Objective To report the spectrum of electron transfer flavoprotein dehydrogenase (ETFDH)gene mutations in 20 Chinese RR-LsM families.Methods Twenty-four RR-LSM patients in the First Hospital of Peking University from January 2003 to May 2010 were collected and the clinical characteristics were analyzed.These patients came from 20 families in North Mainland China.Sixteen families had 1 patient each.and the other 4 families had 2 patients.ETFDH gene analysis was performed in all patients,11 family members and 100 healthy controls.Results The mean onset age was(27.9±9.9)years.The main symptoms were limb weakness(21,87.5%),dysmasesia(15,62.5%),neck weakness (14,58.3%)and myalgia(14,58.3%).Eighteen patients had high level of acyleamitine.Fifteen of 17patients had glutaric aciduria.Seventeen ETFDH mutations,including 13 missense mutations,2 splice mutations,and 2 nonsense mutations,were identified in 19 families:c.998A>G,c.1450T>C,c.1703T>C,c.1717C>T,c.821G>A,c.643G>A,c.251C>T,c.1763A>T,c.IVS7+2T>C and c.IVS6+1G>A were Hovel mutations which were not found in 100 healthy controls.Nine families had the mutation of c.770A>G(P.Y257C)and 5 families had the mutation of c.1227A>C(P.L409F).Conclusions The numerous novel mutations in ETFDH gene indicate that Chinese RR-LSM might have special mutation pattern.c.770A>G(P.Y257C)and c.1227A>C(p.L409F)may be hot spot mutations in North Mainland China.

ObjectiveTo investigate the characteristic of pathology in Chinese patients with Nonaka myopathy.MethodsThirteen patients (7 males and 6 females) diagnosed with Nonaka myopathy in our laboratory from January 2002 to March 2011 were included in this study.Their mean age was 39.5 years old and the mean duration of illness was 4.15 years.The most common symptoms were weakness of raising feet with sparing of quadriceps femoris muscles in the early stage of disease.One patient presented the initial symptoms of upper limb weakness. Muscles biopsies were obtained from all these 13 patients. Histology study including immunohistochemical (IHC) staining with antibody against amyloid 3,phosphorylated tau protein,ubiquitin,glucose-regulated protein of molecular weight 78 000(GRP78),calnexin,caspase-12and Bax were performed.Skeletal muscle samples from 3 chronic fatigue syndrome patients,2 myofibrillar myopathy patients were used for control in the IHC staining. All coding exons of uridinediphospho-N-acetylglucosamine 2-epimerase gene were directly sequenced in genomic DNA from these patients.Results The main pathological changes of tibialis anterior muscle in 12 cases were muscle dystrophy with rimmed vacuoles.The rimmed vacuoles were positive for anti-β-amyloid,tau protein and ubiquitin in IHC studies.In the atrophy fibers,IHC showed the increased expression of endoplasmic reticulum stress related proteins GRP78 and calnexin,and apoptosis proteins of caspase-12 and Bax.ConclusionsThere is accumulation of abnormal proteins in muscle fibers in Chinese patients with Nonaka myopahty.These proteins may stimulate endoplasmic reticulum stress and apoptosis,which may be a mechanism responsible for muscle damage.

Objective To report clinical and pathological features in a Chinese family with CharcotMarie-Tooth disease type 2A2 (CMT2A2). Methods There were 5 patients (2 male and 3 female) in a family with an autosomal dominant inheritance pattern. The index case was a 36 years old woman. She developed progressive distal limb weakness at the age of 6, with pescavus at the age of 8. Other 4 family members presented with similar symptoms between the age of 3-7. Physical examination showed distal limb weakness and wasting, loss of sensory and contracture in all of them. Nerve conduction velocity revealed non-potential in several motor and sensory nerves in the proband and her son. Sural nerve biopsy was performed on the proband. The sequence of MFN2 gene was analyzed in DNA from 5 patients and 3 asymptomatic members. Results Sural nerve biopsy revealed severe loss of myelinated fibers with few regenerating clusters. Electron microscopy revealed aggregation of mitochondrian in the axons. A R94W mutation in MFN2 gene has been identified in 5 patients, but not in unaffected members. Conclusions We confirmed Chinese CMT2A2. Absent of regenerating cluster in the nerve indicated that MFN2 mutation predominantly resulted in lesions in the neurons.

