暂无摘要。

The term laminopathies refers to a group of congenital diseases characterized by accelerated degeneration of human tissues. Mutations in LMNA, LMNB, ZMPSTE24, and other genes lead to structural and functional abnormalities associated with lamins. One subtype of laminopathy is the generalized lipodystrophy-associated progeroid syndrome (GLPS), which occurs in patients with heterozygous mutations of the LMNA gene c.29C>T(p.T10I). This paper reports the first case of GLPS in China and compares the clinical features of other GLPS patients with literature reports. A 16-year-old male patient was treated for diabetic ketoacidosis, presenting with premature aging appearance, systemic lipodystrophy, severe fatty liver, and decreased bone density. After peripheral blood DNA extraction and second-generation sequencing, a heterozygous mutation of exon 1 of the LMNA gene c.29C>T(p.T10I) was detected. This case of GLPS may provide a diagnostic and therapeutic basis for potential patients.

OBJECTIVE: Congenital generalized lipodystrophy (CGL) is a group of rare autosomal inherited diseases characterized by a widespread loss of adipose tissue. The main purpose of this study was to evaluate the features of Chinese patients with CGL2.
METHODS: Three patients diagnosed with CGL2 from our center were reviewed. Data on clinical features, results of laboratory analyses, and previous treatments were retrospectively collected. This study also reviewed studies that reported patients diagnosed with CGL2 in the last 30 years.
RESULTS: All patients presented a lack of subcutaneous fat, hypertriglyceridemia, reversed triangular faces, acanthosis nigricans, and hepatomegaly within the first six months of life. All three patients developed splenomegaly, and mental retardation in later life. Dietary control dramatically lowered triglyceride levels in all patients. One patient presented with diabetes mellitus at 1 year-old. Although combined therapy with low fat diet and metformin maintained normal levels of blood lipid and glucose, this patient developed hypertrophic cardiomyopathy at the age of three. By a literature review on all Chinese cases with CGL2, it is known that classic manifestations such as hypertriglyceridemia, hepatomegaly and diabetes mellitus can occur shortly after birth, and early diagnosis and treatment can improve quality of life. In this cohort, the most frequent variations are c.782dupG and c.974dup in the BSCL2 gene. However, the same genotype may have different clinical phenotypes in patients with CGL2.
CONCLUSIONS: This study not only described the clinical and genetic features of three patients with CGL2 in China, but also reviewed literature about CGL2 around the world.

