核纤层蛋白病性心肌病1例

LMNA基因突变会导致核纤层蛋白结构改变, 进而通过多种机制导致一系列疾病, 主要表现为多系统早衰, 具体可表现为扩张型心肌病、心律失常、代谢异常(如脂肪萎缩、胰岛素抵抗和高甘油三酯血症)、听力受损以及脊柱侧弯等。该文报道1例LMNA R349W突变患者, 具有核纤层蛋白病的一系列典型表现。     

核纤层蛋白心肌病的发病机制及诊治要点

核纤层蛋白A/C位于核膜上。编码核纤层蛋白A/C的基因(LMNA)发生突变可通过一系列机制导致机体产生各种疾病，这一系列疾病统称为核纤层蛋白病，扩张型心肌病(dilated cardiomyopathy, DCM)便是其中之一。本文将介绍LMNA-DCM的发病率、病理生理机制、临床表型和治疗。     

核纤层蛋白A/C基因 Glu82Lys突变与扩张型心肌病

目的 检测中国人家族性扩张型心肌病核纤层蛋白A/C(Lamin A/C)基因突变情况。方法对1个扩张型心肌病家系进行核纤层蛋白A/C、基因突变扫描,聚合酶链反应(PCR)扩增核纤层蛋白A/L’基因1～12号外显子,测序检测突变。对照为60例正常人及9例无明显家族史的扩张型心肌病伴传导阻滞病人。结果 该家系先证者第1号外显子PCR产物测序分析表明该患者核纤层蛋白A/C基因第82密码子位置发生G→A转换,使谷氨酸(Glu)变为赖氦酸(Lys)。该患者临床表现劳力性呼吸困难、心动过缓、胸闷、夜间不能平卧,超声示左心室扩大,心电图显示Ⅲ°房室传导阻滞,现已安装起搏器治疗。患者母亲及哥哥皆有相似临床症状且都已于40余岁心衰死亡,其家属有多人死于相同症状。结论 核纤层蛋白A/C基因Glu82Lys错义突变位于核纤层蛋白的杆状结陶域,有氨基酸的极性改变,该突变表型呈现症状重,发病早,预后差的临床特点,台并Ⅱ-Ⅲ°传导阻滞,提示该突变是致扩张型心肌病的恶性突变。     

核纤层蛋白基因相关性心肌病

核纤层蛋白基因突变可引起心肌病,临床表现以进展性传导系统疾病最为常见,并进一步发展为心力衰竭,患者猝死率高。近年来核纤层蛋白基因相关性心肌病成为心肌病研究领域的热点,使核纤层蛋白基因相关性心肌病的早期诊断、干预和改善预后成为可能。现就常见的核纤层蛋白基因突变位点及其突变致心肌病机制做一综述。     

脂肪源性干细胞在缺血性心脏病中的研究进展

来自中胚层的脂肪组织与骨髓组织一样含有大量能自我更新和多向系分化潜能的细胞群称为脂肪源性干细胞.其取材方便、来源丰富,可在体外稳定增殖传代.研究发现它具有多向系分化潜能,可以分化为间充质来源的脂肪、骨、软骨、骨骼肌、神经、心肌等细胞,用以修复骨、软骨、心肌、骨骼肌、血管以及神经等组织.现主要介绍脂肪源性干细胞移植治疗缺血性心脏病的研究进展.     

