Characteristics of patients with sensory neuropathy diagnosed with abnormal small nerve fibres on skin biopsy.

Clinical, laboratory and electrodiagnostic (EDX) characteristics of 62 patients with sensory neuropathy with abnormal skin biopsies were reviewed. Reduced epidermal nerve fibre density (ENFD) was seen in 71% and morphological changes with normal ENFD were seen in 29% of the patients. Patients with small fibre sensory neuropathy may have associated large fibre loss undetected by routine EDX. Identified associations included abnormal glucose metabolism, Lyme vaccination, monoclonal gammopathy, vitamin B12 deficiency, coeliac disease, and diseases of the connective tissue, inflammatory bowel and thyroid. Sensory neuropathy remained undetermined in 50% of the patients.

Recruitment of the mitochondrial-dependent apoptotic pathway in amyotrophic lateral sclerosis.

Molecular mechanisms of apoptosis may participate in motor neuron degeneration produced by mutant superoxide dismutase-1 (mSOD1), the only proven cause of amyotrophic lateral sclerosis (ALS). Consistent with this, here we show that the proapoptotic protein Bax translocates from the cytosol to the mitochondria, whereas cytochrome c translocates from the mitochondria to the cytosol in spinal cords of transgenic mSOD1 mice during the progression of the disease. Concomitantly, caspase-9 is activated in the spinal cord of transgenic mSOD1 mice. Only in end-stage transgenic mSOD1 mice is the downstream caspase-7 activated and the inhibitor of apoptosis, XIAP, cleaved. These results indicate a sequential recruitment of molecular elements of the mitochondrial-dependent apoptotic pathway in transgenic mSOD1 mice. We also provide immunohistochemical evidence that cytochrome c translocation occurs in the spinal cord of sporadic ALS patients. Collectively, these data suggest that the mitochondrial-dependent apoptotic pathway may contribute to the demise of motor neurons in ALS and that targeting key molecules of this cascade may prove to be neuroprotective.

Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders: preliminary findings.

BACKGROUND: Postmortem studies of the subiculum from subjects with schizophrenia have detected smaller pyramidal cell bodies and diminished immunoreactivity for the dendritic protein, microtubule-associated protein 2. While these findings suggest that subicular pyramidal cell dendrites may be structurally altered in subjects with schizophrenia, this possibility had not been tested directly. METHODS: Rapid Golgi impregnation of archival brain specimens was used to compare the morphologic characteristics of subicular dendrites in subjects with schizophrenia (n = 13) and mood disorders (n = 6) with subjects without psychiatric disease (n = 8). The specimens were processed and analyzed by physicians blind to diagnosis. The extent of dendritic trees in the subiculum and fusiform gyrus was examined by Sholl analysis. Spine density on apical dendrites of subicular pyramidal cells was determined at a fixed distance from the cell body. RESULTS: Spine density and arborization of subicular apical dendrites were significantly related to diagnostic group. Spine density was significantly lower in the schizophrenia and mood disorder groups than in the nonpsychiatric group. Among the mood disorder cases, diminished spine density was apparently related to a strong family history of major psychiatric diseases. There were no significant effects of diagnostic group on Sholl analysis of nonapical subicular dendrites nor on Sholl analysis of dendrites of neocortical pyramidal cells in the fusiform gyrus. CONCLUSIONS: We have observed an association between schizophrenia and major mood disorders and structural abnormalities of subicular apical dendrites. Further studies are needed to test this association in a larger sample and to evaluate the potential role of family history and of confounding factors, such as medications and chronic institutionalization.

Peripherin and neurofilament protein coexist in spinal spheroids of motor neuron disease.

