴或不伴癫痫。在中位年龄 7 岁（IQR 1-15）时，对 27 名未出现发育迟缓或癫痫的 KATP 通道亚基基因突变的指数患者进行了深入的神经心理测试。所有接受测试的指数患者均出现运动协调障碍（特别是视觉空间运动障碍）或注意力缺陷。与 KATP 通道亚基基因突变的指数患者相比，6q24 异常的患者具有特定的特征：涉及心脏、肾脏或泌尿道的发育缺陷（8/36 [22%] 比 2/71 [3%]；p=0.002）、宫内生长受限（34/37 [92%] 比 34/70 [48%]；p<0.0001）和早期诊断（中位年龄 5.0 天，IQR 1.0-14.5 比 45.5 天，IQR 27.2-95.0；p<0.0001）。在中位年龄 17 周（IQR 9.5-39.0）时，89 名（51%）指数患者缓解了新生儿糖尿病，中位随访时间为 4.7 年（IQR 1.5-12.8）。复发很常见，6q24 异常组与 KATP 通道亚基基因突变组之间没有差异（82%比 86%；p=0.36）。
新生儿糖尿病常伴有神经心理功能障碍和特定于潜在遗传异常的发育缺陷。因此，当患者被诊断时，需要进行多学科评估。应在有新生儿糖尿病病史的成人中测试神经心理功能障碍和发育缺陷的特征。
法国罕见病研究计划资助，跨欧洲罕见病研究资助，法国糖尿病协会-法国糖尿病协会，法国糖尿病协会，青少年糖尿病援助组织，法国政府的 CIFRE 资助，HRA-Pharma，法国教育部和研究部，以及法国儿科协会。
