Clinical and electrodiagnostic findings in copper deficiency myeloneuropathy.

INTRODUCTION: Copper deficiency is an increasingly recognised cause of neurological impairment. This retrospective review highlights clinical and electrodiagnostic findings in patients diagnosed at our institution with copper deficiency. METHODS: Clinical, radiographic and electrodiagnostic findings were reviewed in patients with evidence of copper deficiency. Patients with other potential causes of myelopathy or neuropathy were excluded. RESULTS: The predominant clinical feature in all six patients was a sensory ataxia, resulting in marked gait unsteadiness. Nerve conduction studies and needle EMG were performed in all patients and revealed a mild to moderate distal, axonal, sensorimotor peripheral neuropathy. Median and tibial somatosensory evoked potentials were abnormal in all five patients in which it was performed, showing impaired conduction in central or proximal peripheral somatosensory pathways. CONCLUSIONS: This pattern of electrodiagnostic findings suggests that impairment in somatosensory pathways demonstrated by somatosensory evoked potential testing is the main cause of the sensory ataxia in patients with copper deficiency.

Proteolipid protein is necessary in peripheral as well as central myelin.

Alternative products of the proteolipid protein gene (PLP), proteolipid protein (PLP) and DM20, are major components of compact myelin in the central nervous system, but quantitatively minor constituents of Schwann cells. A family with a null allele of PLP has a less severe CNS phenotype than those with other types of PLP mutations. Moreover, individuals with PLP null mutations have a demyelinating peripheral neuropathy, not seen with other PLP mutations of humans or animals. Direct analysis of normal peripheral nerve demonstrates that PLP is localized to compact myelin. This and the clinical and pathologic observations of the PLP null phenotype indicate that PLP/DM20 is necessary for proper myelin function both in the central and peripheral nervous systems.

Peripheral neuropathy associated with monoclonal gammopathy. Studies of intraneural injections of monoclonal immunoglobulin sera.

A causal relationship between paraproteinemia and neuropathies has been suggested. We studied three patients with chronic sensorimotor polyneuropathy associated with plasma cell dyscrasia and monoclonal gammopathies (IgGK, IgMK, IgA lambda). Sural nerve biopsies showed mild (2 cases) to moderate loss of myelinated fibers (1 case). Teased single fiber studies showed segmental demyelination-remyelination in two patients. Direct immunofluorescence demonstrated immune deposits of the myelin sheath of the same specificity as the serum paraprotein, IgGK (1 of 3 cases). Treatment with prednisone, melphalan or chlorambucil, and plasmapheresis resulted in remission (1 case), partial improvement (1 case), or had no effect (1 case), although reduction of monoclonal immunoglobulin occurred in all. To investigate the role the paraproteins might play in the pathogenesis of the neuropathy, patients' serum was injected intraneurally into rat sciatic nerves. None of the animals developed weakness, slowing of in vitro conduction of sciatic nerve, or significant evidence of demyelination by light- or electron-microscopy or teased single fiber studies 48 hours postinjection. Similar injections of rabbit serum with experimental allergic neuritis (EAN) produced focal segmental demyelination. Our studies employing an in vivo bioassay technique failed to establish antimyelin activity of monoclonal immunoglobulin sera.

Late adult-onset metachromatic leukodystrophy. Dementia and polyneuropathy in a 63-year-old man.

A diagnosis of adult-onset metachromatic leukodystrophy (MLD) was established in a living 63-year-old man with progressive dementia and peripheral neuropathy. Decreased nerve conduction velocities and elevated spinal fluid protein concentration led to more specific diagnostic studies required to confirm the diagnosis. This case expands the spectrum of adult-onset MLD to patients with dementia and polyneuropathy past the sixth decade of life. Measurement of nerve conduction velocities may help to uncover cases of adult-onset MLD and should be included in the evaluation of dementia.

Chronic long-interval plasma exchange in myasthenia gravis.

Plasma exchange, when used in conjunction with azathioprine to treat chronic symptoms of myasthenia gravis, can usually be discontinued after a limited period of time without reappearance of symptoms. Patients who cannot be weaned from the procedure are often treated with more potent immunosuppressants to overcome exchange dependence. In view of the cumulative risks of more intensive daily immunosuppression, continuation of intermittent plasma exchange can be an acceptable alternative provided the interexchange interval (IEI) is relatively long. We describe two exchange-dependent patients in whom plasma exchange has been used for 4 1/2 and five years to control their symptoms. In both patients, who also received azathioprine, the IEI gradually lengthened to nine or 12 weeks over two to three years, without the introduction of new immunosuppressants. These cases illustrate that long-term plasma exchange is feasible and effective in selected exchange-dependent patients with myasthenia gravis.

Neurologic aspects of hereditary hemorrhagic telangiectasia. Report of two cases.

