Original Article
Autoantibodies to a 128-kd Synaptic Protein in Three Women with the Stiff-Man Syndrome and Breast Cancer
N Engl J Med 1993; 328:546-551February 25, 1993
- Abstract
Background
The stiff-man syndrome is a rare disease of the central nervous system characterized by progressive rigidity of the body musculature. Autoantibodies directed against glutamic acid decarboxylase are present in about 60 percent of patients with the syndrome. In this group, there is a striking association of the stiff-man syndrome with organ-specific autoimmune diseases, primarily insulin-dependent diabetes mellitus.
Methods
We studied three women with the stiff-man syndrome and breast cancer, seeking autoantibodies directed against nervous system antigens in serum and cerebrospinal fluid by immunocytochemical techniques, Western blotting, and immunoprecipitation.
Results
Autoantibodies directed against a 128-kd brain protein were found in two of the women with the stiff-man syndrome and breast cancer. These results led to a search for breast cancer in the third patient with the stiff-man syndrome, who also had autoantibodies. A small invasive ductal carcinoma was detected by ultrasonography and removed. Serum samples from all three patients were negative for autoantibodies directed against glutamic acid decarboxylase. Autoantibodies against the 128-kd antigen were not detected in control patients with the stiff-man syndrome without breast cancer or in patients with cancer who did not have the syndrome. Within the nervous system, the 128-kd autoantigen was localized in neurons and concentrated at synapses.
Conclusions
In a subgroup of patients with the stiff-man syndrome, the condition is likely to have an autoimmune paraneoplastic origin. The detection of autoantibodies against the 128-kd antigen in patients with this syndrome should be considered an indication to search for an occult breast cancer.
Media in This Article
Figure 1
Photomicrographs of Sections of Rat Cerebellum and Brain Stem Stained with Serum Samples (Diluted 1:20) from Patients 1, 2, and 3 and a Control Patient and with Rabbit Antibodies to Synaptic-Vesicle Proteins.Figure 2
Western Blots of Brain Homogenates Showing Protein Antigens Recognized by Serum and Cerebrospinal Fluid Samples from Patients 1, 2, and 3 and by Serum Samples from Control Patients and Normal Subjects.Article Activity
- Article
The stiff-man syndrome is a rare disorder of the central nervous system characterized by fluctuating but progressive muscle rigidity and spasms1,2. Sixty percent of the patients with this syndrome have autoantibodies directed against glutamic acid decarboxylase,3-6 an enzyme present both in neurons secreting g-aminobutyric acid and in pancreatic beta cells7,8. Glutamic acid decarboxylase autoantibodies are also found in patients with insulin-dependent diabetes mellitus9. Patients with the stiff-man syndrome who have such autoantibodies often have organ-specific autoimmune diseases, in particular insulin-dependent diabetes mellitus3,6. The absence of glutamic acid decarboxylase autoantibodies in 40 percent of the patients with stiff-man syndrome suggests that the pathogenesis of the syndrome may be heterogeneous6,10. In a few patients, the stiff-man syndrome is associated with cancer11-15.
We describe three women with the stiff-man syndrome and ductal breast cancer who had autoantibodies directed against a 128-kd neuronal protein that is concentrated at synapses. None of the patients had glutamic acid decarboxylase antibodies or organ-specific autoimmune diseases.
Case Reports
Patient 1
Patient 1 has been described previously by Piccolo et al.12 (Patient 2 in their report). A 54-year-old woman began to have paresthesia, myalgia, and rigidity of both arms in 1985. In March 1986, she presented with symmetric stiffness of the upper arm and neck muscles that increased markedly on voluntary contraction as well as during passive motion. The patient's cerebrospinal fluid contained IgG, which had an oligoclonal pattern when examined by isoelectrofocusing16. Electromyography revealed continuous motor-unit activity at rest. Diazepam therapy was ineffective, but the patient's neurologic symptoms improved when she was treated with prednisone. In September 1987 an invasive ductal adenocarcinoma of the breast was detected and removed, after which tamoxifen was given. Treatment with prednisone was discontinued in March 1988, and at the most recent follow-up visit the patient was neurologically normal. Autoantibodies against the 128-kd antigen were detected in several serum samples obtained between October 1986 and May 1992 (earlier samples were not available) and in two cerebrospinal fluid samples obtained in October 1986 and January 1987.
