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.

Amyotrophic lateral sclerosis associated with IgG anti-GalNAc-GD1a antibodies.

A variety of immunological abnormalities have been reported in some patients with amyotrophic lateral sclerosis (ALS). It has been postulated that a disturbance of immunoregulation may play a role in the degeneration of motor neurons in ALS. We describe a 62-year-old man with a 9-month history of slowly progressive muscular weakness and atrophy of the upper and lower extremities and dysarthria. Neurological examinations revealed weakness and atrophy with fasciculation in the skeletal muscles including the face and tongue. In the limbs, distal muscles were affected predominantly. Electromyography showed chronic neurogenic changes with denervation potentials. Serum antibody testing demonstrated an increased titer of anti-N-acetylgalactosaminyl GD1a (GalNAc-GD1a) antibodies (IgGx160; normal, less than x40). The patient was treated with intravenous immunoglobulin (IVIg) therapy which was repeated two times at an interval of 2 months. However, the response to IVIg was negligible. To the authors' knowledge, this is the first report on ALS, in which the patient had anti-GalNAc-GD1a IgG antibody.

Familial amyotrophic lateral sclerosis with Gly93Ser mutation in Cu/Zn superoxide dismutase: a clinical and neuropathological study.

We describe a 39-year-old Japanese woman with familial amyotrophic lateral sclerosis (FALS) in whom we identified a missense mutation (Gly93-->Ser) in exon 4 of the Cu/Zn superoxidase dismutase-1 (SOD1) gene in which no pathological data have been available. The disease duration was 16 years, and she died of respiratory failure. The initial sign was weakness of the lower limbs. She had no clear upper motor neuron involvement. Respiratory muscle weakness had developed 1 year before her death. Neuropathological examinations showed simultaneous involvement of the pyramidal tract and lower motor neurons as well as degeneration in the Clarke's nucleus, the spinocerebellar tract, the posterior column, the dentatorubral system, and anterolateral columns of the spinal cord. However, the patient has no Lewy body-like hyaline inclusions (LBHIs), which are characteristic features of mutant SOD1-related FALS with posterior column involvement. Based on clinical, genetic and pathological findings with a review of the literature, we suggest that degeneration of the dentatorubral system and the absence of LBHIs in our case are pathological features in FALS with the Gly93Ser mutation.