The several neurologic manifestations of hereditary hemorrhagic telangiectasia (HHT) may be caused by complications of pulmonary arteriovenous fistulae or associated central nervous system vascular malformations. The presence of skin and mucosal telangiectases should alert the clinician to the possibility of the disorder and in turn of its potential for associated neurologic disease, including cerebral hemorrhage and abscess. This report describes two cases and demonstrates that the clinical spectrum of HHT should be enlarged to include its admittedly rare, but serious, neurologic aspects.

Prediction of early beneficial response to plasma exchange in Guillain-Barré syndrome.

We attempted to identify predictive factors of early beneficial response to plasmapheresis in Guillain-Barré syndrome (GBS). We reviewed 24 patients with typical severe GBS who underwent plasmapheresis and analyzed their outcome at one month. One group of 14 patients, designated as responders, improved dramatically, while ten patients showed little response. Age was the only important clinical predictor, with responders being younger. No other clinical variable (sex, preceding illness, severity, timing of plasmapheresis, cranial nerve involvement, or cerebrospinal fluid findings) reached significance. Among electrophysiologic parameters obtained before plasmapheresis, the amplitudes of compound muscle action potentials with distal stimulation of median and peroneal nerves were significantly reduced in non-responders. Plasmapheresis may improve only a subgroup of patients with GBS. Among patient characteristics, age and amplitudes of compound muscle action potentials are important predictors of early responsiveness.

Peripheral neurofibromatosis and peroneal muscular atrophy.

We studied four patients with peripheral neurofibromatosis and a neuropathy that had the clinical characteristics of peroneal muscular atrophy. Nerve conduction velocities were slowed by less than 40% of normal, and electromyography demonstrated denervation. Sural nerve biopsies from two patients, which were macroscopically free of nerve sheath tumors, were studied by recording the compound action potentials in vitro and by morphometry. These studies demonstrated a chronic axonal neuropathy with reactive Schwann cell changes. Peroneal muscular atrophy in association with neurofibromatosis may be due to progressive neuronal degeneration and may represent another, uncommon manifestation of peripheral neurofibromatosis.

Disulfiram neuropathy: a neurofilamentous distal axonopathy.

Disulfiram is used to treat alcoholism and is known to cause peripheral neuropathy: few reports of biopsied human nerves have revealed axonal degeneration and loss of myelinated fibers. We studied a 22-year-old woman with severe sensorimotor neuropathy following treatment with disulfiram for 6 months. Histologic studies of the sural nerve revealed a neurofilamentous axonopathy with rare enlarged axons distended by neurofilaments. Disulfiram is converted enzymatically to carbon disulfide, which causes neurofilamentous distal axonopathy in animals. Similar changes in human nerve after disulfiram administration suggest that carbon disulfide is the toxic agent.

Myasthenia gravis and Schmidt syndrome.

A patient with myasthenia gravis developed both Addison disease and primary hypothyroidism, with demonstrable anti-adrenal and antithyroid antibodies in her serum. The association of myasthenia gravis with Schmidt syndrome does not seem to be a chance occurrence, considering the autoimmune pathogenesis of each of these disorders.

Ocular bobbing: the myth of its localizing value.

Ocular bobbing is a distinctive eye movement disorder seen in patients with pontine dysfunction. The typical phenomenon consists of abrupt, spontaneous downward jerks of the eyes with a slow return to the midposition in association with paralysis of spontaneous and reflex horizontal eye movements. Bobbing was present in a patient with acute cerebellar hemorrhage in whom no intrapontine lesions could be demonstrated. The myth that this sign is specific for intrapontine destruction has to be abandoned.

Effect of hematin in porphyric neuropathy.

Early, intravenous administration of hematin in a patient with acute intermittent porphyria and severe quadriparesis may have produced partial but remarkable improvement of neuropathy, and resulted in simultaneous decline of porphyrin precursors in the blood. Intermittent, biweekly hematin infusions given 1 month after the onset of the porphyric relapse had no effect on recovery of the residual neuropathy. We believe hematin may be effective in the treatment of porphyric neuropathy, if administered before irreversible neuronal damage has occured.

Duchenne muscular dystrophy: deficiency of dystrophin-associated proteins in the sarcolemma.

Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, is a major component of the subsarcolemmal cytoskeleton and exists in a large oligomeric complex tightly associated with several sarcolemmal glycoproteins which provide a linkage to the extracellular matrix protein, laminin. In the present study, we investigated the status of the dystrophin-associated proteins in the skeletal muscle from 17 DMD patients of various ages. The results revealed a dramatic reduction in all of the dystrophin-associated proteins in the sarcolemma of DMD muscle compared with normal muscle and muscle from a variety of other neuromuscular diseases. This abnormality was common in all 17 DMD patients, irrespective of age. Our results indicate that the absence of dystrophin leads to the loss in all of the dystrophin-associated proteins, which renders DMD muscle fibers susceptible to necrosis. The analysis of dystrophin-associated proteins is important in the assessment of experimental therapies that attempt to replace dystrophin in DMD muscle.