Objective To report filaminopathy with novel insertion mutation in a Chinese family.Methods Total 19 patients from successive 5 generations involved in an autosomal dominant family. The detailed clinical manifestations had been described (Chinese Journal of Neurology, 2008, 41:751-755).The filamin C gene sequencing was performed in 3 patients, 5 family members without symptoms and 50 normal persons. The amplified fragments of the exon 18 in filamin C gene were cloned into pBluesripts vectors, then sequenced and identified with capillary electrophoresis. Results 18-nucleotide deletion and 6-nucleotide insertion were identified in the exon 18 of filamin C gene. The mutation caused the disturbance of the seventh immunoglobulin-like domain in filamin C, leading to the instability of dimmers of filamin C.Another 2 patients in the family had same mutation while 5 family members without symptoms and 50 normal controls were normal. Conclusion The novel nucleotide deletion-insertion in exon 18 of filamin C gene causes filaminopathy. This disease can appear in non-Nordic race.

ObjectiveTo report clinical, pathological and molecular genetic features in a Chinese family with hereditary motor and sensory neuropathy type 6. MethodsThe index case is a 15 years old boy.He developed progressive distal limb weakness at the age of 5.The disease deteriorated slowly,accompanied with contracture of achilles' tendon. At the age of 11 years old he suffered from decrease of visual acuity. At the age of 12, he found the muscular atrophy of both hands without sensory disturbances.Visual evoked potential revealed prolonged latency of bilateral P100. Ophthalmological examination showed bilateral optic atrophy. His mother had the similar symptoms at the age of 7 and reduced visual acuity at the age of 10. Nerve conduction velocity revealed in both pat1ents no compound motor and sensory nerve action potentials in most nerves or slightly reduced nerve conduction velocities with severely reduced amplitudes of the compound motor and sensory nerve action potentials. Sural nerve biopsy was performed on the proband.The sequence of MFN2 gene was analyzed in DNA from the index, his mother and 100 healthy controls.ResultsSural nerve biopsy revealed severe loss of myelinated fibers with few regenerating clusters.Ultrapathological examination showed a few of atypical bulbs of myelinated fibers, occasionally regenerating clusters, mitochondrial swelling and aggregation in a few of axons. A new mutation of W740R mutation in MFN2 gene has been identified in the index case, her mother, but not in 50 healthy controls. Conclusions A novel MFN2 gene mutation result in hereditary motor and sensory neuropathy type 6.Mild visual loss appeares after the lesion of spinal nerves. Demyelination of peripheral nerve appears in the disease.

