本文選題：脂質(zhì)貯積病 + 肌疾病�。� 參考：《山東大學(xué)》2017年碩士論文

【摘要】：研究背景與目的:伴有肌病的中性脂肪沉積病(neutral lipid storage disease with myopathy,NLSDM)是一種十分罕見的常染色體隱性遺傳病,它是由編碼脂肪甘油三酯酯酶(adipose triglyceride lipase,ATGL)的基因(又稱PPNLA2基因)突變導(dǎo)致的。ATGL調(diào)控甘油三酯水解的第一步,它的突變會導(dǎo)致大量甘油三酯在不同的組織細胞中沉積,如骨骼肌細胞、心肌細胞、血液粒細胞等,造成的損害以骨骼肌損害為主,也可伴有心肌損害。NLSDM臨床進展緩慢,主要表現(xiàn)為左右不對稱的四肢近端或遠端無力,目前無有效療法。本研究擬對山東大學(xué)齊魯醫(yī)院神經(jīng)肌肉病理實驗室2006年1月～2016年11月間診治的7例NLSDM患者進行隨訪,并對其臨床、病理及基因突變特點進行回顧與分析。本研究的主要目的是總結(jié)NLSDM的臨床、病理與基因突變特點,為NLSDM的診斷與治療提供一定參考和幫助。對象和方法:研究對象為山東大學(xué)齊魯醫(yī)院神經(jīng)肌肉病理實驗室2006年1月～2016年11月診治的7例NLSDM患者。7例患者均在齊魯醫(yī)院神經(jīng)內(nèi)科門診進行詳細的病史采集、內(nèi)科查體和神經(jīng)系統(tǒng)體格檢查,并進行血清學(xué)、電生理學(xué)、影像學(xué)、肌肉組織活檢和PNPLA2基因等輔助檢查�；颊叩谋鶅黾∪鈽吮厩衅缶薪M織化學(xué)染色(H-E、MGT、NADH-TR、SDH、COX、SDH/COX、PAS、ORO、ATPase)和免疫組織化學(xué)染色(Dystrophin-Rod,Dystrophin-C,Dystrophin-N,Dysferlin,α-sarcoglycan,β-sarcoglycan,γ-sarcoglycan,δ-sarcoglycan,Caveolin-3,MHC-1,CD3,CD4,CD8,CD20,CD68)。結(jié)果:7例患者中,女性2人,男性5人�；颊咂鸩∧挲g為22～45歲,平均年齡為36.7歲�；颊呔驮\時年齡28～49歲,平均40.6歲。7例患者起病至診斷的時間間隔為1～7年,其中2例約為1年,3例超過6年,最長達7年,平均4年。7例患者均成年起病,起病隱匿,病情緩慢進展,為單側(cè)或雙側(cè)左右不對稱的肢體無力和肌肉萎縮,四肢遠近端均可受累。7例患者就診時主要臨床表現(xiàn)為上肢抬舉無力、拿捏物體困難、下蹲起立困難、行走姿勢異常、上樓困難、行走無力、易絆倒、全身疲勞等。其中,5例患者就診時肌無力現(xiàn)象累及雙側(cè)肢體(5/7),2例患者只累及一側(cè)肢體(2/7)。4例患者就診時同時累及上下肢(4/7),2例患者只累及上肢(2/7),1例患者只累及下肢(1/7)。3例患者就診時肌無力癥狀近端明顯(3/7),4例患者遠端明顯(4/7)。7例患者均出現(xiàn)腱反射出現(xiàn)減弱或消失(7/7)。除骨骼肌受累之外,7例患者就診時其他系統(tǒng)受累情況不明顯,7例患者均無心臟受累、高TG血癥、肝腫大及聽力下降。7例患者外周血ORO涂片均可見有Jordans小體。患者就診時CK值在651～2419U/L,平均1527.9U/L。肌電圖檢查示:2例患者為正常肌電圖;3例患者為肌源性損害肌電圖;1例患者為神經(jīng)源性損害肌電圖,上下肢均可見強直電位;1例患者既有肌源性損害(以上肢為主),也有神經(jīng)源性損害(以下肢為主)。7例患者均行肌肉活檢,6例患者取肱二頭肌,1例患者取腓腸肌。肌肉活檢后行冰凍切片染色,結(jié)果均顯示為肌源性損害病理改變。在H-E染色上7例患者均可見肌纖維大小明顯不等,小纖維可為小圓形、小多邊形、小長條型和小角形;7例患者肌纖維內(nèi)均存在大量細小空泡或粗大空泡,兩型纖維均可存在;5例患者可見內(nèi)核纖維輕至中度增加,所占比例為10%～50%,達到50%者有3例;2例患者可見肥大及劈裂肌纖維;3例患者可見選擇性Ⅰ型纖維萎縮;5例患者可見Ⅰ型纖維優(yōu)勢;其中2例患者可見選擇性Ⅰ型纖維優(yōu)勢伴萎縮;1例患者可見Ⅱ型纖維優(yōu)勢;5例患者可見壞死伴吞噬肌纖維;4例患者可見再生肌纖維;2例患者可見少量核袋;4例患者可見散在炎細胞浸潤;1例患者可見血管周圍有炎細胞浸潤;3例患者可見肌內(nèi)膜明顯增生,1例輕度增生。在MGT染色上,5例患者可見鑲邊空泡;1例患者肌內(nèi)神經(jīng)內(nèi)有髓纖維減少。在SDH染色上,有3例患者酶活性普遍減低。在ORO染色上,7例患者肌纖維內(nèi)脂滴含量均顯著增多,肌膜下可見大的圓形或橢圓形脂滴,肌纖維內(nèi)脂滴較為細小。在免疫組織化學(xué)染色上,7例患者中有1例MHC-1呈弱陽性表達,1例血管周圍炎細胞CD3呈陽性表達,5例壞死伴吞噬肌纖維CD68呈陽性表達。7例患者均行PNPLA2基因檢測。其中6例患者為PNPLA2基因純合子突變,分別為IVS6+1GT 剪切突變、c.467del C 堿基缺失突變(2 例)、c.475_478dupCTCC,p.(Gln160Profs*19)移碼突變、c.6dupT,p.(Pro3fs)移碼突變、c.434GA,p.(Ser145Asn)錯義突變;1例患者為IVS6+2TC剪切突變和c.749AC(Q250P)錯義突變的復(fù)合雜合突變。其中c.434GA,p.(Ser145Asn)錯義突變和c.6dupT,p.(Pro3fs)移碼突變未見文獻報道,通過生物信息學(xué)軟件分析,推測均有致病性。本組7例患者中有6例患者至少攜帶1個無正常功能蛋白表達的嚴重突變。本研究中7例NLSDM患者服用強的松、復(fù)合維生素B、維生素B1、維生素B2、維生素B3、維生素B6、維生素B12、維生素E、輔酶Q10、左旋肉堿、薄芝糖肽等進行治療,肌無力和肌萎縮癥狀均未得到緩解和改善。7例患者目前均已自行停藥。截至最后一次隨訪(2017年3月),7例患者的肌無力和肌萎縮癥狀均在緩慢進展,左右側(cè)不對稱。隨訪時有2例出現(xiàn)雙側(cè)聽力下降,2例出現(xiàn)耳鳴,7例均無明顯心臟受累、糖尿病及高TG血癥。結(jié)論:1.本組病例均成年起病,起病隱匿,臨床主要表現(xiàn)為左右不對稱的進行性四肢肌無力和肌萎縮,肢體遠近端均可受累,半數(shù)以上遠端受累為主。肌無力和肌萎縮癥狀緩慢進展。2.本組病例除骨骼肌受累之外,其他系統(tǒng)受累不明顯。3.Jordans小體可為臨床快速篩查NLSDM提供依據(jù),結(jié)合肌活檢中兩型肌纖維內(nèi)大量脂滴沉積,可病理診斷為NLSDM。本組病例中半數(shù)以上會伴有鑲邊空泡、壞死伴吞噬及再生肌纖維和炎性細胞浸潤。4.本組病例均存在PNPLA2基因突變,包括6例純合突變,1例復(fù)合雜合突變。有6例患者至少攜帶1個無正常功能蛋白表達的嚴重突變。c.434GA錯義突變和c.6dupT移碼突變國內(nèi)外迄今未有報道。5.本病尚缺乏特異性治療。
