Clinical, muscle pathology and molecular biological features of late ⁃ onset glycogen storage disease typeII

Objective To investigate the clinical, imaging, pathological and molecular biological features of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes(MELAS) in children. Methods The clinical, imaging, pathological and molecular biological features of 12 children with MELAS diagnosed through muscle biopsy or gene sequencing in the Fifth Affiliated Hospital of Zhengzhou University from January 2011 to December 2015 were retrospectively analyzed. Results (1) Clinical features: the main manifestations included headache and vomiting in 11 cases, epileptic seizures in 9 cases, short stature in 8 cases, hairy in 7 cases, intolerance fatigue in 7 cases, cognitive decline in 7 cases, visual disturbance in 6 cases, hearing disturbance in 6 cases, and 5 cases had positive family history.In addition, 7 cases had the serum lactic acid level increase in a rest for 10 min after exercise.(2) Imaging features: 4 cases showed bilateral basal ganglia calcification symmetry in 8 patients who underwent head CT scan.The most frequently involved parts of the lesion were occipital in 10 cases, temporal in 9 cases and parietal lobe in 7 cases in stroke-like episodes.The lesions were lamellar necrosis.The abnormal areas by MRI showed low signal intensity on T1 weighted imaging, high signal intensity on T2 weighted imaging and fluid attenuated inversion recovery, high or equal signal intensity on diffusion weighted imaging, high or low signal intensity on apparent diffusion coefficient; the lactate peak significantly increased on magnetic resonance spectroscopy.The distribution was not in accordance with the control region of the cerebral vessels.Dynamic observation revealed that the lesions were reversible and migratory.(3) Myopathological features: muscle biopsy was performed in all children, and ragged-red fibers were found in 10 cases by improved Gomori staining, strongly succinate dehydrogenase-reactive were found in 9 cases, and the lipid droplets slightly increased in 8 cases by oil red O staining.Besides, the crystalline inclusion bodies in mitochondria were arranged in a parking lot pattern in 9 cases by electromicroscope.(4) Molecular biological characteristics: the mitochondrial gene mutations were analyzed in peripheral blood of 9 children and their parents, including 8 cases with A3243G mutation and 1 case with G13513A mutation.Five mothers had the same A3243G mutation site in 8 cases. Conclusions Children with MELAS have complex and varied clinical manifestations and certain characteristic of neuroimaging.Moreover, muscle pathology and gene sequencing have important diagnostic value.Fully understanding the clinical, muscle pathology, imaging and molecular biological characteristics of children with MELAS can be helpful to the early diagnosis and treatment, also reduce misdiagnosis. Key words: Mitochondrial encephalomyopathy; Lactic acidosis; Stroke-like episodes; Clinical manifestation

To delineate the characteristics of the clinical manifestation, pathology of skeletal muscle and gene mutations of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episode (MELAS) in children. The clinical manifestation, laboratorial data, brain images, muscle pathology and mitochondrial gene mutations were analyzed in 24 patients with MELAS who were diagnosed in Department of Pediatrics, Peking University First Hospital. Their prognosis was evaluated by following up. Symptoms of central nervous system such as stroke-like episodes, vomiting, convulsion and headache were present in all the 24 cases. Nine cases had the symptoms of myopathy. Twenty cases had developmental delay. Short stature, being thin and hairy was very common in these cases. Serum lactate level increased in all the cases, pyruvate increased in 17 cases. Elevated CSF lactate was found in 2 cases. Magnetic resonance imaging (MRI) was performed on 24 cases, out of them 23 were abnormal. The lesions mainly involved cerebral lobes. Occipital lobe was the most common site of lesions. Computed tomography (CT) was performed on 13 cases, low density lesions were present in 10 cases, basal ganglia calcifications in 5 cases. Muscle biopsy was performed on 8 cases, ragged-red fibers (RRF) were found in 4/8 cases, and abnormal accumulation of mitochondria were found in 3/8 cases. The mtDNA gene mutational analysis showed A3243G mutation in these patients. The mutation rates varied from 11.6% to 75.0%. The same mutation were found in 4/5 mothers who had the genetic tests, and the mutation rates of the mothers varied from 15.0% to 23.6%. The clinical information of 11 cases was available through recent following up. Three cases died, the others had some degrees of mental retardation. Children with MELAS had various clinical manifestations. Central nervous system and skeletal muscle were usually involved. Short stature and hypertrichosis were common signs. The prognosis of this disease was disappointing. mtDNA A3243G was the most common mutation in MELAS. Fully understanding the characteristics of its clinical manifestation, laboratory tests, brain image, muscle pathology and molecular features can be helpful to the early diagnosis and treatment.

