AGPAT2 基因变异致先天性全身脂肪营养不良症1 例报告并文献复习

目的分析AGPAT2基因变异致先天性全身脂肪不良症(CGL)的诊断和治疗。方法回顾分析1例AGPAT2基因变异致CGL患儿的临床资料、实验室检查及基因测序结果,并结合国内外文献进行分析总结。结果女性患儿,12岁,多饮多尿伴体质量下降1个月。患儿三角面容,皮下脂肪极少,肌肉发达,腋下黑棘皮症。实验室检查提示糖尿病、高脂血症以及脂肪肝。基因检测提示患儿AGPAT2基因复合杂合变异,c.379GC源自父亲,c.317-10TA源自母亲。根据美国医学遗传学与基因组学学会指南分析,c.379GC变异为疑似致病变异,c.317-10TA变异临床意义未明。患儿经皮下胰岛素注射及口服二甲双胍治疗后血糖控制可。结论该例为国内报道的第2例AGPAT2基因变异致CGL,且为新发现的基因变异。     

先天性及获得性脂肪营养不良北大核心CSCD

脂肪营养不良是多种原因导致的以机体脂肪组织不同程度缺失为主要特征的一组疾病,患者往往会合并多种代谢紊乱,如胰岛素抵抗、糖尿病、高三酰甘油血症和肝脏脂肪变性。通过可观察到的脂肪缺失程度和分布情况,本病可分为全身性、部分性和局部性3大类,而根据病因不同又进一步分为先天性和获得性2类。目前为止已报道了11个基因（ AGPAT2、BSCL2、CAVI、PTRF、PPARG、LMNA、ZMPSTE24、AKT2、CIDEC、PLINI、WRN）与先天性脂肪营养不良发病相关。最常见的获得性脂肪营养不良是长时间应用以蛋白水解酶抑制剂为核心药物的高效抗反转录病毒治疗所致的人类免疫缺陷病毒（HIV）感染者的脂肪营养不良。其他获得性脂肪营养不良与自身免疫有关,常伴补体异常。脂肪营养不良患者可以通过整容手术来改善外观,大部分患者在早期就出现多种代谢并发症,治疗上需要饮食、运动、降糖药和降脂药等多方面的配合,重组人瘦素类似物美曲普汀对治疗伴低瘦素血症的脂肪营养不良患者临床疗效显著,耐受性好。     

特殊面容、反复高甘油三酯1年余

患儿,女,1岁9个月,新生儿期即发现高甘油三酯血症,伴逐渐出现的特殊面容和体征：全身皮肤黝黑、皮下脂肪消失,颈部黑棘皮,毛发增多、浓密,面部呈空双颊,四肢肌肉肥大,肝脏肿大,以及中性粒细胞缺乏。单基因病全外显子组测序发现患儿存在已报道的先天性全身脂肪营养不良（CGL）的BSCL2基因突变：c.974（外显子7）_c.975（外显子7）insG纯合突变,其父母均为该位点的杂合子。确诊CGL,但不能明确中性粒细胞缺乏与CGL的关系。予低脂及高碳水化合物饮食控制后甘油三酯可维持正常,体征无明显变化。CGL为罕见的常染色体隐性遗传的系统性疾病,表现为新生儿期出现的全身皮下脂肪消失、四肢肌肉肥大和代谢紊乱：如高甘油三酯、高胰岛素血症、高血糖等,95%的CGL由AGPAT2或BSCL2突变导致。     

儿童全身性脂肪营养不良伴糖尿病1例报告

先天性全身脂肪营养不良(congenital generalizeslipodystrophy)由Berardinelli眼1演于1954年首先报道,1959年Seip眼2演又作了报道,故本病又名Berardinelli蛳Seip综合征(Berar鄄dinelli蛳Seip congenitallipodystrophy,BSCL),是非常少见的一种遗传代谢疾病,可存在糖耐量异常,合并糖尿病。儿童BSCL合并糖尿病国内尚未见报道,兹将此例报告如下。1临床资料男,7岁4个月,浙江人。因“自幼腹部膨隆,反复牙龈出血1年”入院。G1P1,足月顺产,无窒息抢救史,出生体重2250g。父母为表兄妹近亲结婚。生后母乳喂养至6个月,6个月后添加辅食。运动发…     