We have compared the immunolocalization of neurofilament protein (NF) with two other neuronal-specific intermediate filament proteins in large spinal axonal swellings (spheroids) of motor neuron disease and controls. All spheroids labeled each of the three different subunits of NF, the low, middle, and high molecular weight polypeptides. In doublelabel immunofluorescence, 300 axonal swellings were immunostained for NF, and 87% of them contained the intermediate protein peripherin. The pattern of immunostaining of NF and peripherin was indistinguishable at a high resolution viewed in 1 microns optical sections by confocal microscopy. A minority of the spheroids contained alpha-internexin, another intermediate protein, but it was weakly immunoreactive. The immunostaining of axonal swellings was similar for all epitopes tested in motor neuron disease and control subjects. The findings suggest that peripherin as well as neurofilament protein are major components of the proliferated intermediate filaments in spheroids.

Human monoclonal IgM anti-Gal(beta 1-3)GalNAc autoantibodies bind to the surface of bovine spinal motoneurons.

An IgM monoclonal autoantibody (M-protein) with anti-Gal(beta 1-3)GalNAc activity from a patient with lower motor neuron disease bound to the surface of motoneurons isolated from bovine spinal cord. The Gal(beta 1-3)GalNAc epitope is shared by the gangliosides GM1 and GD1b and by several glycoproteins in the nervous system, and binding was abolished by preabsorbing the patient's serum with GM1. Antibodies specific for GM1, however, which do not bind to GaL(beta 1-3)GalNAc, did not bind to the motoneurons. This suggests that Gal(beta 1-3)GalNAc bearing glycoproteins or glycolipids other than GM1 are expressed on the surface of motoneurons, while GM1 may be absent or shielded, and that antibody binding to the cell surface might contribute to the development of the motor neuron disease.

A monoclonal IgA in a patient with amyotrophic lateral sclerosis reacts with neurofilaments and surface antigen on neuroblastoma cells.

A 75-year-old woman had breast carcinoma, an IgA paraprotein and autopsy-proven amyotrophic lateral sclerosis. Autopsy tissues showed immune-reactive IgA within surviving motor neurons and deposits of IgA and C3 within renal glomeruli. By indirect immunofluorescence, the patient's serum contained high-titer IgA that bound to axons and to the perikarya of nerve cells in central and peripheral nervous system. The IgA paraprotein reacted with the 200 kDa, high molecular weight subunit of neurofilament protein (NFH) in Western blots of purified neurofilaments. It also reacted with dephosphorylated NFH and with NFH expressed as a fusion protein in E. coli, suggesting that the autoantibody recognized a peptide epitope. The IgA crossreacted with a surface antigen of cultured human neuroblastoma cells but mouse monoclonal antibodies to NFH did not. Absorption of the patient's serum with neurofilaments eliminated IgA binding to neuroblastoma cells, indicating that the same antibodies bound to both determinants. The IgA paraprotein seems to be an autoantibody with specificity for neurofilament protein and a cell surface component of neuronal cells; the antibody may have been important in the pathogenesis of neuronal degeneration.

Immunocytochemical analysis of normal and acid maltase-deficient muscle cultures.

Muscle cultures from patients with infantile and later-onset acid maltase deficiency (AMD) and from unaffected controls were studied immunocytochemically with anti-acid maltase (anti-AM) antibodies and fluorescein-labeled goat anti-rabbit IgG second antibody. In control muscle cells, an intense granular distribution of staining was seen, consistent with lysosomal localization of AM. Cultured muscle cells from two patients with infantile AMD (Pompe's disease) did not fluoresce, whereas cells from two patients with AMD of later onset did fluoresce, showing a distribution similar to that of controls.

The neuromuscular manifestations of human immunodeficiency virus infections.

We studied 14 patients with neuromuscular disorders and concomitant infection with human immunodeficiency virus to define clinical syndromes and prognosis. Eight patients had painful sensorimotor peripheral neuropathy; two, chronic inflammatory demyelinating polyneuropathy; two, mononeuropathy or mononeuropathy multiplex; one, recurrent myoglobinuria; and one, chronic proximal weakness and elevated creatine kinase levels. All eight patients with painful neuropathy had overt symptoms of acquired immunodeficiency syndrome. Chronic inflammatory demyelinating polyneuropathy was the first manifestation of acquired immunodeficiency syndrome in both patients with this syndrome. Both died from overwhelming sepsis within six months of the neuropathy's onset. Patients with mononeuropathy multiplex had a variable course. Immunosuppressant medication had no effect in two patients.