Congenital generalized lipodystrophy (CGL) is an extremely rare genetic disease mainly characterized by absence of whole-body adipose tissue and metabolic dysfunctions such as insulin resistance, diabetes mellitus, hypertriglyceridemia, hepatic steatosis, and acanthosis nigricans. In this study, we reported a novel case of a young woman patient with CGL. The patient came to the hospital for early-onset lipodystrophy and diabetes. She was 19-year-old with a height of 160 cm, a weight of 46 kg, BMI of 17.9 kg/m2, and a serum leptin level of 0.14 μg/L. Genomic DNA was extracted from blood samples of the patient and her family members, including her mother, father and brother. Genetic analysis revealed compound heterozygous mutations of the BSCL2 gene (c.560A>G and c.565G>T) in the patient. Her father carried a heterozygous mutation (c.565G>T), and her mother carried a heterozygous mutation (c.560A>G) in the BSCL2 gene. The mutant p.Y187C plasmid was transfected into HEK293T cells. The protein expression of SEIPIN and its interaction with glycerol-3-phosphate acyltransferase (GPAT3) were observed to be reduced. In addition, based on primary cultured skin fibroblasts from the patient, SEIPIN protein was decreased, and lipid droplets were much smaller when fatty acid was stimulated compared with those observed from healthy subject controls. However, histone deacetylase inhibitors (HDACis) was found capable of rescuing SEIPIN protein in fibroblasts of the patient. In addition, we further summarized and discussed gene mutations of BSCL2 reported in the current literature. Collectively, these findings have expanded the clinical phenotype and pathogenic gene spectrum of CGL, which might help clinicians to achieve better management of lipodystrophy.
先天性全身性脂肪萎缩(congenital generalized lipodystrophy,CGL)是一种极端罕见的常染色体隐性遗传病,表现为明显的全身脂肪极度缺失,肌肉感明显,并伴有一系列的代谢指标异常,包括严重的胰岛素抵抗,高血糖,高脂血症,脂肪肝以及黑棘皮等。本文针对1例CGL患者及其家系进行研究。先证者为19岁年轻女性,自幼皮下脂肪缺如,血清瘦素水平仅0.14 μg/L。对患者及其亲属(父母、弟弟)进行全基因组检测,显示该患者BSCL2基因5号外显子存在复合杂合突变(c.560A>G和c.565G>T),c.560A>G突变导致对应编码的187位的氨基酸由酪氨酸突变为半胱氨酸(p.Y187C),从而引起BSCL2编码的SEIPIN蛋白发生错义突变;c.565 G>T突变引起对应编码的189位氨基酸转为终止密码子(p.E189X),产生蛋白截短突变。经Sanger测序验证,患者父亲携带c.565G>T杂合突变,患者母亲携带c.560A>G杂合突变,患者弟弟未携带BSCL2基因致病性突变。本研究通过转染突变p.Y187C质粒至HEK293细胞,观察到SEIPIN蛋白量及与甘油-3-磷酸酰基转移酶(glycerol-3-phosphate acyltransferase, GPAT3)互作减少;原代培养的患者皮肤成纤维细胞体外功能实验表明,患者的SEIPIN蛋白量明显低于正常健康人,加入组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitors, HDACis)可部分挽救SEIPIN蛋白表达。此外,油酸刺激下患者皮肤成纤维细胞脂滴小于正常健康人。本文同时综述国内外既往文献中报道的BSCL2基因突变位点,丰富了CGL的临床表型谱和致病基因突变谱,有助于提高临床医生对CGL的临床诊治和致病机制的理解。.

Seipin, a protein encoded by the Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) gene, is famous for its key role in the biogenesis of lipid droplets and type 2 congenital generalised lipodystrophy (CGL2). BSCL2 gene mutations result in genetic diseases including CGL2, progressive encephalopathy with or without lipodystrophy (also called Celia\'s encephalopathy), and BSCL2-associated motor neuron diseases. Abnormal expression of seipin has also been found in hepatic steatosis, neurodegenerative diseases, glioblastoma stroke, cardiac hypertrophy, and other diseases. In the current study, we comprehensively summarise phenotypes, underlying mechanisms, and treatment of human diseases caused by BSCL2 gene mutations, paralleled by animal studies including systemic or specific Bscl2 gene knockout, or Bscl2 gene overexpression. In various animal models representing diseases that are not related to Bscl2 mutations, differential expression patterns and functional roles of seipin are also described. Furthermore, we highlight the potential therapeutic approaches by targeting seipin or its upstream and downstream signalling pathways. Taken together, restoring adipose tissue function and targeting seipin-related pathways are effective strategies for CGL2 treatment. Meanwhile, seipin-related pathways are also considered to have potential therapeutic value in diseases that are not caused by BSCL2 gene mutations.