Objective To investigate the clinical features,etiology and risk factors of the inpatients with ischemic stroke in the Department of Cardiology.Methods The medical records of the inpatients with ischemic stroke and the inpatients in a control group were collected retrospectively.The demographics,vascular risk factors,clinical features,and other related factors were compared in both groups.Multivariate logistic regression analysis was used to analyze the independent risk factors for in-hospital ischemic stroke in the Department of Cardiology.Results A total of 2 789 inpatients in departments of cardiology were enrolled,and 26 of them (0.93％) had in-hospital stroke.One hundred thirty inpatients from 2 763 patients without in-hospital stroke were used randomly as control cases.The proportions of the inpatients of hypertension (73.08％ vs.50.77％ ; x2=4.348,P=0.037),atrial fibrillation (50.00％ vs.15.38％; x2=15.56,P=0.000),infection (30.77％ vs.7.69％ ; x2 =11.304,P =0.003),smoking (46.15％ vs.21.54％ ; x2 =6.886,P =0.009),alcohol (26.92％ vs.11.54％ ;x2 ＝ 4.233,P =0.040),previous stroke history (19.23％ vs.4.61％ ;x2 =7.062,P =0.008),and taking anti-hypertensive drugs (42.31％ vs.21.54％ ;x2 =4.985,P =0.026),as well as systolic blood pressure (143.43 ± 18.59 mm Hgvs.129.52 ± 23.52 mm Hg; t =3.209,P=0.003; 1 mmHg =0.133 kPa),diastolic blood pressure (88.77± 11.35 mm Hg vs.77.55± 14.60 mmHg; t=2.421,P =0.020),and homocysteine levels (19.27 ± 11.08 μnol/L vs.15.30 ±5.25 μmol/L; t =2.814,P =0.006) in the stroke group were significantly higher than those in the control group in the Department of Cardiology.Multivariate logistic regression analysis showed that atrial fibrillation (odds ratio [OR] 3.310,95％ confidence interval [CI] 1.207-9.076; P =0.020),infection (OR 3.270,95％ CI 1.024-10.438; P =0.045),systolic blood pressure (OR 1.023,95％ Cl 1.002-1.045; P =0.031),and homocysteine level (OR 1.089,95％ CI 1.009-1.175; P =0.029) were the independent risk factors for in-hospital ischemic stroke in the Department of Cardiology.Conclusions Atrial fibrillation,infection,systolic blood pressure,and high homocysteine levels are the independent risk factor for in-hospital ischemic stroke in the Department of Cardiology.Active intervention and control these risk factors may have great significance for reducing its risk.

Objectives To report the clinical and myopathological features in a case with Danon disease caused by a novel mutation in the lysosome-associated membrane protein-2 ( LAMP2 ) B gene.Methods A 16-year-old boy presenting progressive muscle weakness and atrophy, accompanied with spinal ankylosis was clinically evaluated including electrocardiogram, echocardiogram and electromyogram.Muscle biopsy was carried out in the patient.The histological staining, ultrastructural examination, and immunohistochemical staining with antibodies against dystrophin, merosin and C5b9 were performed in frozen sections.LAMP2B sequence was analyzed in the patient and his parents.Results Electrocardiogram in the patient showed Ⅰ atrioventricular block; echocardiogram revealed focal hypertrophy in mitral valve with mild cardiac diastolic dysfunction; electromyogram indicated myogenic and neurogenic patterns.Muscle pathology study revealed numerous vacuoles located at the fibers.Dystrophin, merosin and C5b9 was immuno-positive around the vacuoles.Electron microscopy revealed vacuoles surrounded by sarcolemma and abnormal lysosome aggregating at the fibers.A novel nonsense mutation ( K402X ) in the LAMP2B gene has been identified in the patient but not in his mother and 50 normal controls.Conclusions Danon disease caused by K402X mutation in C-terminus of LAMP2B presented benign course of the disease characterized by prominent vacuolar skeletal myopathy, mild cardiac abnormalities and peripheral neuropathy.

ObjectiveWe report the clinical and pathological features of 8 Chinese myopathy patients with antibodies to the signal recognition particle(SRP).MethodsSerum myositis antibody profiles were tested with immunoblotting.Muscle biopsies were performed for histological,enzyme histochemical and immunohistochemical stainings.The first antibody in the immunohistochemical staining was mouse anti-human monoclonal antibodies including CD8,CD20,CD68,MHC- Ⅰ and CD31.ResultsEight cases showed stark positive of anti SRP antibody,3 of them with positive anti Ro-52 antibody.The muscle biopsies showed necrotic and regenerative muscle fibers associated with infiltration of macrophage,but scattered T lymphocytes in 2 patients.Two of them presented with fiber hypertrophy and proliferation of connective tissue.There were some fibers with positive MHC-Ⅰexpression.Capillaries were almost normal.Conclusion The muscle weakness of myopathy with antibodies to SRP presents as a chronic progressive course and could associate with lung involvement.Fiber necrosis and regeneration are the main myopathological features,which can mimic muscular dystrophy in some cases.