Patient 2
A 76-year-old woman began to have contractures and weakness of the arms in 1985. She was found to have fixed rigidity of the shoulders; contractures of the arms, wrists, and fingers; and absent arm reflexes in 1987. Electromyography revealed continuous motor-unit activity at rest. No oligoclonal bands of IgG were detected in the cerebrospinal fluid. The patient also had a breast mass, which proved to be a poorly differentiated ductal adenocarcinoma. The breast cancer was excised, and the patient was treated with tamoxifen, diazepam, and baclofen. Her condition deteriorated slowly, with increasing rigidity of the arms, trunk, and eventually legs, and she died two years after surgery for a myocardial infarction. No autopsy was performed. Autoantibodies against the 128-kd antigen were detected in the only serum sample tested, which was obtained a few weeks after surgery in 1987.
Patient 3
A 66-year-old woman began to experience progressive rigidity of the legs in 1989, which was partially relieved by bromazepam. Eight months later she was admitted to the hospital in opisthotonus, with board-like rigidity of the abdomen. Physical and emotional stimuli caused painful muscle spasms. Electromyography revealed continuous motor-unit activity at rest. A diagnosis of stiff-man syndrome was made according to the criteria of Lorish et al.2. Oligoclonal bands of IgG were found in the cerebrospinal fluid. Autoantibodies against the 128-kd antigen were detected in both the serum and cerebrospinal fluid. This finding prompted a search for an occult breast tumor. A micronodular mass was detected in the left breast by ultrasonography and was surgically removed. Pathological examination revealed an invasive ductal carcinoma. The patient was treated with tamoxifen, diazepam, and prednisone. She improved markedly and became able to walk unassisted. Autoantibodies against the 128-kd antigen were detected in multiple serum samples obtained in 1990, 1991, and 1992.
In none of the patients could it be established whether the breast cancer antedated the neurologic symptoms. In all three patients, tests of serum for organ-specific autoantibodies (islet-cell antibodies, gastric parietal-cell antibodies, thyroglobulin antibodies, and thyroid microsomal [peroxidase] antibodies) other than antineuronal antibodies were negative.
Methods
In addition to testing serum samples from the 3 patients, we tested serum samples from 73 other patients with the stiff-man syndrome who did not have breast cancer (of whom 43 had positive tests for glutamic acid decarboxylase autoantibodies), 120 patients with a variety of other neurologic diseases, 30 patients with a variety of histologically confirmed cancers (ductal breast cancer in 17 patients, ovarian adenocarcinoma in 4 patients, squamous-cell carcinoma in 3 patients, and neurofibroma, ovarian teratoma, ovarian fibrothecoma, embryonal stromal sarcoma, endometrial adenocarcinoma, and embryonal carcinoma of the testis in 1 patient each), and 16 normal subjects. The rabbit serum directed against glutamic acid decarboxylase (serum 7673),9 rabbit serum directed against synapsin I,17 and rabbit serum directed against synaptophysin18 have been described previously.
Fragments of normal and cancerous breast tissue were obtained at operation from Patient 3. We also studied fragments of cerebral cortex obtained from the margins of brain tumors excised surgically from four patients and 45 abnormal human tissues: 12 ductal breast carcinomas, 6 fibrocystic breast tissues, 2 breast fibroadenomas, 4 ovarian adenocarcinomas, 1 ovarian fibrothecoma, 2 cystic ovarian teratomas, 2 testicular seminomas, 2 embryonal carcinomas of the testis, 1 testicular teratocarcinoma, 1 endometrial adenocarcinoma, 1 endometrial stromal sarcoma, 4 adenocarcinomas of the colon, 3 squamous-cell carcinomas (head, neck, and lung), 1 undifferentiated large-cell carcinoma of the lung, 1 mediastinal neurofibroma, 1 pheochromocytoma, and 1 non-Hodgkin's lymphoma.
Indirect immunoperoxidase and immunofluorescence staining of frozen sections of formaldehyde-fixed rat tissues3,4 or of snap-frozen acetone-fixed human tissues19 was performed as previously described3,4,19. Serum and cerebrospinal fluid samples were routinely tested at dilutions of 1:20 and 1:2, respectively3,4. A specific signal could be detected with dilutions of up to 1:100. For autoantibody affinity purification, frozen sections of formaldehyde-fixed rat cerebellum or liver were allowed to react with human serum as described for immunocytochemical techniques3,4. Bound autoantibodies eluted with a low-pH buffer were used for Western blotting studies. Tissue homogenization, sodium dodecyl sulfate-polyacrylamide-gel electrophoresis, and Western blotting were performed as previously described4. Human serum was routinely used at a dilution of 1:250. Immunoprecipitation was performed as previously described9.
