Neil E. Anderson

Autoantibodies in paraneoplastic syndromes associated with small‐cell lung cancer

An antineuronal autoantibody has been identified in serum from 14 patients, 8 women and 6 men, with small-cell lung carcinoma (SCLC) and a neurologic disorder. Neurologic symptoms began prior to diagnosis of the SCLC in 12 patients. The dominant neurologic disorder was a subacute sensory neuronopathy (SSN) in eight patients, SSN plus lower motor neuron weakness (2 patients), SSN plus autonomic neuropathy (1 patient), cerebellar ataxia (1 patient), myelopathy (1 patient), and multifocal nervous system disease (encephalomyelitis) in one patient. The presence of the same autoantibody in patients with SSN, encephalomyelitis, and autonomic neuropathy suggests that these diseases are different manifestations of the same nosologic process. With one exception, treatment of the tumor, immunosuppressive drugs, and plasmapheresis did not influence the course of the neurologic illness. The autoantibody was not identified in sera from more than 400 controls subjects, including patients with SSN associated with other tumors, SSN without malignancy, other paraneoplastic syndromes, and SCLC without neurologic symptoms. The autoantibody is a highly specific marker of the paraneoplastic syndromes associated with SCLC and its detection in a patient not known to have cancer should prompt a careful search for SCLC.

Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C

Spinal muscular atrophies (SMA, also known as hereditary motor neuropathies) and hereditary motor and sensory neuropathies (HMSN) are clinically and genetically heterogeneous disorders of the peripheral nervous system. Here we report that mutations in the TRPV4 gene cause congenital distal SMA, scapuloperoneal SMA, HMSN 2C. We identified three missense substitutions (R269H, R315W and R316C) affecting the intracellular N-terminal ankyrin domain of the TRPV4 ion channel in five families. Expression of mutant TRPV4 constructs in cells from the HeLa line revealed diminished surface localization of mutant proteins. In addition, TRPV4-regulated Ca2+ influx was substantially reduced even after stimulation with 4αPDD, a TRPV4 channel-specific agonist, and with hypo-osmotic solution. In summary, we describe a new hereditary channelopathy caused by mutations in TRPV4 and present evidence that the resulting substitutions in the N-terminal ankyrin domain affect channel maturation, leading to reduced surface expression of functional TRPV4 channels.

Opsoclonus, myoclonus, ataxia, and encephalopathy in adults with cancer : a distinct paraneoplastic syndrome

The clinical and pathological findings in 4 adults with cancer and opsoclonus were compared with those of 15 other patients described elsewhere. The clinical syndrome of paraneoplastic opsoclonus is characterized by the acute onset of opsoclonus and truncal ataxia, often accompanied by encephalopathy, myoclonus and a cerebrospinal fluid pleocytosis. Unlike most other paraneoplastic syndromes, the course is often remitting and relapsing. Neuropathological examination in 3 of our patients showed lymphocytic cuffing of occasional blood vessels throughout the central nervous system, associated with a mild, diffuse proliferation of microglia in 1 patient. Apart from a mild, patchy loss of Purkinje cells in 1 patient, there was no loss of neurons from the cerebellum, brainstem, cerebral hemispheres, or spinal cord. These patients differ from those with the more common paraneoplastic cerebellar degeneration by the predominance of truncal over limb ataxia, the presence of myoclonus, the absence of severe dysarthria, a tendency for remission, and the preservation of Purkinje cells.

Partial characterization of the Purkinje cell antigens in paraneoplastic cerebellar degeneration

Serum from seven patients with paraneoplastic cerebellar degeneration contained anti-Purkinje cell antibodies. The samples were examined by immunoblotting to determine whether they recognized common antigens in isolated human Purkinje cell neurons. Two groups of antigens were detected by all seven sera with Mr 62/64 kd and 34 to 38 kd, both of which contributed to the Purkinje cell antigens detected immunohistochemically. These reactivities were absent from all controls tested. These antibodies may play a role in the pathogenesis of paraneoplastic cerebellar degeneration.

A variant of the anti‐Purkinje cell antibody in a patient with paraneoplastic cerebellar degeneration

An anti-Purkinje cell antibody was found in the serum and CSF of a man with adenocarcinoma of the lung and paraneoplastic cerebellar degeneration (PCD). This antibody differed from the autoantibodies found in patients with gynecologic cancer and PCD in that it produced a different pattern of Purkinje cell cytoplasmic staining, did not react with PCD antigens in Purkinje cell Western blots, and the antigen had a different species distribution. Unlike the antinuclear antibody found in patients with PCD and small-cell lung carcinoma, the antigen was restricted to the cytoplasm of Purkinje cells. If autoantibodies are important in the pathogenesis of PCD, this case illustrates that they can recognize different antigenic epitopes in the nervous system, but cause similar clinicopathologic syndromes.

Confirmation of a hereditary motor and sensory neuropathy IIC locus at chromosome 12q23-q24

Hereditary motor and sensory neuropathy type IIC (HMSN IIC) is an autosomal dominant axonal neuropathy. The cardinal features include distal muscle wasting and weakness, vocal cord paralysis, and mild sensory impairment. Recently, HMSN IIC locus was mapped to chromosome 12q23‐24. Two families affected by HMSN IIC were identified and evaluated for linkage to this region. Segregation analysis in both families was consistent with linkage to chromosome 12q23‐24. Combined analysis generated a multipoint LOD score of 2.1 at marker D12S1583 and refined the HMSN IIC gene interval to The clinical and molecular findings are discussed.Ann Neurol 2005;57:293–297

The control of voice onset time and vowel duration after paraneoplastic cerebellar degeneration: An acoustic study

Speech production was examined in a group of six subjects with paraneoplastic cerebellar degeneration, a neurological disorder that produces severe dysarthria. Subjects were recorded repeating CVC and CVCV syllables that included the stop consonant [p b t d k g] and the vowels [i a u]. Vowel durations preceding voiced and voiceless segments and voice onset time (VOT) were measured. The vowel duration measures assessed the preservation of intrinsic duration properties, and the variation of these properties in conditioning phonological contexts. The VOT measure assessed the coordination of two independent articulatory events. Results indicated that the cerebellar subjects normally differentiated among individual vowels, and altered vowel duration as a function of phonological context. In contrast, they tended to reduce VOT for voiceless segments, and, in the case of the most impaired subject, the voiceless segments were always perceived as being voiced. Although the VOT durations were reduced, there was no ...

The control of voice onset time and vowel duration after paraneoplastic cerebellar degeneration: Correlation with regional cerebral glucose metabolism using positron emission tomography

In a companion report, an impairment in voice onset time (VOT) control was described for a group of subjects with paraneoplastic cerebellar degeneration who could otherwise produce appropriate segmental duration. The underlying neurophysiological changes were related to regional cerebral metabolic rates for glucose (rCMRGlu) determined by F18‐fluorodeoxyglucose/positron emission tomography (PET). Nine cerebellar subjects and 18 normal controls were studied with eyes patched while listening to music and periodic verbal briefings. The rCMRGlu was calculated for each of 28 anatomically defined regions of interest (ROI). The cerebellar subjects could be differentiated from normals by their lower global metabolic rate, and by their rCMRGlu pattern. For those cerebellar subjects who could participate in the acoustic study, cerebellar rCMRGlu was significantly below normal range (p < 0.05) in all but one case. Severity of VOT abnormality appeared to be related not only to cerebellar rCMRGlu, but to abnormally lo...