回顾分析LMNA c.1045C>T突变所致核纤层蛋白病的临床表型

目的 对LMNA c.1045C>T突变所致核纤层蛋白病的临床表型进行汇总分析,提高对此种疾病的认识和诊治水平。方法结合北京协和医院诊治的1例LMNA c.1045C>T突变患者临床特点,总结文献收集的20例同一突变位点病例的临床资料并进行分析。结果 LMNA c.1045C>T突变患者无性别差异,平均年龄32.9岁（14～46岁）,临床表现为多系统受累,包括心肌病和/或心力衰竭（60%）、心律失常（60%,其中以传导异常为主）、脂肪萎缩（90%）、胰岛素抵抗或糖尿病（70%）、高甘油三酯血症（75%）、早发动脉粥样硬化（30%）和蛋白尿肾病（80%）。患者会出现相关心血管并发症,导致不良预后。其中3例发生心肌梗死,3例安装植入式心律转复除颤器（均为一级预防）。5例（25%）患者死亡或进行心脏移植,2例为猝死,另外2例分别死于感染性心内膜炎和感染后多脏器功能衰竭,1例因非缺血性心力衰竭进行心脏移植。针对上述患者出现的系统受累进行治疗有助于改善心力衰竭、胰岛素抵抗、血脂异常和血压,预防动脉粥样硬化和猝死的发生。结论 LMNA c.1045C>T突变导致的核纤层蛋白...     

原发性肥大性骨关节病一例并文献复习

目的 提高临床医生对原发性肥大性骨病的认识.方法 报道1例原发性肥大性骨病,对其患者的临床表现、实验室和辅助检查以及诊治过程进行回顾性分析,并进行疾病相关文献复习.结果 患者为男性,无家族史,发病年龄16岁;有杵状指(趾)、皮肤增厚、关节肿胀和多汗,X线示骨皮质增厚、骨膜增生,符合肥厚性骨关节病的诊断;应用少量非甾体抗炎药治疗后关节肿胀症状很快缓解.结论 青少年男性出现杵状指(趾)、皮肤增生等表现,应及时进行骨骼x线检查,如有骨皮质增厚,可确定原发性肥大性骨关节病的诊断.     

伊曲康唑联合手术成功治疗系统性红斑狼疮并发原发性播散型隐球菌病1例

隐球菌病是由新生隐球菌引起的脑、脑膜、肺、皮肤或全身性的慢性、亚急性甚至急性感染。新生隐球菌呈全球分布, 多见于鸽子排泄物中。原发性播散性皮肤隐球菌感染、骨骼隐球菌感染均较少见。本文报道1例SLE患者, 出现躯干、四肢皮肤结节、破溃及左足踝肿痛症状, 根据皮肤、骨骼组织病理发现有荚膜的孢子以及真菌培养的结果, 同时结合患者的发病部位、皮损类型、患者的免疫功能, 确诊为原发性播散性皮肤隐球菌感染、骨骼隐球菌感染。经伊曲康唑联合手术治疗后, 病情基愈, 随访2年, 无复发, 以供临床医师参考。     

单基因突变所致的胰岛素抵抗综合征

临床上存在多种由单基因突变所导致的胰岛素抵抗综合征,如胰岛素受体基因突变造成的严重胰岛素抵抗综合征,核纤层蛋白(LMNA)基因突变导致的脂肪营养不良综合征等,以下将对这些疾病的临床特点、突变基因及发病机制作一综述.     

脂膜炎患者的临床特征及治疗随访分析

目的 探讨脂膜炎的临床特征、治疗及预后.方法 随访在我院住院诊断为脂膜炎的患者,对原发性脂膜炎皮肤型和系统型患者的临床特征和治疗随访的结果进行分析.结果 61例患者平均随访49.2个月(2～216个月),17例达到临床缓解,26例反复发作,18例继发结缔组织病(CTD)、血液病、肿瘤和结核.43例原发性脂膜炎患者平均发病年龄(33±17)岁,男女比例1:1.15,皮肤型12例,系统型31例.系统型患者出现肝脏病变25例,脾脏的肿大23例,肺部受累11例,肾脏受累12例,心脏受累3例.系统型9例出现血白细胞减少,而皮肤型为0,两者比较P=-0.044.组织病理学上原发性脂膜炎16.3%患者可见核尘.皮肤型4例单用激素或对症治疗,8例激素联合免疫抑制剂治疗,平均随访63.2个月,7例缓解,5例反复发作;系统型11例单用激素或对症治疗,20例激素联合免疫抑制剂治疗,平均随访47.5个月,10例缓解,21例反复发作.结论 脂膜炎可继发CTD、肿瘤、血液病和结核感染.系统型患者最常受累的脏器为肝脾,可出现白细胞减少.激素和免疫抑制剂治疗部分患者缓解,大多数激素减量易复发.     