一家系两兄弟共患先天性肌营养不良1A型临床表型和基因突变分析

目的　回顾性分析1例先天性肌营养不良1A型（MDC1A）及其家系的临床资料特点,并探讨其基因突变类型。方法　收集2015年7月郑州大学第三附属医院小儿神经内科收治的MDC1A型患儿及其家系2代共4名成员临床资料,包括病史、体格检查、生化检查、肌电图及头颅MRI,抽取先证者及其家系成员外周血,通过二代测序法进行基因检测,并通过一代测序法进行位点验证及家系验证。结果　两兄弟均于出生后6个月内起病,因运动发育落后就诊,查体：肌无力,肌张力低下,膝腱反射消失,肌酸激酶升高,肌电图为肌源性损害,头颅MRI提示脑白质异常信号,LAMA2基因检测发现先证者及其哥哥均为c.909+7A＞G和c.2413C＞T的复合杂合突变,c.909+7A＞G为剪切变异,来源于父亲;c.2413C＞T为无义变异,来源于母亲,两者均为未报道的新变异。结论　基因检测有助于早期明确诊断。具有相同遗传背景的MDC1A患儿,其临床表型与疾病的严重程度相近。     

先天性全身性脂肪营养不良一例

患儿女,4岁2个月,浙江青田人。因“面容特殊、多毛4年余”入院。外院及本院门诊曾诊断为“早老症”。患儿出生时即发现面容特殊,消瘦似“猴子”貌,全身多毛,以胸、背部及双下肢为重,皮肤较黑,出汗较多,无多饮多尿,进食可。平时体健,否认慢性腹泻史。第3胎第1产,足月剖腹出生,无窒息抢救史,出生体重3．0kg,周岁会走,2岁会叫爸爸、妈妈,现只能数10以内的数,不会讲故事。但身高一直较同龄儿高。父母体健,非近亲结婚。家族中无类似疾病患者。     

先天性全身性脂肪营养不良BSCL2基因突变1例并文献复习

目的 报告1例先天性全身性脂肪营养不良（CGL）患儿的临床特点及随访情况,提高对该病的认识。 方法 分析1例CGL患儿病史、实验室检查和5年随访资料,对先证者及其父母行基因检测,系统复习国内外文献报告的CGL病例,归纳临床表型。 结果 男,5岁11个月,因“腹胀、消瘦5年余”就诊。患儿足月顺产,出生无窒息抢救史,5月龄会抬头,1岁会扶走。患儿1月龄渐出现腹胀、消瘦,2月龄渐出现皮下脂肪消失,肌肉渐发达,3~4月龄渐出现全身皮肤色素沉着,以颈部和腋下显著,5~6月龄渐出现全身皮肤毛发增多、增粗。查体：神清,空双颊,全身皮下脂肪消失,肌肉发达,四肢静脉血管显露。全身皮肤偏黑,多毛,颈部、腋下黑棘皮（+++）,皮肤弹性略差,心、肺查体未见异常,肝右肋下可扪及8 cm,质地中等。神经系统查体未见异常。智力测试72。双侧睾丸3 mL,阴茎5 cm×1.8 cm,阴毛Tanner 2期。父母体健,非近亲婚配。家族中无类似疾病患者。临床诊断先天性CGL,嘱低脂、高碳水化合物饮食。口服葡萄糖耐量试验提示糖耐量异常,予饮食控制。患儿BSCL2基因(NM_032667.6)存在：①错义突变c.713G>A, p.Gly238Asp（杂合）;②碱基重复c.782dupG, p.Ile262Hisfs*12（杂合）;其父亲携带错义突变c.713G>A, p.Gly238Asp（杂合）,母亲携带碱基重复c.782dupG, p.Ile262Hisfs*12（杂合）。经系统检索有10篇文献中的17例CGL患儿进入文献汇总分析,其临床主要特征：全身皮下脂肪消失、肌肉发达、皮下静脉显露、肢端肥大、多毛、黑棘皮症、高胰岛素血症、高甘油三酯血症、肝脾大、脂肪肝、肝功能异常和心肌病等。 结论 CGL罕见,易合并代谢性疾病。全身脂肪消失的患儿应首先考虑本病,基因确诊后应密切随访其代谢状况。本例患儿BSCL2基因携带的突变位点之一c.713G>A, p.Gly238Asp为首次报道。     