目的 探讨儿童中央轴空病的临床、肌肉病理和分子生物学特征。 方法 收集2011年1月至2016年3月郑州大学第五附属医院诊治的5例儿童中央轴空病的病历资料，对其临床、肌肉病理和分子生物学特征进行回顾性分析。 结果 1.临床特征：主要为出生时肌张力严重低下、非进展或缓慢进展的对称性四肢近端无力、高腭弓、脊柱侧弯、关节脱位等。2.肌肉病理特征：可见萎缩和肥大肌纤维，结缔组织增生，肌纤维中央异常结构不明显；还原型辅酶Ⅰ四氮唑还原酶、琥珀酸脱氢酶、细胞色素C氧化酶染色均可见典型中央轴空现象，部分肌纤维存在偏心轴空、多轴空和微小轴空；单磷酸腺苷脱氢酶染色可见酶活性不均匀、轴空边缘深染；苏丹黑B、高碘酸－Schiff反应染色显示中央轴空区域脂质和糖原减少；三磷酸腺苷酶学染色显示轴空主要位于Ⅰ型肌纤维，Ⅰ型肌纤维占绝对优势。3.分子生物学特征：RYR1基因外显子100～102发生突变，依次为c.14566C>T、c.14582G>A、c.14387A>G、c.14677C>T和c.14693T>C，3例患儿的父亲或母亲有同样的突变。 结论 儿童中央轴空病临床表现复杂，肌肉病理是诊断的金标准，RYR1基因突变主要集中于C端外显子100～102，认识这些特征有助于早期诊治、减少误诊。

Idiopathic inflammatory myopathies (IIMs) are autoimmune disorders significantly impacting skeletal muscles; however, the precise correlation between muscle magnetic resonance imaging (MRI) findings, muscle pathology, disease subtypes and clinical characteristics remains uncertain. Thus, we investigated the association of muscle MRI findings in IIMs with muscle pathology and clinical features. New-onset IIM patients underwent proximal upper and/or lower limb muscle MRI. Patterns of muscle oedema on MRI were categorised into fascial, honeycomb, peripheral, foggy, dense, or coarse dot patterns and compared with inflammatory cell infiltration sites in corresponding muscle biopsies. The incidence of MRI patterns was examined in patient subgroups using myositis-specific antibodies (MSAs) and 2017 EULAR/ACR classification criteria. Univariate and multivariate analyses were conducted to determine the odds ratios (ORs) of MRI findings for clinical characteristics. Fifty-six of 85 patients underwent muscle biopsy. Foggy, honeycomb and fascial patterns at biopsy sites correlated with inflammatory cell infiltration in the endomysium (OR 11.9, P = 0.005), perimysium (OR 6.0, P = 0.014) and fascia (OR 16.9, P < 0.001), respectively. Honeycomb and foggy patterns were characteristic of patients with anti-TIF1γ or anti-Mi2 antibodies and MSA-negative dermatomyositis, and those with anti-SRP or anti-HMGCR antibodies and MSA-negative polymyositis (PM), respectively. The honeycomb pattern positively correlated with malignancy (OR 6.87, P < 0.001) and Gottron sign (OR 8.05, P = 0.002); the foggy pattern correlated with muscle weakness (OR 11.24, P = 0.005). The dense dot pattern was associated with dysphagia (OR 6.27, P = 0.006) and malignancy (OR 8.49, P = 0.002). Muscle MRI holds promise in predicting muscle pathology, disease subtypes and clinical manifestations of IIMs.

