A case of polyarteritis nodosa associated with cytomegalovirus infection.

A 77-year-old man suffering from prolonged fever of unknown origin and bilateral leg edema was referred to our hospital. On physical examination, he had fever, general fatigue, bilateral lower leg edema, and muscle weakness of the right upper extremity and left lower extremity. Neurological examination indicated motor and sensory disturbance. Electromyography revealed mononeuritis multiplex and myopathy. A biopsy of the left biceps muscle indicated necrotizing vasculitis with fibrinoid necrosis. Considering all the data together, he was diagnosed as having polyarteritis nodosa (PAN) and concurrent active cytomegalovirus (CMV) infection. His symptoms improved promptly on treatment with 50 mg of prednisolone. This case emphasizes the importance of CMV infection as one of possible etiologies of PAN and reports a therapeutic strategy for this syndrome.

Multiple deletions in mitochondrial DNA in a patient with progressive external ophthalmoplegia, leukoencephalopathy and hypogonadism.

Progressive external ophthalmoplegia (PEO) is one of a number of major types of mitochondrial disorders. Most sporadic PEO patients have a heteroplasmic large deletion of mitochondrial DNA (mtDNA) in the mitochondria in skeletal muscles. We herein analyzed mtDNA deletions using sub-cloning and Sanger sequencing of PCR products in a 31-year-old Japanese man with multiple symptoms, including PEO, muscle weakness, hearing loss, leukoencephalopathy and hypogonadism. A large number of multiple deletions was detected, as well as four kinds of deletion breakpoints identified in different locations, including m.3347_12322, m.5818_13964, m.5829_13964 and m.5837_13503.

Prognostic impact of left ventricular noncompaction in patients with Duchenne/Becker muscular dystrophy--prospective multicenter cohort study.

BACKGROUND: The reported prevalence of left ventricular noncompaction (LVNC) varies widely and its prognostic impact remains controversial. We sought to clarify the prevalence and prognostic impact of LVNC in patients with Duchenne/Becker muscular dystrophy (DMD/BMD). METHODS: We evaluated the presence of LNVC in patients with DMD/BMD aged 4-64 years old at the study entry (from July 2007 to December 2008) and prospectively followed-up their subsequent courses (n=186). The study endpoint was all-cause death and the presence of LVNC was blinded until the end of the study (median follow-up: 46 months; interquartile range: 41-48 months). RESULTS: There were no significant differences in baseline characteristics between patients with LVNC (n=35) and control patients without LVNC (n=151), with the exception of LV function. Patients with LVNC showed, in comparison with patients without LVNC, a significant negative correlation between age and LVEF (R=-0.7 vs. R=-0.4) at baseline; and showed a significantly greater decrease in absolute LVEF (-8.6 ± 4.6 vs. -4.3 ± 4.5, p<0.001) during the follow-up. A worse prognosis was observed in patients with LVNC (13/35 died) than in patients without LVNC (22/151 died, Log-rank p<0.001). Multivariate Cox analysis revealed that LVNC is an independent prognostic factor (relative hazard 2.67 [95% CI: 1.19-5.96]). CONCLUSION: LVNC was prevalent in patients with DMD/BMD. The presence of LVNC is significantly associated with a rapid deterioration in LV function and higher mortality. Neurologists and cardiologists should pay more careful attention to the presence of LVNC.

Efficacy and tolerance of gastrostomy feeding in Japanese muscular dystrophy patients.

Although muscular dystrophy patients often have feeding difficulty and need long-term enteral nutrition, only a few reports have described gastrostomy feeding in these patients. This study was designed to evaluate the efficacy and tolerance of gastrostomy feeding in patients with muscular dystrophy. We performed a retrospective, multicenter study on 144 patients with muscular dystrophy who received gastrostomy feeding between 2007 and 2009 in 25 neuromuscular centers in Japan. There were 77 Duchenne muscular dystrophy (median age at gastrostomy placement 26 years, range 13-47 years), 40 myotonic dystrophy (median age 54.5 years, range 13-70 years), 11 Fukuyama congenital muscular dystrophy (median age 22 years, range 13-29 years), 5 limb girdle muscular dystrophy (median age 62 years, range 43-78 years), and 5 facioscapulohumeral muscular dystrophy (median age 52 years, range 28-67 years) patients. Many benefits including amelioration of malnutrition, swallowing difficulty and respiratory status were observed after the introduction of gastrostomy feeding. Especially in patients with Duchenne muscular dystrophy, mean body weight significantly increased after gastrostomy placement. Although most complications, which are commonly observed in other populations, were tolerable, respiratory failure and peritonitis were important concerns. These findings suggest that gastrostomy placement at an appropriate time is advisable in patients with muscular dystrophy.