POLG 基因变异致线粒体病一家系分析

目的分析POLG基因变异致线粒体病的临床表型及基因变异。方法回顾分析于2019年5月就诊,并经采集外周血DNA进行医学外显子、外显子-内含子交界区靶向二代测序和一代验证,1个确诊为POLG基因变异致线粒体病家系的临床资料。结果先证者,男,10岁,与其同卵双胎哥哥均有相同的体征,深感觉受损、腱反射消失、肌肉可疑萎缩。先证者3个兄姐先后于1岁多夭折。提取患儿及其父母的外周血,先证者及同卵双胎哥哥POLG基因均存在G.2558A(p.R853Q)、c.2890T(p.R964C)复合杂合变异,分别来源于患儿父母亲。结论 POLG基因复合杂合变异线粒体病家系成员有不同的表型;POLG相关疾病,即使同种基因变异,其临床异质性也较大。     

先天性糖基化障碍Ie 型合并先天性肌营养不良表型患儿临床和基因分析

目的探讨多萜醇磷酸甘露糖基转移酶1(DMP1)基因变异致先天性糖基化障碍Ie型(CDG-Ie)合并先天性肌营养不良表型的临床表现及基因变异。方法回顾分析1例CDG-Ie型合并先天性肌营养不良表型患儿的临床资料及基因检测结果。结果男性患儿,1月龄即发现头围小,随后有智力、运动发育迟缓、小头畸形、癫痫性脑病、肌力和肌张力减弱、双足挛缩、扁鼻梁、小下颌、双眼上斜、追光差等表现,血清肌酸肌酶升高。头颅磁共振示脑萎缩,脑外间隙弥漫性增宽,脑内髓鞘化明显偏弱。脑电图为暴发-抑制改变。基因测序显示患儿DPM1基因存在复合杂合变异,c.669-3CG和c.677GT;家系分析提示c.669-3CG来自母亲,c.677GT来自父亲。确诊为CDG-Ie。结论 CDG-Ie是CDG的罕见类型,常合并先天性肌营养不良表型,早期基因检测有助明确诊断。     

Merosin缺乏性先天性肌营养不良1A型1例报告

目的探讨LAMA2基因突变致先天性肌营养不良的临床特点及诊断方法。方法回顾分析1例merosin缺乏性先天性肌营养不良1A型(MDC1A)患儿的临床资料。结果患儿男性,2岁2个月首次就诊。临床表现为精神运动发育迟缓,不能站立、行走,口齿不清。肌酸激酶显著升高;头颅磁共振提示双侧脑室前角、后角周围及半卵圆中心深部白质呈长T1长T2、FLAIR序列大片高信号影。基因检测显示患儿有分别源自父亲的剪接突变(c.4718-1GA)、源自母亲的移码突变(c.4529delC),为复合杂合突变。查阅既往文献及数据库未见报道。根据ACMG指南,两种变异均判定为致病性变异,确诊为MDC1A。结论 MDC1A为LAMA2基因突变所致,肌肉活检及LAMA2基因检测可明确诊断。本次发现的基因突变为首次报道,扩充了先天性肌营养不良的基因突变谱。     

Two Japanese infants with congenital generalized lipodystrophy due to BSCL2 mutations

Background: Congenital generalized lipodystrophy (CGL), Berardinelli‐Seip syndrome, is a rare autosomal recessive disorder characterized by the generalized absence of adipose tissue at birth, severe insulin resistance early in life, hypertriglyceridemia, hepatomegaly, and the development of diabetes mellitus during puberty. Recently, two genes, BSCL2 and AGPAT2, were identified as causative genes for CGL. It has been reported that patients with BSCL mutations present with more severe clinical findings than those with AGPAT2 mutations. However, the clinical course of CGL caused by BSCL2 mutations in infancy has not been fully elucidated. Methods: Two Japanese infantile patients with CGL from independent families were examined and underwent an oral glucose tolerance test. Insulin resistance and insulin secretion were estimated using the homeostasis model assessment for insulin resistance and the insulinogenic index, respectively. Sequence analysis of the entire coding region of BSCL2 and AGPAT2 was performed. Results: Both CGL patients presented with normal glycemic profiles after oral glucose tolerance tests; however, the values from the homeostasis model assessment of insulin resistance were elevated and well above the cut‐off point for diagnosis of infant insulin resistance in both patients. One patient possessed a known homozygous nonsense mutation in exon 8 (c.823C>T) of BSCL2; the other had a novel homozygous missense mutation in exon 5 (c.560A>G) of BSCL2. Conclusion: Japanese CGL patients with BSCL2 mutations presented with severe insulin resistance, even during infancy, prior to the development of diabetes mellitus.     