A Comprehensive Stratification Integrated the Clinical, Pathological, and Molecular Biological Features to Distinguish High-Risk Mantle Cell Lymphoma

目的 探讨30岁以下青年乳腺癌的临床病理学特征及分子生物学特点.方法 回顾性分析105例30岁以下青年女性单侧原发性乳腺癌患者的临床和病理资料,并与157例同期随机选取的中老年乳腺癌患者作对照,分析其病理类型、临床分期、腋淋巴结状况、雌激素受体(ER)、孕激素受体(PR)、C-erbB2及血管内皮生长因子(VEGF)蛋白表达状况.结果 青年乳腺癌误诊率为45.71%;以浸润性导管癌为主,但浸润性小叶癌占27.9%,明显高于对照组(P=0.039);腋淋巴结转移率、C-erbB2和VEGF蛋白表达水平均高于对照组,ER、PR水平低于对照组(P＜0.05);两组临床分期无统计学差异(P＞0.05).结论 30岁以下青年乳腺癌具有独特的病理学特征和分子生物学特点,且误诊率高,进展快,转移早,提示预后差;患者年龄不是影响乳腺癌预后的独立指标;早期诊断是提高青年乳腺癌患者生存率的唯一有效手段。

Muscle pathology and clinical features of the sarcolemmopathies

To evaluate and compare the clinical and pathologic characteristics and outcomes after hepatic resection of large hepatocellular carcinoma (SLHCC), small HCC (SHCC), and nodular HCC (NHCC). Traditional viewpoint insists that the classification and prognosis of HCC are determined by the size of HCC. As a result, large HCC is often considered as advanced and unresectable. However, we have observed a unique type of HCC-SLHCC, which is large in size but exhibits good clinical, pathologic, and molecular biologic characteristics as well as prognosis. From January 1992 to December 2002, a total of 481 consecutive patients were diagnosed with HCC and received hepatic resection. In this series of patients, the clinical and pathologic data, surgical outcome, and long-term survival of patients with SLHCC (group A, n = 260) were analyzed retrospectively and compared with patients who had SHCC (group B, n = 135) or NHCC (group C, n = 86). Postresection prognostic factors of HCC were also evaluated by univariate and multivariate analysis using Cox's proportional hazards model. The clinical and pathologic characteristics of SLHCC and SHCC were similar except for tumor necrosis and tumor size. Patients of SLHCC had significantly longer operative time, higher intraoperative blood loss, higher intraoperative blood transfusion, and higher postoperative morbidity than SHCC. However, the 2 groups were similar in duration of hospital stay and overall morbidity. Overall survival and disease-free survival in group A and group B were similar and significantly better than those in group C. Multivariate analysis revealed that large amount of intraoperative blood transfusion and vein invasion were independently significant factors for overall survival of patients with HCC. The clinical and pathologic characteristics and the outcome after hepatic resection of SLHCC are similar to that of SHCC, but significantly better than NHCC. We propose SLHCC as a specific subtype of HCC and hepatic resection as its choice of standard treatment.

