Daigo Miyazaki

Matrix metalloproteinase-2 ablation in dystrophin-deficient mdx muscles reduces angiogenesis resulting in impaired growth of regenerated muscle fibers

Matrix metalloproteases (MMPs) are a family of endopeptidases classified into subgroups based on substrate preference in normal physiological processes such as embryonic development and tissue remodeling, as well as in various disease processes via degradation of extracellular matrix components. Among the MMPs, MMP-9 and MMP-2 have been reported to be up-regulated in skeletal muscles in the lethal X-linked muscle disorder Duchenne muscular dystrophy (DMD), which is caused by loss of dystrophin. A recent study showed that deletion of the MMP9 gene in mdx, a mouse model for DMD, improved skeletal muscle pathology and function; however, the role of MMP-2 in the dystrophin-deficient muscle is not well known. In this study, we aimed at verifying the role of MMP-2 in the dystrophin-deficient muscle by using mdx mice with genetic ablation of MMP-2 (mdx/MMP-2(-/-)). We found impairment of regenerated muscle fiber growth with reduction of angiogenesis in mdx/MMP-2(-/-) mice at 3 months of age. Expression of vascular endothelial growth factor-A (VEGF-A), an important angiogenesis-related factor, decreased in mdx/MMP-2(-/-) mice at 3 months of age. MMP-2 had not a critical role in the degradation of dystrophin-glycoprotein complex (DGC) components such as β-dystroglycan and β-sarcoglycan in the regeneration process of the dystrophic muscle. Accordingly, MMP-2 may be essential for growth of regenerated muscle fibers through VEGF-associated angiogenesis in the dystrophin-deficient skeletal muscle.

AH amyloidosis associated with an immunoglobulin heavy chain variable region (VH1) fragment: a case report

We report a 67-year-old male patient who suffered from nephrotic syndrome and progressive renal dysfunction with monoclonal gammopathy (IgMκ). Renal biopsy demonstrated amyloid deposition in glomeruli. Immunohistochemical studies of the renal amyloid using a number of antibodies, including anti-λ and anti-κ light chains, AA, β2-microglobulin, and transthyretin, showed negative findings. Biochemical analysis of the deposited amyloid fibrils in gastroduodenal mucosa revealed that the amyloid fibrils were composed of an immunoglobulin heavy chain variable region (VH) fragment belonging to the VH1 subgroup, and a diagnosis of AH amyloidosis was made. In our institute, three patients with AH amyloidosis including the present one have been identified during the past 2 years, so AH amyloidosis seems to be by no means a rare disorder.

Comparison of the phenotypes of patients harboring in-frame deletions starting at exon 45 in the Duchenne muscular dystrophy gene indicates potential for the development of exon skipping therapy.

Exon skipping therapy has recently received attention for its ability to convert the phenotype of lethal Duchenne muscular dystrophy (DMD) to a more benign form, Becker muscular dystrophy (BMD), by correcting the open reading frame. This therapy has mainly focused on a hot-spot (exons 45–55) mutation in the DMD gene. Exon skipping of an entire stretch of exons 45–55 is an approach applicable to 46.9% of DMD patients. However, the resulting phenotype is not yet fully understood. Here we examined the clinical profiles of 24 patients with BMD resulting from deletions starting at exon 45. The Δ45–55 group ranged in age from 2 to 87 years; no mortality was observed, and one patient was ambulatory at 79 years of age. The age at which patients became wheelchair-bound in the Δ45–48 group (18–88 years old) was approximately 50 years. Cardiomyopathy was well controlled by pharmaceuticals in both deletion groups. In contrast, the Δ45–47 and Δ45–49 groups exhibited more severe phenotypes than those with other mutations: the age at which patients in the Δ45–49 group became wheelchair-bound was around 30–40 years. Our study shows that clinical severity differs between each hot-spot deletion.

Characterization of deletion breakpoints in patients with dystrophinopathy carrying a deletion of exons 45-55 of the Duchenne muscular dystrophy (DMD) gene.

Deletion of exons 45–55 (del45–55) in the Duchenne muscular dystrophy gene (DMD) has gained particular interest in the field of molecular therapy, because it causes a milder phenotype than DMD, and therefore, may represent a good candidate for the goal of a multiple exon-skipping strategy. We have precisely characterized deletion breakpoints in three patients with del45–55 in DMD. Two of them were young adult males of the X-linked dilated cardiomyopathy phenotype, and the third patient revealed the mild Becker muscular dystrophy phenotype of late onset. The deletion breakpoints differed among patients. The deletion started at nt 226 604, 231 518, 117 284 in intron 44, and ended at nt 64 994, 59 314, 71 806 in intron 55, respectively. Deletion junctions showed no significant homology between the sequences adjacent to the distal and proximal end joints in these patients. Deletion breakpoints were not primarily associated with any particular sequence element, or with a matrix attachment region. However, there were several palindromic sequences and short tandem repeats at or near the breakpoints. These sequences, with a marked propensity to form secondary DNA structure intermediates, may predispose local DNA to breakage and intragenic recombination in these patients.