[Abstract]:Background and objective: neutral lipid storage disease with myopathy (NLSDM) is a very rare autosomal recessive hereditary disease, which is controlled by the mutation of the gene encoding the triglyceride esterase (adipose triglyceride lipase, ATGL) of the fat (adipose triglyceride lipase, ATGL), also known as the PPNLA2 gene). The first step of ester hydrolysis, its mutation can cause a large number of triglycerides to be deposited in different tissue cells, such as skeletal muscle cells, cardiac myocytes, and hematogenous cells, causing damage mainly in skeletal muscle damage, but also associated with myocardial damage.NLSDM clinical progress slowly, mainly manifested by the near or distal weakness of the left and right extremities. 7 patients with NLSDM from January 2006 to November 2016 in the neuromuscular pathology laboratory of Qilu Hospital of Shandong University were followed up and the clinical, pathological and gene mutation characteristics were reviewed and analyzed. The main purpose of this study was to summarize the clinical, pathological and gene mutation characteristics of NLSDM, NLSD The diagnosis and treatment of M provided some reference and help. Object and methods: 7 patients with NLSDM from January 2006 to November 2016, the neuromuscular pathology laboratory of Qilu Hospital of Shandong University, were collected in the Department of Neurology Department of the Department of Neurology for detailed medical history collection, medical examination and nervous system physical examination. Serology, electrophysiology, imaging, muscle tissue biopsy, and PNPLA2 genes were examined. The frozen muscle specimens of the patients were stained with histochemical staining (H-E, MGT, NADH-TR, SDH, COX, SDH/COX, PAS, ORO, ATPase) and immunohistochemical staining (Dystrophin-Rod, Dystrophin-C, alpha, alpha, beta, etc.) Lycan, gamma -sarcoglycan, Delta -sarcoglycan, Caveolin-3, MHC-1, CD3, CD4, CD8, CD20, CD68). Results: of 7 patients, 2 women and 5 men. The onset age was 22~45 years and the average age was 36.7 years. The age of the patients was 28~49 years old, and the average age of 40.6 years of.7 was 1~7 years, 2 cases were 1 years, 3 cases were about 1 years. More than 6 years, the maximum of 7 years, the average 4 years of.7 patients were all onset, the onset of disease, slow progress, unilateral or bilateral asymmetry of limb weakness and muscle atrophy, and the extremities of the extremities can be affected by.7 patients in the main clinical manifestations of the upper limb