N88S seipin mutant transgenic mice develop features of seipinopathy/BSCL2-related motor neuron disease via endoplasmic reticulum stress.

Heterozygosity for mutations (N88S and P90L) in the N-glycosylation site of seipin/BSCL2 is associated with the autosomal dominant motor neuron diseases, spastic paraplegia 17 and distal hereditary motor neuropathy type V, referred to as 'seipinopathies'. Previous in vitro studies have shown that seipinopathy-linked mutations result in accumulation of unfolded proteins in the endoplasmic reticulum (ER), leading to the unfolded protein response and cell death, suggesting that seipinopathies is closely associated with ER stress. To further understand the molecular pathogenesis of seipinopathies, we generated a transgenic (tg) mouse line expressing the human N88S seipin mutant with the murine Thy-1 promoter to permit analyses of in vivo phenotypic changes. The N88S seipin tg mice develop a progressive spastic motor deficit, reactive gliosis in the spinal cord and neurogenic muscular atrophy, recapitulating the symptomatic and pathological phenotype in patients of seipinopathy. We also found that expression of mutant seipin in mice upregulated the ER stress marker, immunoglobulin-heavy-chain-binding protein, protein disulfide isomerase and X-box binding protein 1, but was not linked to significant neuronal loss in affected tissue, thereby indicating that ER stress is sufficient, while neuronal death is not necessary, for the development of motor phenotypes of seipinopathies. Our findings in the mutant seipin tg mouse provide clues to understand the relationship with ER stress and neurodegeneration, and the seipin tg mouse is a valid tool for the development of novel therapeutic strategies against ER stress-related diseases.

Polymyositis associated with autoimmune hepatitis, primary biliary cirrhosis, and autoimmune thrombocytopenic purpura.

We describe a 40-year-old woman with polymyositis (PM) who developed autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and autoimmune thrombocytopenic purpura (AITP) concurrently. About 4 years earlier, she suffered from muscle weakness probably due to PM. When she visited our hospital, she had polyarthritis, myalgia, symmetrical proximal limb-muscle weakness, elevated muscle enzymes, and myogenic abnormalities on electromyogram. Pathological findings obtained by muscle biopsy showed histological findings consistent with PM. Her serum liver enzymes were also elevated. The histology obtained by liver biopsy revealed the mixture findings of chronic active hepatitis and biliary cirrhosis. As antibodies to mitochondria M2 and liver/kidney microsome type 1 (LKM-1) were present, we concluded her liver disease was due to an overlap of AIH and PBC. Furthermore, purpura on the legs with thrombocytopenia appeared in parallel with liver dysfunction. She was diagnosed as having AITP by clinical and laboratory findings. Her serum showed a speckled pattern in immunofluorescence antinuclear antibody testing, but the antigen specificities were distinct from those of the known myositis-related autoantigens. This is a first case report of PM accompanied by AIH, PBC, and AITP. It was notable that there was an overlap of disease-associated immunological findings and immunogenetic backgrounds. This case provides a possible insight into the mechanisms and interplay of autoimmune diseases.

MELAS with diffuse degeneration of the cerebral white matter: report of an autopsy case.

Up to now diffuse white matter demyelination of the cerebrum has been reported in only a few cases of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS). Here we document an autopsy case with this rare neuropathology. Most MELAS cases are diagnosed antemortem by A3243G transition of mitochondrial DNA. While cerebral damage including necrotic foci in the cerebral cortex are common findings in MELAS, prominent white matter involvement best characterizes this MELAS case. There were numerous necrotic foci, varying in size and chronological stage, in the cerebral white matter. In the areas of the white matter without necrotic foci, there was diffuse fibrillary gliosis with the loss of axons and oligodendrocytes. The gliosis was dominant in the deep white matter, sparing the U-fiber. The cerebral cortex showed diffuse cortical atrophy with few scattered necrotic foci. Distribution of the cerebral lesions does not coincide with the territory of blood supply. The vascular wall presented only slight to mild hyalinosis. We assumed a common pathogenesis to the cortical lesions and the white matter change. The pathogenesis of the present diffuse cerebral lesions may not be just secondary to circulatory disturbance but partly due to metabolic abnormality.