Myopathien, Myositiden, Vaskulitiden mit Muskelbeteiligung

Muscle and nerve biopsies provide valuable information contributing to the diagnosis of diseases of the peripheral nervous system and skeletal muscle. The application of modern histological, immunohistochemical, electron microscopic and molecular methods establishes a definite diagnosis in many cases and narrows the spectrum of possible entities in most of the remaining cases. Inflammatory myopathies and neuropathies are distinguished from non-inflammatory muscular and peripheral nervous conditions. The latter include muscular dystrophies and congenital myopathies, hereditary neuropathies, metabolic diseases affecting skeletal muscle and peripheral nerves as well as degenerative myopathies and neuropathies including sporadic motor neuron diseases.     

Compound heterozygosity for mutations in LMNA in a patient with a myopathic and lipodystrophic mandibuloacral dysplasia type A phenotype

CONTEXT: Mandibuloacral dysplasia type A (MADA; OMIM 248370) is a rare progeroid syndrome characterized by dysmorphic craniofacial and skeletal features, lipodystrophy, and metabolic complications. Most Italian patients carry the same homozygous missense mutation (p.R527H) in the C-terminal tail domain of the LMNA gene, which encodes lamin A/C, an intermediate filament component of the nuclear envelope. OBJECTIVE: The objective of the study was to identify novel LMNA mutations in individuals with clinical characteristics (bird-like facies, mandibular and clavicular hypoplasia, acroosteolysis, lipodystrophy, alopecia) observed in other well-known patients. DESIGN: The LMNA gene was sequenced. Functional properties of the mutant alleles were investigated. PATIENT: We report a 27-yr-old Italian woman showing a MADA-like phenotype. Features include a hypoplastic mandible, acroosteolysis, pointed nose, partial loss of sc fat, and a progeric appearance. Due to the absence of clavicular dysplasia and normal metabolic profiles, generally associated with muscle hyposthenia and generalized hypotonia, this phenotype can be considered an atypical laminopathy. RESULTS: We identified a patient compound heterozygote for the p.R527H and p.V440M alleles. The patient's cells showed nuclear shape abnormalities, accumulation of pre-lamin A, and irregular lamina thickness. Lamins A and C showed normal expression and localization. The electron microscopy detected heterochromatin defects with a pattern similar to those observed in other laminopathies. However, chromatin analysis showed a normal distribution pattern of the major heterochromatin proteins: heterochromatin protein-1beta and histone H3 methylated at lysine 9. CONCLUSIONS: The clinical and cellular features of this patient show overlapping laminopathy phenotypes that could be due to the combination of p.R527H and p.V440M alleles.     

A benign course of multicentric Castleman's disease with involvement of the spleen and bone marrow

The multicentric variant of Castleman's disease (MCCD) is associated with a rapidly progressive and fatal course. The case described herein manifested unique clinical and histological features. Initial presentation as isolated splenomegaly was subsequently followed by widespread organ involvement, including lymph nodes and bone marrow. In spite of this, the patient had a very benign course of her disease. The case serves to expand even further the already wide clinical spectrum of Castleman's disease.     