Objective To report the inflammatory myopathy with abundant macrophages presenting with abundant foam cells in a Chinese patient.Methods A 44 year-old man with rheumatoid arthritis manifested as progressive proximal muscle weakness in the upper limbs for 13 months and in the lower limbs for 11 months.Laboratory tests showed that serum creatine kinase level was increased,whereas neither the myositis antibody nor paraneoplasma antibodies were detectable,including anti-Jo-1 antibody.Electromyogram showed a classic myogenic pattern with irritable sarcomembrane excitement.Muscle biopsies were carried out in the left and right biceps brechii in 2 months and 13 months of the disease course respectively.The muscle sections were processed with standard histological,enzyme histochemistrical and immunohistochemical workup.Results The first muscle biopsy revealed CD8 positive T lymphocytes infiltrating into major histocompatibility complex (MHC)-Ⅰ positive fibers and distributing around endomysium,accompanied with scattered necrosis and regeneration.The second muscle biopsy showed perifascicular atrophy,fragmented perimysial connective tissue,and a large amount of CD68 positive foam cells and Touton cells accumulating within perimysial connective tissues and endomysium.Some CD20 positive B lymphocytes and plasmacytes were found around perivascular space,but CD8 positive T lymphocytes were only accumulated in the endomysium.MHC- Ⅰ was darkly expressed in the sarcolemma.Conclusions Inflammatory myopathy with abundant macrophages can present with foam cells infiltrating in perimysial and endomysium.The disease can be associated with rheumatoid arthritis and refractory to corticosteroid therapy.

Objectives To analyse the clinical and MRI features of cerebral autosomal dominant arteriopathy with subcortical infarct and leucoencephalopathy (CADASIL) in mainland China and compare these features with those reported in other countries.Methods All 26 CADASIL families were collected in First Hospital of Peking University from January 2003 to October 2009, and the diagnosis was confirmed by ultrastructural examination or Notch3 gene analysis.The age of onset, initial symptoms, main symptoms in 102 patients were described and the features with those reported in Germany, Japan, Arab and France were compared using x2 test.The cranial MRI changes in 35 patients were analysed and compared with the British and French patients.Results 102 patients had their initial symptoms between 22-80 years with the mean age of onset at (43.9 ± 11.0) years.There was no significant difference in the frequency of ischemic stroke or TIA (79.41% ) between our patients and the patients in other countries.Dementia rate (50.00% ) was significantly greater than that of Arab (21.05% ,x2 =5.513, P =0.020) and French patients(31.11%,x2 =4.517, P =0.034).The frequency of mood disturbances ( 14.71% ) was significantly lower than that of German patients (30.39% ,x2 =7.185, P =0.007).The frequency of migraine ( 13.73% ) was similar to that of France but lower than that of Japan (40%, x2 = 12.658, P = 0.000), Germany (38.24%, x2 =15.932, P=0.000) and Arab (42.11% ,x2 =6.869, P=0.009).Cranial MRIs were abnormal in all 35patients, but no lesion was seen in the medulla oblongata.Lacunar infarcts in the basal ganglia (82.86% )were significantly more frequent than that of French patients (60% , x2 = 5.663, P = 0.017).The frequency of leukoaraiosis in the cerebrum was similar to that of French patients.Anterior temporal involvement (68.57%) was significantly lower than of British patients ( 95%, x2 = 5.211, P = 0.022 ).Conclusion The clinical symptoms and MRI changes of CADASIL in different countries were not identical.Abnormal anterior temporal pole signal on MRI is not a sensitive marker for diagnosis of CADASIL in Chinese patients.