Immune brachial plexus neuropathy: suggestive evidence for an inflammatory-immune pathogenesis.

We report brachial plexus biopsy findings from two Australian and two American patients with brachial plexus neuropathy. There were florid multifocal mononuclear inflammatory cell infiltrates. Present evidence suggests that these brachial neuropathies have an immune basis.

Probable adult polyglucosan body disease.

Adult polyglucosan body disease is a clinicopathologic entity characterized by progressive upper and lower motor neuron dysfunction, sensory loss in the lower extremities, sphincter dysfunction, and occasionally dementia. Pathologically, numerous large polyglucosan bodies are noted in peripheral nerves, cerebral hemispheres, and the spinal cord, as well as in other systemic tissues. We present a case of probable adult polyglucosan body disease based on clinical history and examination, magnetic resonance images, and sural nerve biopsy findings.

First report of mosaic trisomy 12 in a liveborn individual.

Trisomy 12 mosaicism was found in a 36-year-old woman with minor anomalies, neuromuscular abnormalities, and moderate mental retardation. Trisomy 12 was present in 13% of the lymphocytes but not in skin fibroblasts. Previous reports of dup (12p) and dup(12q) are reviewed. To our knowledge this is the first report of a "complete" trisomy 12 in a liveborn individual.

Peripheral neuropathy caused by proteolipid protein gene mutations.

Pelizaeus-Merzbacher disease (PMD) is a dysmyelinating disorder of the central nervous system typically caused by duplications or missense mutations of the proteolipid protein (PLP) gene. Most investigators have found that peripheral nerve function and structure is normal in PMD patients. We have found that null mutations of the PLP gene cause demyelinating peripheral neuropathy, whereas duplications and a proline 14 to leucine mutation do not affect nerve function. A family with a nonsense mutation at position 144, which affects only PLP but not the alternatively spliced gene product DM20, has a very mild syndrome, including normal peripheral nerve function. Our findings suggest that DM20 alone is sufficient to maintain normal nerve function and that there may be domains of PLP/DM20 that have a relatively more active role in the peripheral nervous system compared with that in the central nervous system.

Purification of rat Schwann cells from cultures of peripheral nerve: an immunoselective method using surfaces coated with anti-immunoglobulin antibodies.

We report a method for deriving purified rat Schwann cells by immunoselective removal of fibroblasts. Contaminating fibroblasts labeled with antibody against specific surface marker Thy 1.1 are bound on plastic surfaces coated with a second antibody. The efficacy of the method is demonstrated by flow cytometry and by specific Schwann cell Ran-1 immunofluorescence.

Glia maturation factor promotes proliferation and morphologic expression of rat Schwann cells.

Glia maturation factor (GMF) is an acidic protein with a molecular weight of about 20,000 daltons, found in the adult brain of many species. Previously GMF was observed to stimulate the proliferation and subsequent maturation of rat astroblasts in culture. We investigated the effects of GMF on Schwann cells. Schwann cells were dissociated from rat sciatic nerve and purified by means of antimitotic agents and by selective immunoadsorption of contaminating fibroblasts. Cultured Schwann cells after 3 passages assumed a flat polygonal shape. Exposure of the cells to GMF converted the cells to the elongated, spindle morphology typical of Schwann cells. GMF also stimulated a 7-fold increase in DNA synthesis when compared with control cultures grown in F10 medium containing 5% fetal calf serum. The mitogenic activity of GMF was still detectable at 5 ng protein/ml medium. The maximal effect on DNA synthesis occurred 72 h after the initial exposure to GMF. Although the cells were positive for the Schwann cell marker Ran-1, GMF failed to induce the production of myelin-associated glycolipids (galactocerebroside) and proteins (Po) nor did it induce the astrocytic marker glial fibrillary acidic protein (GFAP). The effects of GMF on Schwann cells extend its biological role beyond the central nervous system.

Endogenous immunoreactive glia maturation factor-like molecule in cultured rat Schwann cells.

Using the monoclonal antibody G2-09 raised against bovine glia maturation factor (GMF), we demonstrated that cultured rat Schwann cells and Schwannoma cells, but not their conditioned media, possessed endogenous GMF-like immunoreactivity. The presence of immunoreactive GMF correlated well with GMF bioactivity. The GMF-like factor in Schwann cells was characterized by immunodotting, immunofluorescence, immunoadsorption and immunoblotting. Immunofluorescence confirmed the intracellular location of GMF. Immunoadsorption completely eliminated the GMF-like bioactivity from the cell extracts. Immunoblotting identified a protein band with a molecular weight of 14,000. Thus, the evidence strongly supports the argument that the GMF-like factor in rat Schwann cells is identical with GMF from the bovine brain. The GMF-like molecule in Schwannoma cells showed properties similar to those in Schwann cells, but for unknown reasons was not detectable by immunofluorescence. The presence of GMF in cultured rat Schwann cells suggests that the factor may play a role in the peripheral nervous system.