Granulomatous angiitis of the brain. An inflammatory reaction of diverse etiology.

Granulomatous angiitis of the brain (GAB) is defined histologically by granulomatous inflammation of intracranial blood vessels. We have studied four patients with autopsy-proved GAB who had, respectively, Hodgkin's lymphoma, herpes zoster, neurosarcoidosis, and no associated illness. Headache, fever, or mental change was followed by hemiparesis or quadriparesis, coma, and death in all four patients. There were no diagnostic findings from cerebral computed tomograms, cerebrospinal fluid, or cerebral angiograms; the diagnosis was established only by postmortem examination. Vasculitis was limited to the brain in all four patients, and involved large arteries, small arteries and veins, or both large and small vessels. Differences in etiology and different particulars of the pathologic conditions imply that GAB is a nonspecific reaction, not a unique disease. The diagnosis, moreover, cannot be proved without histologic confirmation. A biopsy specimen is the only way to ascertain the diagnosis in living patients.

Inclusion body myositis mimicking motor neuron disease.

OBJECTIVE: To describe the clinical and electrophysiologic features of patients with inclusion body myositis that was misinterpreted as motor neuron disease. PATIENTS AND METHODS: We retrospectively retrieved the medical records of 70 patients with a pathologic diagnosis of inclusion body myositis. From this group, we selected those who had been first diagnosed as having motor neuron disease or amyotrophic lateral sclerosis. We reviewed the clinical, electrophysiologic, laboratory, and morphologic studies. RESULTS: Nine (13%) of 70 patients with inclusion body myositis had been diagnosed as having motor neuron disease. Six of the 9 patients had asymmetric weakness; in 4 the distal arm muscles were affected. Eight patients had finger flexor weakness. Tendon reflexes were preserved in weak limbs in 6, hyperactive in 2, and absent in 1. Four patients had dysphagia. Fasciculation was seen in 2 patients. None had definite upper motor neuron signs or muscle cramps. Routine electromyographic studies showed fibrillation potentials and positive sharp waves in all 9. Fasciculation potentials were seen in 7 and long-duration polyphasic motor unit potentials were seen in 8. There was no evidence of a myogenic disorder in these 9 patients. Muscle biopsy was done because of slow progression or prominent weakness of the finger flexors and was diagnostic of inclusion body myositis. A quantitative electromyogram was myopathic in 4 of the 5 patients studied. CONCLUSIONS: Inclusion body myositis may mimic motor neuron disease. Muscle biopsy and quantitative electromyographic analysis are indicated in patients with atypical motor neuron disease, especially those with slow progression or early and disproportionate weakness of the finger flexors.

Primary lateral sclerosis. A clinical diagnosis reemerges.

Adults with slowly progressive noninherited gait disorders may show no abnormalities on examination other than signs implicating the corticospinal tracts. That is the syndrome of "primary lateral sclerosis" (PLS), a clinical diagnosis that has been avoided because it is a diagnosis of exclusion, proven only at autopsy. Now, modern technology can exclude other disorders that can cause the syndrome with an accuracy of about 95%. That serves to eliminate the following: compressive lesions at the foramen magnum or cervical spinal cord, multiple sclerosis, amyotrophic lateral sclerosis, Chiari malformation, syringomyelia, biochemical abnormality, and persistent infection with human immunodeficiency virus or human T-lymphotrophic virus type I. We studied three autopsy-proved cases of PLS; six living patients in whom PLS was diagnosed clinically after comprehensive evaluations that excluded the alternative diagnoses; and two patients with this syndrome of PLS and antibodies to human immunodeficiency virus seropositivity that clinically resembled PLS. Primary lateral sclerosis is now a respectable and permissible diagnosis.

Erroneous diagnosis corrected after 28 years. Not spinal muscular atrophy with ophthalmoplegia but minicore myopathy.