Clinical and histopathological features of myopathies in Japanese patients with anti-SRP autoantibodies.

To elucidate the clinical and histopathological features associated with autoantibodies to the signal recognition particle (SRP), we have studied 23 Japanese patients with this specificity among 3,500 patients with polymyositis/dermatomyositis and other connective tissue diseases. Anti-SRP antibodies were determined based on analysis of RNA and protein components by immunoprecipitation assays. The pathological analysis was performed by using special stainings including alkaline phosphatase, myosin ATPase, and modified Gomori trichrome stainings. Twenty-one (92%) of these 23 patients had myositis, 8 of whom (38%) required cytotoxic agents or intravenous immunoglobulin therapy in addition to corticosteroid therapy. Four patients (16%) had rheumatoid arthritis, two of whom had no features of myositis. Muscle biopsy specimens of 11 patients were examined histologically in detail. All 11 had muscle fiber necrosis and/or regeneration, but only one had infiltration of inflammatory cells. Six of the 11 (55%) patients showed type I fiber predominance by ATPase staining, while eight control myositis patients without anti-SRP antibodies did not. There was no correlation of other neurogenic features in histology with the presence of anti-SRP antibodies. These studies suggest that anti-SRP autoantibodies are most likely to be related to myopathies that are resistant to corticosteroid therapy and without inflammation histopathologically.

Dysphagia in patients with Duchenne muscular dystrophy evaluated with a questionnaire and videofluorography.

PURPOSE: To investigate swallowing problems in patients with Duchenne muscular dystrophy (DMD) using a questionnaire and videofluorography (VF). METHOD: A questionnaire survey was performed of swallowing-related symptoms and VF in 31 male patients with DMD (mean age 19.9 years, range 9 - 26 years). The relationships among age, frequency of symptoms and VF abnormalities were analysed using Spearman's rank correlation. The differences in VF abnormalities among different food textures were analysed with the Kruskal - Wallis test. RESULTS: Symptoms related to pharyngeal phase dysfunction were more frequent than those related to oral and oesophageal phases. Coughing while eating was seen in 71% of the patients, choking while eating in 32% and the need to clear the throat in 26%. VF abnormalities were observed in 30 patients (96.8%). Common VF abnormalities included pooling in the valleculae (90.3%) and in the pyriform sinus (90.3%). Pharyngo-oral regurgitation was seen in 35.5% of the patients. Pooling in the pyriform sinus after repeated swallowing seen in VF correlated significantly with symptoms related to the pharyngeal phase (Spearman's rho 0.356 - 0.544). CONCLUSION: Because oropharyngeal dysphagia in DMD was evident in teenage patients as well as those without clinical symptoms, VF is recommended in patients with DMD.

Inflammatory myopathy with anti-Golgi antibody and anti-SS-A/Ro antibody.

We report a 74-year-old woman with anit-Golgi antibody and anti-SS-A/Ro antibody who contracted inflammatory myopahy presenting 'ALS-like' symptoms. We identified anti-Golgi antibody directly using confocal microscopy and successfully treated her with steroid. This report suggests that there is a new categorized subgroup of inflammatory myopathy with these specific antibodies and the pattern of autoantibody in these patients indicates the specific clinical course and treatment strategy.

[Long-term prognosis of the patients of myotonic dystrophy with tube feeding].

We studied the long-term prognosis of the patients of myotonic dystrophy with tube feeding. Subjects were 51 patients (31 male patients and 20 female patients) of typical myotonic dystrophy who were at least once admitted in our hospital. We examined the age of the introduction of tube feeding, the cause of the introduction, respiratory and motor ability at the introduction, the duration of tube feeding, the cause of death and the extension of CTG repeats in the patients. Comparing with the patients with tube feeding and the patients without it, we also examined the prognosis after the introduction of tube feeding. Tube feeding was introduced in 13 cases. The mean age of tube feeding was 57.9 +/- 8.3 years old. The mean age of death of non tube feeding group was 55.9 +/- 5.5 years old. These show tube feeding was introduced in more elderly patients. Statstically the tube feeding was effective, but poor prognosis even after the introduction of tube feeding was suggested because the mean survival time after the introduction was about 850 days. We could not find any correlation between the age of the introduction of tube feeding and the extension of CAG report.

[Management of patients with Duchenne muscular dystrophy].