BACKGROUND: Congenital generalized lipodystrophy (CGL) is a clinically heterogeneous disorder characterized by near total absence of adipose tissue along with metabolic complications. Diabetes mellitus developed from CGL usually present between ages 15 and 20 years, and there are few reports in neonate.
METHODS: In this report, we described a rare clinical presentation of CGL in a 12-day-old Chinese female neonates with hyperglycemia, hyperlipidemia, and subsequently appeared diabetes, hepatomegaly and fatty liver. The two clinical-exome sequencing identified heterozygous null mutations (c.793C > T and c.565G > T) in BSCL2 gene which was inherited from father and mother respectively. To date, it was the firstly reported CGL patient with neonatal onset diabetes. The neonate was treated with antibiotic, insulin and deeply hydrolyzed formula milk to significantly decrease FBG and serum trigylcerides levels.  CONCLUSIONS: Our case report analyzes the causes of early onset diabetes may relate with the locus of BSCL2 gene mutations and infection induction. It also suggests the importance of early identification, genetic analysis, and symptomatic treatment in the CGL, which are essential for improving the prognosis of children.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disease with a prevalence of less than one in ten million. To our knowledge, ~500 cases, including 95% of BSCL2, have been reported in the literatures, but no types of CGL with NOTCH2 gene mutation has been described.

OBJECTIVE: To explore the genetic basis for an infant with congenital generalized lipodystrophy.
METHODS: Peripheral blood samples of the child and her parents were collected for the extraction of genomic DNA. All exons and flanking sequences of the AGPAT2 gene were subjected to Sanger sequencing.
RESULTS: The child was found to harbor compound heterozygous c.792_805delGGAGAACGGGGCCA (p.Gln264Hisfs*208) and c.335C>T (p.P112L) variants in exons 6 and 3 of the AGPAT2 gene, which were respectively inherited from her mother and father. c.792_805delGGAGAACGGGGCCA (p.Gln264Hisfs*208) was previously unreported, while c.335C>T (p.P112L) was known to be pathogenic.
CONCLUSIONS: The compound heterozygous variants of the AGPAT2 gene probably underlie the disease in this child.

A boy, aged 66 days, was admitted to the hospital due to subcutaneous nodules for 46 days and abdominal distension for 10 days. The main clinical manifestations were loss of adipose tissue, subcutaneous nodules, insulin-resistant diabetes, hypertriglyceridemia, and hepatic steatosis. The boy was diagnosed with congenital generalized lipodystrophy type 1 (CGL1). His condition was improved after administration of middle-chain fatty acid formula milk and insulin injection or oral metformin. Gene testing revealed a homozygous mutation, c.646A>T, in the AGPAT2 gene, and both his parents were carriers of this mutation. This case of CGL1 has the youngest age of onset ever reported in China and multiple subcutaneous nodules as the initial symptom.

Berardinelli-Seip congenital lipodystrophy (BSCL) is a heterogeneous autosomal recessive disorder characterized by an almost total lack of adipose tissue in the body. Mutations in the AGPAT2, BSCL2, CAV1 and PTRF genes define I-IV subtype of BSLC respectively and clinical data indicate that new causative genes remain to be discovered. Here, we retrieved 341 cases from 60 BSCL-related studies worldwide and aimed to explore genotype-phenotype correlations based on mutations of AGPAT2 and BSCL2 genes from 251 cases. We also inferred new candidate genes for BSCL through protein-protein interaction and phenotype-similarity.
Analysis results show that BSCL type II with earlier age of onset of diabetes mellitus, higher risk to suffer from premature death and mental retardation, is a more severe disorder than BSCL type I, but BSCL type I patients are more likely to have bone cysts. In BSCL type I, females are at higher risk of developing diabetes mellitus and acanthosis nigricans than males, while in BSCL type II, males suffer from diabetes mellitus earlier than females. In addition, some significant correlations among BSCL-related phenotypes were identified. New candidate genes prediction through protein-protein interaction and phenotype-similarity was conducted and we found that CAV3, EBP, SNAP29, HK1, CHRM3, OBSL1 and DNAJC13 genes could be the pathogenic factors for BSCL. Particularly, CAV3 and EBP could be high-priority candidate genes contributing to pathogenesis of BSCL.
Our study largely enhances the current knowledge of phenotypic and genotypic heterogeneity of BSCL and promotes the more comprehensive understanding of pathogenic mechanisms for BSCL.