OBJECTIVE: To correct, after 28 years, the previously reported diagnosis of ophthalmoplegia in a patient with presumed childhood spinal muscular atrophy. DESIGN: Clinical follow-up, laboratory, electrophysiologic, and muscle biopsy data are provided. RESULTS: The findings of clinical follow-up examination, electrophysiologic tests, and histologic examination of muscle specimens led to a revised diagnosis of minicore myopathy. CONCLUSIONS: Spinal muscular atrophy was diagnosed in 1967, before histochemical techniques for examining muscle tissue and quantitative electromyography became widely available. Modern laboratory techniques later made the diagnosis of minicore myopathy possible. Progressive external ophthalmoplegia has been described in 24% of patients with minicore myopathy, but there have been only 7 reports of ophthalmoplegia with spinal muscular atrophy since 1954, and some of these diagnoses have been questioned.

Axonal neuropathy in a patient with IgM M-protein reactive with nerve endoneurium.

IgM M-proteins have been found in patients with axonal neuropathies, but it is not known whether these M-proteins bind to nerve components or actually cause the neuropathy. In one patient with axonal neuropathy studied, the IgM M-protein bound to chondroitin sulfate, and there were deposits of IgM in the endoneurium of the patient's nerve. A monoclonal anti-idiotype antibody generated against that M-protein was used to study the binding of the M-protein to normal nerve and to distinguish it from binding of other IgM species that might be present in the patient's serum. In immunofluorescence studies, the M-protein bound to the endoneurium in normal nerve and to connective tissue in other organs. In immunoblot studies, the M-protein bound to several protein bands in nerve and other tissues. The data suggest that the M-protein bound to mucopolysaccharides in nerve endoneurium and connective tissue.

Antisulfatide antibody and neuropathy in a patient with Gaucher's disease.

We report the presence of antisulfatide antibodies in a patient with type I Gaucher's disease and peripheral neuropathy. The association of Gaucher's disease with hypergammaglobulinemia and monoclonal gammopathy is well documented whereas its association with peripheral neuropathy is rare. We discuss whether antibodies directed against the sulfatide antigen are related to Gaucher's disease or are a coincidental association.

Experimental demyelination of nerve induced by serum of patients with neuropathy and an anti-MAG IgM M-protein.

Demyelination of feline sciatic nerve was induced by intraneural injection of serum from three patients with neuropathy and an IgM M-protein that reacted with myelin-associated glycoprotein (MAG). Demyelination exceeded that induced by serum from 18 other individuals, including six IgM M-proteins unreactive with MAG. The myelinolytic effect required active human complement and was abolished by exposure of serum to homogenate of human peripheral nerve that removed 90% of the M-protein. Immunofluorescence studies demonstrated deposition of the injected M-protein and complement on the surface of myelin sheaths, implying that the M-protein reacted with epitopes of myelin exposed to the extracellular space.

Localization of GM1 and Gal(beta 1-3)GalNAc antigenic determinants in peripheral nerve.

Anti-GM1 antibodies in patients with motor neuropathy or motor neuron disease frequently recognize the Gal(beta 1-3)GalNAc epitope, which is shared by several glycoproteins in peripheral nerve. In this study, cholera toxin (CT), which is specific for GM1, and the lectin peanut agglutinin (PNA), which binds to Gal(beta 1-3)GalNAc-bearing glycoproteins, were used in tissue section and intraneural injection studies to examine the distribution of GM1 and Gal(beta 1-3)GalNAc epitopes in human and rat peripheral nerve by epifluorescence and confocal microscopy. In tissue sections, CT stained the compact myelin in both human and rat nerves, whereas PNA was localized at the outer edge of the myelin sheath or Schwann cell membrane. Following intraneural injection into rat sciatic nerves, both CT and PNA bound to the nodes of Ranvier, although CT was concentrated in the paranodal myelin region whereas PNA was concentrated at the nodal gap. These structures may be targets for anti-GM1 antibodies in peripheral nerve.