Radiological features in generalized lipodystrophy

Seven patients with congenital generalized lipodystrophy and one patient with acquired generalized lipodystrophy have been followed up for 38 years. Various radiological techniques have been used, and the major findings are summarized. All patients had an advanced skeletal age. A sclerotic skeleton was a major feature in childhood in the congenital form, later turning into osteolytic lesions or more distinct sclerotic patches in adolescence or early adulthood. In the acquired form the skeleton was slightly osteoporotic without cystic changes. Ultrasonography and computerized tomography examinations revealed hepatosplenomegaly with fatty infiltration in both types. Lack of subcutaneous and intrabdominal fat was easily confirmed with computerized tomography. Five patients with the congenital form underwent pneumoencephalography, which revealed dilated brain ventricles and basal cisterns. Cardiomegaly and large kidneys were also a major feature.     

Successful cardiac transplantation in a patient with congenital generalized lipodystrophy

We report a case of a 12‐yr‐old boy referred to our unit with congenital generalized lipodystrophy and dilated cardiomyopathy related to a lamin gene mutation. He progressively developed end‐stage heart failure and was referred for heart transplant evaluation. The patient's lipid profile, glucose level, and renal function were normal, and vascular retinopathy was ruled out. He underwent orthotopic bicaval HT and had an uneventful recovery. He was discharged home two wk after surgery with good graft function. During follow‐up, he developed hyperglycemia and dyslipidemia, which were controlled by increasing leptin dose and starting oral antidiabetic drugs. The patient is currently doing well two yr after transplantation.     

Congenital generalized lipodystrophy with insulin-resistant diabetes

Hyperglycemia, glucose intolerance, hyperinsulinemia and resistance to exogenous insulin were found in a 10-year-old Japanese boy diagnosed as having congenital generalized lipodystrophy.Studies on insulin receptors of circulating mononuclear leucocytes indicated that insulin-resistant diabetes combined with congenital generalized lipodystrophy may be due to disturbance of insulin binding to membrane receptors. No insulin-binding antibody or antibody that impairs insulin-receptor binding was found.Plasma glucagon showed an exaggerated response to L-arginine before treatment. After treatment with a controlled diet and an oral sulfonylurea (500 mg/day) for 4 weeks, there was improvement in the plasma glucagon response to L-arginine. Improvement in the hyperglycemia, hyperinsulinemia and acanthosis nigricans was also observed.On the other hand, on completion of a 7-day high-fat diet, a marked increase in serum free fatty acids, triglycerides and -lipoproteins was observed. The total plasma post-heparin lipolytic activity during the high fat diet was within the normal range. However, the level of protamine-inactivated activity was 3 times that of the control.     

Generalized lipodystrophy, congenital and acquired (lipoatrophy)

This review is based on longitudinal studies on our seven patients with congenital generalized lipodystrophy, our patient with acquired generalized lipodystrophy, and published papers on these subjects. An inability to store energy in adipose tissue is of pathogenetic importance. In congenital lipodystrophy, insulin resistance is present from birth, resulting in hyperinsulinaemia, dyslipidaemia, and insulin-resistant diabetes with an anabolic syndrome worsened by a voracious appetite. Clinically, we observed increased height velocity in pre-school age children, and organomegaly with hypertrophic cardiomyopathy, which seems to be lethal in early adulthood: three of our patients died at the ages of 24,32 and 37 years. The oldest alive, 39 years, suffers from stenocardia. Regarding treatment, it is most important to reduce energy consumption. The congenital form is recessively inherited. The aetiology may be related to insulin receptor or postreceptor mechanisms. Acquired generalized lipodystrophy seems to be an autoimmune disorder with secondary destruction of the adipose organ; the anabolic syndrome with insulin-resistant diabetes is secondary. Our patient died when 24 years old from pneumonia.