Prerequisites and strategies for prenatal diagnosis of respiratory chain deficiency in chorionic villi

Prenatal diagnosis for respiratory chain deficiencies is a complex procedure that requires a thorough diagnostic work-up of the index patient. This includes confirmation of the clinical and metabolic evaluations through histological and enzymatic examinations of tissue biopsies. Prenatal diagnosis currently relies on biochemical assays of respiratory chain complexes in chorionic villi or amniocytes and is possible by mutation analysis of nuclear genes in a limited but increasing proportion of cases. Based on a recent survey of prenatal diagnosis in families with complex I and complex IV deficiencies, performed at Nijmegen Centre for Mitochondrial Disorders (NCMD), prerequisites and strategies for performing prenatal diagnosis have been developed to increase reliability. Biochemical investigations in chorionic villi can be done reliably if the respiratory chain enzyme deficiency is expressed in both skeletal muscle and skin fibroblasts to rule out tissue specificity. No mitochondrial DNA defects must be suspected or established. The NCMD does not offer prenatal diagnosis until all the prerequisites have been confirmed. We expect prenatal diagnosis at the molecular level to become more feasible in time as the mutational spectrum broadens with advances in medical research.     

Etiological investigations in apparent type 2 diabetes: when to search for lamin A/C mutations?

Prevalence of diabetes is increasing worldwide in epidemic proportions. Its appropriate clinical management requires a careful etiological diagnosis.

Laminopathies recently emerged as clinically heterogeneous genetic disorders due to mutations in lamins or lamin-associated proteins, which are components of the nuclear envelope. Laminopathies regroup at least eight distinct diseases, belonging to the groups of skeletal and/or cardiac muscular dystrophies, axonal neuropathies, premature ageing syndromes and familial lipodystrophies, all resulting from alterations in LMNA, encoding type A-lamins. Pathophysiological mechanisms explaining how mutations in an unique gene could lead to such various phenotypes are still unknown, but probably involve alterations in cellular mechanical stress responses, in gene expression, and/or in post-translational maturation of lamin A.

Familial Partial Lipodystrophy of the Dunnigan type (FPLD2), with specific features of pseudo-cushingoid lipodystrophy, marked insulin resistance and muscular hypertrophy, and a relatively homogeneous genotype, was thought, until recently, to be the only laminopathy causing diabetes. However, recent studies have revealed that insulin resistance and diabetes could be key features of attenuated or more complex phenotypes of laminopathy.

In the light of these recent findings, this review will describe the clinical, morphological and biological features that should lead clinicians to consider the diagnosis of laminopathy in a diabetic patient. The recognition of such an etiology for diabetes is important not only for its appropriate medical treatment, but also because specific investigations are required to detect possible asymptomatic life-threatening complications. In addition, the molecular screening of family members allows an earlier efficient clinical management of affected relatives.     

A new clinical condition linked to a novel mutation in lamins A and C with generalized lipoatrophy,insulin-resistant diabetes,disseminated leukomelanodermic papules,liver steatosis,and cardiomyopathy

A-Type lamins, arising from the LMNA gene, are intermediate filaments proteins that belong to the lamina, a ubiquitous nuclear network. Naturally occurring mutations in these proteins have been shown to be responsible for several distinct diseases that display skeletal and/or cardiac muscle or peripheral nerve involvement. These include familial partial lipodystrophy of the Dunnigan type and the mandibuloacral dysplasia syndrome. The pathophysiology of this group of diseases, often referred to as laminopathies, remains elusive. We report a new condition in a 30-yr-old man exhibiting a previously undescribed heterozygous R133L LMNA mutation. His phenotype associated generalized acquired lipoatrophy with insulin-resistant diabetes, hypertriglyceridemia, hepatic steatosis, hypertrophic cardiomyopathy with valvular involvement, and disseminated whitish papules. Immunofluorescence microscopic analysis of the patient's cultured skin fibroblasts revealed nuclear disorganization and abnormal distribution of A-type lamins, similar to that observed in patients harboring other LMNA mutations. This observation broadens the clinical spectrum of laminopathies, pointing out the clinical variability of lipodystrophy and the unreported possibility of hypertrophic cardiomyopathy and skin involvement. It emphasizes the fact that the diagnosis of genetic alterations in A-type lamins requires careful and complete clinical and morphological investigations in patients regardless of the presenting signs.     