Muscle phosphofructokinase deficiency: abnormal polysaccharide in a case of late-onset myopathy.

A 61-year-old woman with muscle phosphofructokinase (PFK) deficiency had mild limb weakness all her life but no cramps or myoglobinuria. For 5 years the limb weakness progressed. In muscle, PFK activity was 1% of normal and glycogen concentration was elevated (2.13%). By light microscopy, a minor component of the accumulated glycogen appeared as PAS-positive, diastase-resistant inclusions in 10% of muscle fibers. The inclusions had a filamentous fine structure that resembled the abnormal long-chain glycogen of brancher enzyme deficiency. Iodine absorption spectra of both the inclusions and a diastase-resistant fraction of isolated glycogen resembled amylopectin. The abnormal polysaccharide in PFK deficiency may be related to greatly elevated concentration of muscle glucose-6-phosphate, an activator of the chain-elongating enzyme glycogen synthase.

Antisulfatide antibodies in neuropathy: clinical and electrophysiologic correlates.

OBJECTIVE: To investigate the clinical and electrophysiologic characteristics of the neuropathy associated with elevated serum antisulfatide antibodies. METHODS: Clinical, electrophysiologic, morphologic, and laboratory data of 25 patients with significantly elevated (>25,600) antisulfatide antibodies were reviewed. RESULTS: Four groups were distinguished based on clinical and electrophysiologic data: Group 1, eight patients with predominantly small fiber sensory neuropathy (32%); Group 2, five patients with mixed large and small fiber sensory neuropathy (20%); Group 3, seven patients with axonal sensorimotor neuropathy (28%); and Group 4, three patients with demyelinating sensorimotor neuropathy (12%). One additional patient had mononeuritis multiplex and one had ALS. An immunoglobulin M (IgM) monoclonal gammopathy was found in 30% of the patients tested, but not in any of the Group 1 patients with small fiber sensory neuropathy. Serum IgM level was elevated in 12 patients, of whom six had a concomitant monoclonal gammopathy. Morphologic studies in five patients showed predominantly axonal degeneration, with three of the patients also exhibiting additional features of demyelination. CONCLUSIONS: Antisulfatide antibodies are associated with several subtypes of peripheral neuropathy. Predominantly sensory or sensorimotor axonal neuropathies are most common in this series, with the sensory component either small fiber or mixed fiber type. A smaller demyelinating group indistinguishable from patients with chronic inflammatory demyelinating polyradiculopathy was also seen. One third of patients had a concomitant IgM monoclonal gammopathy, and approximately one half had elevated serum IgM.

Familial amyloidotic polyneuropathy presenting with carpal tunnel syndrome and a new transthyretin mutation, asparagine 70.

We report familial amyloidotic polyneuropathy in a pedigree of German ancestry residing in New Jersey. Eight affected subjects presented in the third to seventh decade with carpal tunnel syndrome (CTS) and one subject presented with vitreous opacification. Transmission was autosomal dominant and survival was prolonged. Affected subjects were heterozygous for a novel mutation in serum transthyretin (TTR), resulting in an asparagine for lysine substitution at residue 70 of the TTR monomer. We report two methods for rapid identification of the mutation based on the polymerase chain reaction. This pedigree further emphasizes the evolving phenotypic and genotypic heterogeneity of the transthyretinopathies. Familial or sporadic CTS or unexplained vitreous opacification suggest the possibility of TTR amyloidosis and should prompt a search for TTR mutations.

Progressive dementia, visual deficits, amyotrophy, and microinfarcts.

Data from three patients and 22 previously reported cases suggest that cerebral microinfarction causes a recognizable clinical syndrome. All cases present with stroke, followed by progressive dementia and often with visual field deficits, peripheral vascular disease, and signs of motor neuron dysfunction. The average age at onset is 45, and most patients have been men. Many patients have had valvular or ischemic heart disease; in one of our cases, mitral stenosis caused embolic microinfarcts.