lifting, difficulty in holding objects, squatting difficulties, walking posture Often, it was difficult to go upstairs, unable to walk, easy to stumble, and fatigue. Among them, 5 patients were involved in bilateral limbs (5/7), 2 cases involved only one side limb (2/7).4 patients involved upper and lower limbs (4/7) while 2 cases were only involved in the upper limb (2/7), and 1 patients were only involved in the.3 cases of lower limbs (1/7) patients with myasthenia. The proximal end of the form was obvious (3/7). 4 patients with far distal (4/7).7 cases showed a weakening or disappearance of the tendon reflex (7/7). In addition to the skeletal muscle involvement, 7 patients were not involved in other systemic involvement, 7 cases had no heart involvement, high TG, hepatomegaly and hearing loss in the peripheral blood ORO smears in the peripheral blood were all Jordans small. The CK value of the patients was from 651 to 2419U/L, and the average 1527.9U/L. electromyography examination showed that 2 patients were normal EMG, 3 patients were myogenic electromyography, 1 patients were neurogenic damage electromyography, and the upper and lower extremities were both tetanic potential; 1 patients had both muscular damage (mainly upper limbs) and neurogenic damage (lower limbs with lower extremity). .7 patients underwent muscle biopsy in all cases. 6 patients took the biceps brachii muscle and 1 patients took the gastrocnemius muscle. After the muscle biopsy, the frozen section staining was performed. All the results showed the pathological changes of myogenic damage. In 7 cases of H-E staining, the size of the muscle fibers was obviously different, and the small fibers could be small round, small polygon, small strip type and small angle shape; 7 cases were found. There were a large number of fine vacuoles or large vacuoles in the muscle fibers of the patients, and two types of fibers could exist in the 5 patients. The proportion of the core fiber was 10% to 50%, 50% had 3 cases, 2 patients showed the hypertrophy and cleavage muscle fibers, and 3 patients showed the type I fiber atrophy; 5 patients showed type I fiber superiority. Of the 2 patients, selective type I fiber dominance and atrophy were seen; 1 patients showed type II fiber dominance; 5 patients showed necrosis with phagocytic fibers; 4 patients showed regenerative muscle fibers; 2 cases showed a small number of nuclear bags; 4 cases showed infiltration of inflammatory cells; 1 patients showed infiltration of inflammatory cells around blood vessels; 3 patients were visible. The intimal hyperplasia and 1 mild hyperplasia were seen in 1 cases. In 5 patients, the side vacuoles were seen in 5 patients and 1 cases of intramuscular myelinated fibers decreased. In the SDH staining, the enzyme activity was reduced in 3 patients. In