Primary adrenal insufficiency in a child with a mitochondrial DNA deletion

Mitochondrial disorders can affect any organ system, but certain tissues, such as skeletal muscle, heart, and brain are more susceptible to oxidative phosphorylation defects because of their high energy requirements. Endocrinological manifestations, especially diabetes mellitus, are common but they rarely dominate the clinical picture. We describe a 5-year-old girl who died of primary adrenal insufficiency with a mitochondrial disease. Biochemical studies in muscle showed decreased respiratory chain enzyme activities. We detected a novel 7.0 kb mtDNA deletion in muscle from the proband, but not in her mother's white blood cells. Our findings further enlarge the spectrum of clinical presentation associated with mitochondrial DNA deletions.     

Infantile systemic hyalinosis: report of three Iranian children and review of the literature

Infantile systemic hyalinosis (ISH) is a rare autosomal recessive disease characterized by diffuse hyaline deposits in the skin, gastrointestinal tract, muscle and endocrine glands. The clinical features are evident either at birth or within 6 months of life. The disease is manifested by painful progressive joint contractures, thick skin with hyperpigmentation, susceptibility to bone fractures, infections, failure to thrive and persistent diarrhea due to protein-losing enteropathy. Here, we report three unrelated Iranian children with a limited range of joint movements in the first month of life, skin hyperpigmentation and painful joint contractures. Pathological findings also confirmed the diagnosis of ISH in these patients.     

Danon disease: intrafamilial phenotypic variability related to a novel LAMP-2 mutation

Danon disease is an X-linked lysosomal disorder, characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation. We report a family with a novel mutation, in which the mother and her three sons were affected with various clinical presentations. A massive hypertrophy of the left ventricle was the predominant feature in the three male patients, with different degrees of severity of cardiac symptoms, from isolated palpitations to cardiac failure and sudden death. Muscle pain and weakness were also variable, but constantly associated with increased plasma CK levels. Finally, the male patients had variable degree of a mental retardation. The mother had an attenuated phenotype, limited to a mild hypertrophic cardiomyopathy with premature ventricular contractions diagnosed during her 40’s. Microscopy examination of skeletal muscle biopsy, performed in the youngest patient, demonstrated atrophic myofibers with intracytoplasmic vacuoles suggesting lysosomal glycogen storage disease. Immunohistochemistry analyses in muscle specimen showed no detectable Lysosomal-Associated Membrane Protein-2 (LAMP-2), in keeping with the diagnosis of Danon disease. However, a very low expression of a shortened LAMP-2 protein could be evidenced by Western-blot in the patient’s fibroblasts. Molecular investigations identified a novel splicing mutation (IVS6 + 1delG) in the LAMP-2 gene. This case report highlights the intrafamilial variability of Danon disease phenotype. In this case, morphological examination of muscle biopsy, showing lysosomal storage myopathy, and immunohistochemistry analyses can provide key elements for orienting etiologic investigations.     

Multiple hereditary exostoses and enchondromatosis

Multiple hereditary exostoses (MHE) and enchondromatosis are rare multifocal benign disorders usually causing skeletal deformities appearing already in childhood. MHE is a dominant autosomal inherited disorder characterized by multiple osteochondromas (exostoses) growing outward from the metaphyses of long bones as well as from flat bones. They may cause reduced joint motion and pain due to tendon, muscle, and nerve compression.Enchondromatosis (or Ollier's disease) is a noninherited disorder characterized by the presence of multiple intraosseous enchondromas located asymmetrically in the skeleton and with a wide variation regarding location, size, and number ranging from the involvement of a single hand to the involvement of the entire skeleton. It can occur together with soft-tissue hemangiomas in Maffucci's syndrome. Clinical problems caused by the enchondromas are mainly related to skeletal deformities causing malalignment and restricted motion of joint.In both disorders, there is a risk of malignant transformation as well as secondary degenerative joint changes.