Elevation of serum heat-shock protein levels in amyotrophic lateral sclerosis

Heat-shock proteins (HSPs) have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). In this study, we aimed to examine whether the serum levels of HSPs (HSP27, HSP70, and HSP90) are altered in patients with ALS. We included 58 patients diagnosed with ALS and 85 control individuals. Serum HSP levels of patients and controls were determined using enzyme-linked immunosorbent assay. The serum levels of HSP70 and HSP90 were significantly higher in patients than in controls. In contrast, serum levels of HSP27 did not differ significantly between the patient and control groups. Moreover, serum levels of HSP70 and HSP90 in patients remained high throughout the duration of the disease. Taken together, our findings suggest that HSPs might have a role in ALS progression throughout the course of the disease. Further studies are needed to clarify the role of HSPs in the pathogenesis of ALS.

Differential roles of MMP-9 in early and late stages of dystrophic muscles in a mouse model of Duchenne muscular dystrophy

Matrix metalloprotease (MMP)-9 is an endopeptidase associated with the pathogenesis of Duchenne muscular dystrophy (DMD). The precise function of MMP-9 in DMD has not been elucidated to date. We investigated the effect of genetic ablation of MMP-9 in the mdx mouse model (mdx/Mmp9(-/-)). At the early disease stage, the muscles of mdx/Mmp9(-/-) mice showed reduced necrosis and neutrophil invasion, accompanied by down-regulation of chemokine MIP-2. In addition, muscle regeneration was enhanced, which coincided with increased macrophage infiltration and upregulation of MCP-1, and resulted in increased muscle strength. The mdx/Mmp9(-/-) mice also displayed accelerated upregulation of osteopontin expression in skeletal muscle at the acute onset phase of dystrophy. However, at a later disease stage, the mice exhibited muscle growth impairment through altered expression of myogenic factors, and increased fibroadipose tissue. These results showed that MMP-9 might have multiple functions during disease progression. Therapy targeting MMP-9 may improve muscle pathology and function at the early disease stage, but continuous inhibition of this protein may result in the accumulation of fibroadipose tissues and reduced muscle strength at the late disease stage.

Giant cauda equina schwannoma

Schwannoma is a benign tumor that often grows from the spinal root. A 42-year-old woman first experienced lumbar pain and left-side ischiadic neuralgia at the age of 40 years. Her symptoms progressed gradually; she developed dysesthesia of the left leg and urinary incontinence 6 months before admission. Thereafter, she had gait disturbance, lumbago and pain in both legs. On admission, she had flaccid paraplegia and sensory loss below Th10. Magnetic resonance imaging showed a large tumor occupying the whole lumbar and upper sacral canal associated with thoracolumbar cord syrinx (Fig. 1a,b). The tumor was lobularly enhanced (Fig. 1c,d). A restricted biopsy of the tumor led to the diagnosis of schwannoma (Fig. 1e,f). Because schwannoma grows along with the nerve root from the intradural space to outside of the spinal canal, it sometimes presents as a dumbbell-like appearance. The tumor also grows

Slowly progressing lower motor neuron disease caused by a novel duplication mutation in exon 1 of the SOD1 gene

Familial amyotrophic lateral sclerosis accounts for about 5% of all cases of the neurodegenerative disorder amyotrophic lateral sclerosis. Genetic mutations in Cu/Zn superoxide dismutase (SOD1) have been associated with one kind of familial amyotrophic lateral sclerosis (ALS1). We identified a novel duplication mutation in exon 1 of the SOD1 gene in a Japanese family whose members had lower motor neuron diseases. The patients showed slow disease progression, with the onset of lower limb muscle weakness and exertional dyspnea. Some patients had mild motor and sensory neuropathy and/or bladder dysfunction, which is further evidence that SOD1 mutation results in a predominantly lower motor neuron phenotype.

Hypertrophic Pachymeningitis as an Early Manifestation of Relapsing Polychondritis: Case Report and Review of the Literature.

Neurological involvement in relapsing polychondritis (RP) is relatively rare. We describe the case of an 80-year-old man who presented with hypertrophic pachymeningitis (HP) together with arthritis as the first manifestation of RP. Auricular chondritis, which subsequently determined the diagnosis of RP, occurred a few weeks after the detection of HP. The neurological symptoms, as well as arthritis, were promptly improved by treatment with corticosteroids. It is generally difficult to diagnose RP in the absence of typical cartilaginous involvement; however, the present case suggests that HP may occur as an early clinical manifestation of RP.

Crossed Cerebellar Diaschisis in Status Epilepticus.

Crossed cerebellar diaschisis (CCD) is an interesting phenomenon which classically refers to the depressed blood flow and metabolism affecting one cerebellar hemisphere after a contralateral hemispheric infarction. However, CCD can also be caused by a prolonged seizure. We herein report a case of CCD due to status epilepticus in a patient who showed unique magnetic resonance imaging findings.