the ORO staining, the content of lipid droplets in the muscle fibers increased significantly in 7 cases, and the large round or oval lipid droplets and muscle fibers under the musculi membrane were observed. In immunohistochemical staining, 1 of the 7 cases of MHC-1 showed weak positive expression, 1 cases of peripheral inflammatory cells CD3 positive expression, 5 cases of necrotic and phagocytic CD68 positive expression in.7 patients with PNPLA2 gene detection. 6 cases were PNPLA2 homozygous mutation, respectively IVS6+1GT shear. Mutation, c.467del C base deletion mutation (2 cases), c.475_478dupCTCC, P. (Gln160Profs*19) code mutation, c.6dupT, P. (Pro3fs) shift mutation, c.434GA, P. (Ser145Asn) missense mutation; 1 cases were compound heterozygous mutation of IVS6+2TC shear mutation and missense mutation. S) the change of code mutation was not reported. In the 7 patients of this group, 6 patients had at least 1 serious mutations without normal functional protein expression. In this study, 7 patients with NLSDM took prednisone, vitamin B, vitamine B1, vitamin B2, vitamin B3, vitamin B6, vitamin B1. 2, vitamin E, coenzyme Q10, L-carnitine, thin ganoderma and so on, myasthenia and atrophy of myasthenia and amyotrophic symptoms have not been alleviated and improved in.7 patients. As of the last follow-up (March 2017), the symptoms of myasthenia and atrophy of myasthenia and myasthenia in 7 patients were slowly progressing and asymmetrical in the left and right side. 2 cases appeared bilateral at follow-up. Hearing loss, tinnitus in 2 cases, and no obvious heart involvement, diabetes and hyperTG in 7 cases. Conclusion: 1. of the cases were all onset and occult. The main clinical manifestations were progressive myasthenia and atrophy of extremities and extremities. More than half of the extremities were involved. Myasthenia and atrophy of myasthenia and myasthenia were slow. Slow progress.2., in addition to skeletal muscle involvement, other system involvement, not obvious.3.Jordans body can provide a basis for rapid clinical screening of NLSDM, combined with a large number of lipid droplets in two types of muscle fibers in muscle biopsy, and the pathological diagnosis is that more than half of the cases in the NLSDM. group are accompanied by border vacuoles, necrosis, phagocytosis, and regenerative muscle fibers. PNPLA2 gene mutations were present in all cases of inflammatory cell infiltration in.4., including 6 cases of homozygous mutation and 1 complex heterozygous mutations. 6 patients carried at least 1 severe mutations without normal functional protein expression,.C.434GA missense mutation and c.6dupT code shift mutation at home and abroad.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R596;R746

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本文編號：1861538