Pompe disease is a hereditary neuromuscular disorder attributed to acid α-glucosidase deficiency, and accurately identifying this disease is essential. Our aim was to discriminate normal muscles from neuropathic muscles in children affected by Pompe disease using a texture-feature parametric imaging method that simultaneously considers microstructure and macrostructure. The study included 22 children aged 0.02–54 months with Pompe disease and six healthy children aged 2–12 months with normal muscles. For each subject, transverse ultrasound images of the bilateral rectus femoris and sartorius muscles were obtained. Gray-level co-occurrence matrix-based Haralick’s features were used for constructing parametric images and identifying neuropathic muscles: autocorrelation (AUT), contrast, energy (ENE), entropy (ENT), maximum probability (MAXP), variance (VAR), and cluster prominence (CPR). Stepwise regression was used in feature selection. The Fisher linear discriminant analysis was used for combination of the selected features to distinguish between normal and pathological muscles. The VAR and CPR were the optimal feature set for classifying normal and pathological rectus femoris muscles, whereas the ENE, VAR, and CPR were the optimal feature set for distinguishing between normal and pathological sartorius muscles. The two feature sets were combined to discriminate between children with and without neuropathic muscles affected by Pompe disease, achieving an accuracy of 94.6%, a specificity of 100%, a sensitivity of 93.2%, and an area under the receiver operating characteristic curve of 0.98 ± 0.02. The CPR for the rectus femoris muscles and the AUT, ENT, MAXP, and VAR for the sartorius muscles exhibited statistically significant differences in distinguishing between the infantile-onset Pompe disease and late-onset Pompe disease groups (p < 0.05). Texture-feature parametric imaging can be used to quantify and map tissue structures in skeletal muscles and distinguish between pathological and normal muscles in children or newborns.

Pompe disease (PD) is a metabolic myopathy due to acid alpha-glucosidase deficiency and characterized by extensive glycogen storage and impaired autophagy. We previously showed that modulation of autophagy and lysosomal exocytosis by overexpression of the transcription factor EB (TFEB) gene was effective in improving muscle pathology in PD mice injected intramuscularly with an AAV-TFEB vector. Here we have evaluated the effects of TFEB systemic delivery on muscle pathology and on functional performance, a primary measure of efficacy in a disorder like PD. We treated 1-month-old PD mice with an AAV2.9-MCK-TFEB vector. An animal cohort was analyzed at 3 months for muscle and heart pathology. A second cohort was followed at different timepoints for functional analysis. In muscles from TFEB-treated mice we observed reduced PAS staining and improved ultrastructure, with reduced number and increased translucency of lysosomes, while total glycogen content remained unchanged. We also observed statistically significant improvements in rotarod performance in treated animals compared to AAV2.9-MCK-eGFP-treated mice at 5 and 8 months. Cardiac echography showed significant reduction in left-ventricular diameters. These results show that TFEB overexpression and modulation of autophagy result in improvements of muscle pathology and of functional performance in the PD murine model, with delayed disease progression.

BackgroundAssociations between muscle pathology and clinical features in inflammatory myositis(IM) are not well definedObjectivesto describe the pathological findings in REMICAM1 muscle biopsies, and analyse their associations with clinical featuresMethodsAll patients...

Amyotrophic lateral sclerosis (ALS) is a fatal adult‐onset disease primarily characterized by upper and lower motor neuron degeneration, muscle wasting and paralysis. It is increasingly accepted that the pathological process leading to ALS is the result of multiple disease mechanisms that operate within motor neurons and other cell types both inside and outside the central nervous system. The implication of skeletal muscle has been the subject of a number of studies conducted on patients and related animal models. In this review, we describe the features of ALS muscle pathology and discuss on the contribution of muscle to the pathological process. We also give an overview of the therapeutic strategies proposed to alleviate muscle pathology or to deliver curative agents to motor neurons. ALS muscle mainly suffers from oxidative stress, mitochondrial dysfunction and bioenergetic disturbances. However, the way by which the disease affects different types of myofibers depends on their contractile and metabolic features. Although the implication of muscle in nourishing the degenerative process is still debated, there is compelling evidence suggesting that it may play a critical role. Detailed understanding of the muscle pathology in ALS could, therefore, lead to the identification of new therapeutic targets.

Do immune cells promote the pathology of dystrophin-deficient myopathies?

BackgroundClinical and molecular features have been used to predict how RA patients will respond to distinct treatments. Clinical datasets are more readily available, more easily analyzed, and less costly to...

Needle electromyography, muscle MRI, and muscle pathology: Correlations in idiopathic inflammatory myopathies