As there is no cure in Duchenne muscular dystrophy (DMD), we must pay attention to the management of its cardiopulmonary complications. In 1984, DMD patients died at the mean age of 18.2 years in my hospital. From autopsy findings, the cause of death was respiratory failure in 75% of them, and left-sided heart failure 12.5%. First, we had to know the relationship between cardiac and respiratory systems. Based on the findings of right-sided heart catheterization, patients with respiratory failure were classified into Forrester's subset 1' normal left ventricular function. These results showed that these patients require treatment with a respirator, but not with digitalis and/or diuretics. Since 1984, we tried cuirass ventilation, which prolonged their lives by about 3 years. Since 1991, NIPPV was introduced in Japan, and prolonged their lives by about 5.5 years. Nowadays TIPPV with tracheostomy is not the first choice of treatment, but we do not hesitate to select this treatment any more. As for left-sided heart failure, brain natriuretic peptide (BNP) is now considered a useful parameter of left ventricular function. Japanese clinical researcher proposed treatment based on values of BNP in left-sided heart failure. In 1980s, the mean interval from the onset of heart failure to death was only 16 months. Recently we feel that better results have already been accomplished. In 2002 Kawai reported that average age at death in Japan was 26.8 years old. More efforts must be made until cure of this disease is found.

FSHD-like patients without 4q35 deletion.

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by progressive weakness and wasting of facial, shoulder-girdle and upper arm muscles. Despite of the characteristic clinical features, the diagnosis of FSHD is sometimes difficult because clinical symptoms are extremely variable including facial sparing type, limb-girdle type, and distal myopathy type. Most of the FSHD patients have a deletion in the subtelomeric region of chromosome 4q35 (FSHMD1A), however the linkage analysis in some families suggested genetic heterogeneity. In the present study, we identified 40 patients without a deletion in the 4q35 region (non-4q35del) among 200 Japanese patients who were clinically suspected to have FHSD. All non-4q35del patients had shoulder-girdle weakness and 75% also had facial weakness. Eight patients showed clinical features that were indistinguishable from FSHD, but two of them had Becker muscular dystrophy. FSHD is clinically, and most likely genetically, as well, variable. Other forms of muscular dystrophy can also mimic FSHD.

[Cardiopulmonary failure in Duchenne muscular dystrophy--pathophysiology and management].

As there is no cure in patients with Duchenne muscular dystrophy (DMD) yet, we must pay attention to manage cardiopulmonary complications in DMD. They died at 18.2 years old in 1984 in my hospital. From autopsy findings, respiratory failure occupied 75%, and left-sided heart failure occupied 12.5%. First of all, we had to know the relationship between cardiac system and respiratory system. Right-sided heart catheterization revealed that respiratory failure patients were divided into Forrester's subset 1 (left ventricular function was within normal limits). So, it is unnecessary to give digitalis and/or diuretics for patients with respiratory failure. They only need respirator treatment. We tried cuirass ventilation since 1984. This respirator elongated their lives about 3 years. Since 1991 NIPPV was introduced in Japan, this treatment elongated their lives about 5.5 years. Nowadays TIPPV with tracheostomy is not first choice of treatment but we select this treatment not so unwillingly as before. As for left-sided heart failure, BNP (brain natriuretic peptide) is now considered useful parameter for left ventricular function. Japanese clinical researcher proposed treatment based on Values of BNP in left-sided heart failure. In 1980s, from the onset of heart failure until death was only 16 months, we feel that better results already accomplished. Kawai reported that average age at death in Japan was 26.8 years old in 2002. Our efforts must be done more and more until cure of this disease can be found.

Increased expression level of the splicing variant of SIP1 in motor neuron diseases.

Survival motor neuron (SMN) interacting protein 1 (SIP1) interacts with SMN protein and plays a crucial role in the biogenesis of spliceosomes. We have identified three novel splicing variants of the SIP1 (SIP1-beta, -gamma and -delta), in addition to the full-length SIP1-alpha. SIP1-alpha as found to be ubiquitously expressed at high levels in the various normal tissues examined. In contrast, SIP1-beta and -gamma were expressed at very low levels in these tissues. In muscle specimens from patients with spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), the expression of SIP1-alpha was dramatically decreased compared to that observed in the normal tissues. In addition, the expression of SIP1-beta was significantly increased in tissues derived from patients with either disease. These findings suggest that an aberrant alternative splicing event in SIP1 occurs tissues derived from patients with the motor neuron diseases, and contributes to the pathological process of SMA and ALS.