Increased expression of valosin-containing protein in the skin of patients with amyotrophic lateral sclerosis.

Valosin-containing protein (VCP) may have a pivotal role in ubiquitin-dependent protein degradation and is implicated in the pathogenesis of neurodegenerative diseases. Skin studies from patients with amyotrophic lateral sclerosis (ALS) have shown unique abnormalities. We undertook a quantitative immunohistochemical study of VCP in the skin from patients with ALS and control participants. The proportion of VCP-positive (VCP+) cells in the epidermis in patients with ALS was significantly higher (p<0.001) than in controls. There was a significant positive relationship (r=0.59, p<0.01) between this proportion and duration of illness in patients with ALS. The optical density of VCP+ cells in the epidermis in patients with ALS was higher (p<0.001) than in controls. There was a significant positive relationship (r=0.61, p<0.01) between the immunoreactivity and duration of illness in patients with ALS. These data suggest that changes in VCP identified in skin from patients with ALS are likely to be related to the disease process.

Increased progranulin in the skin of amyotrophic lateral sclerosis: an immunohistochemical study.

It has been demonstrated that progranulin (PGRN) is a neurotrophic factor that enhances neuronal survival and axonal growth. Several lines of evidence have indicated that PGRN plays a role in the pathomechanism of amyotrophic lateral sclerosis (ALS). However, there has no study of PGRN in ALS skin. We made a quantitative immunohistochemical study of the expression of PGRN in the skin from 18 patients with sporadic ALS and 13 control subjects. Immunohistochemistry for PGRN demonstrated cytoplasmic activity in the epidermis and in some blood vessels and glands. Numerous PGRN-positive (PGRN+) cells were observed in the epidermis in ALS patients, which became more marked as ALS progressed. PGRN immunoreactivity of PGRN+cells was markedly positive in the epidermis in ALS patients. The proportion of PGRN+cells in the epidermis in ALS patients was significantly higher (p<0.001) than in controls. There was a significant positive relationship (r = 0.83, p<0.001) between the proportion and duration of illness in ALS patients. These data suggest that changes of PGRN in ALS skin are related to the disease process and that metabolic alteration of PGRN may take place in the skin of patients with ALS.

Familial amyotrophic lateral sclerosis with Cys111Tyr mutation in Cu/Zn superoxide dismutase showing widespread Lewy body-like hyaline inclusions.

We described a 43-year-old Japanese man with familial amyotrophic lateral sclerosis (FALS) in whom we identified a missense mutation (Cys111→Tyr) in exon 4 of the Cu/Zn superoxidase dismutase-1 (SOD1) gene in which no pathological data have been reported. The disease duration was 5 years, and he died of respiratory failure. The initial sign was weakness of the right leg. He had no clear upper motor involvement. Neuropathological examinations showed neuronal intracytoplasmic Lewy body-like hyaline inclusions (LBHIs) not only in the anterior horn cells of the spinal cord, but also in many other affected neurons. LBHIs were seen in the anterior horn cells, Onufrowicz nucleus, Clarke's nucleus, intermediolateral nucleus, and posterior gray horn of the spinal cord. In addition, LBHIs were observed in the periaqueductal gray matter, nucleus raphe dorsalis, locus ceruleus, trigeminal motor nucleus, vestibular nucleus, dorsal vagal nucleus, hypoglossal nucleus, and reticular formation of the brain stem. These are very specific findings that neuronal LBHIs in our case are for more widespread reported cases, and similar cases to ours have never reported in FALS.

Adult dermatomyositis with severe polyneuropathy: does neuromyositis exist?

Peripheral nerve involvement in dermatomyositis (DM) has been known as neuromyositis. However, the pathogenic mechanism is not clear, and the association between DM and peripheral neuropathy is still controversial. Our patient exhibited symptomatic polyneuropathy that was documented electrophysiologically in addition to typical features of DM. The sural nerve biopsy showed evidence of a continuing neuropathic process of axonal type. There was no finding of inflammatory cells infiltrating the vessels. Neither methylprednisolone nor intravenous immunoglobulin (IVIg) improved neurological symptoms including muscle weakness and sensory disturbance. Clinical, electrophysiological, and neuropathological features in our case demonstrate the association of DM and polyneuropathy. The possibility that the same pathological process affecting skin and skeletal muscles also affected peripheral nerves in our patient should be considered.

Immunohistochemical studies of vascular endothelial growth factor in skin of patients with amyotrophic lateral sclerosis.

Vascular endothelial growth factor (VEGF) is a disulfide-linked dimeric glycoprotein that enhances vascular permeability, induces chemotaxis and activation of monocytes/macrophages, and promotes growth of vascular endothelial cells. Furthermore, VEGF is a multifunctional cytokine, which influences neural cells directly, enhancing neuronal survival, axonal outgrowth, and Schwann cell proliferation. So far studies of the skin of amyotrophic lateral sclerosis (ALS) have shown unique pathological and biochemical abnormalities in collagen, elastic fibers, and the ground substance. However, the expression of VEGF in ALS skin has not previously been studied. We made a quantitative immunohistochemical study of the expression of VEGF in the skin from 15 patients with ALS and 15 control subjects. VEGF immunoreactivity was markedly positive in the epidermis and moderately positive in some dermal blood vessels and glands in ALS patients. These findings became more conspicuous as ALS progressed. The optical densities for VEGF immunoreactivity of the epidermis in ALS patients were significantly higher (p<0.001) than in control subjects. In addition, there was an appreciable positive correlation (r=0.85, p<0.001) in ALS patients between the densities for VEGF immunoreactivity and duration of illness, but there was no such correlation in control subjects. These data suggest that changes of VEGF in ALS skin are likely to be related to the disease process and that metabolic alterations of VEGF may take place in the skin of patients with ALS.