Results
Immunocytochemical Identification of Antineuronal Autoantibodies
Immunocytochemical analysis of serum samples from all three patients (Figure 1Figure 1
Photomicrographs of Sections of Rat Cerebellum and Brain Stem Stained with Serum Samples (Diluted 1:20) from Patients 1, 2, and 3 and a Control Patient and with Rabbit Antibodies to Synaptic-Vesicle Proteins.) and cerebrospinal fluid samples from Patients 1 and 3 (samples from Patient 2 were not available) showed that all stained the gray matter of rat brain as detected by light microscopy. The distribution of immunoreactivity was similar to that of the synaptic-vesicle proteins synapsin I17 (compare Panel D, Panel E, and Panel F in Figure 1 with Panel G) and synaptophysin18 (compare Panel J with Panel K), suggesting that the autoantigen or autoantigens are concentrated at synapses. In addition, there was a variable degree of diffuse cytoplasmic staining in a subpopulation of neuronal perikarya and dendrites (Figure 1B, 1H, and 1I). None of the control serum samples, whether obtained from patients with neurologic diseases, patients with cancer, or normal subjects, stained brain tissue in this way. The serum samples from the three patients stained more neurons and synapses than a serum sample from a control patient with the stiff-man syndrome who had antibodies directed against glutamic acid decarboxylase (compare Panel B in Figure 1 with Panel C). The results were similar in studies using human cerebral cortex.Western Blotting Studies
The serum samples from the three patients and the cerebrospinal fluid samples from Patients 1 and 3 recognized the same protein doublet of approximately 128 kd when tested by Western blotting on monodimensional gels (Figure 2Figure 2
Western Blots of Brain Homogenates Showing Protein Antigens Recognized by Serum and Cerebrospinal Fluid Samples from Patients 1, 2, and 3 and by Serum Samples from Control Patients and Normal Subjects.) and bidimensional gels (not shown) of extracts of human cerebral cortex and rat brain. None of the samples reacted with the glutamic acid decarboxylase band. Conversely, serum samples from other patients with the stiff-man syndrome, including those who had glutamic acid decarboxylase autoantibodies, did not react with the 128-kd antigen (Figure 2A, lane 4). The 128-kd antigen was not recognized by any of the other control serum samples (Figure 2A, lanes 5 and 6).To confirm that the 128-kd antigen was responsible for the immunoreactivity in brain sections, a serum sample from Patient 3 was affinity-purified by absorption to and elution from sections of rat cerebellum and then tested by Western blotting. The affinity-purified antibodies, like the unpurified serum, selectively labeled the 128-kd antigen. No labeling of the 128-kd antigen was seen when the serum was affinity-purified with sections of rat liver.
The Western blot technique involves denaturation of the antigen (Figure 2). To exclude the possibility that the serum samples from Patients 1, 2, and 3 reacted with native glutamic acid decarboxylase, they were tested in an immunoprecipitation assay with Triton X-100-treated extracts of rat brain. The serum samples from each patient precipitated the 128-kd antigen but not glutamic acid decarboxylase (Figure 3AFigure 3
Immunoprecipitation of Rat-Brain Proteins with Serum from Patients with the Stiff-Man Syndrome and a Normal Subject., lanes 4, 5, and 6). Conversely, control serum samples containing glutamic acid decarboxylase autoantibodies precipitated glutamic acid decarboxylase but not the 128-kd antigen (Figure 3B, lanes 2 and 3). Neither the 128-kd antigen nor glutamic acid decarboxylase was immunoprecipitated by serum samples from the control subjects, including samples from other patients with the stiff-man syndrome that did not contain glutamic acid decarboxylase antibodies (Figure 3, lanes 7, 8, and 9).The 128-kd antigen was recovered in both particulate and soluble fractions after high-speed centrifugation of a homogenate of rat brain (data not shown). Thus, the 128-kd antigen is not an intrinsic membrane protein.
Detection of the 128-kd Antigen in Nonneuronal Normal and Cancerous Tissues
Serum from Patient 3 was used to detect the possible presence of the 128-kd antigen outside the brain by Western blotting. A band with the same electrophoretic mobility as the large isoform of the 128-kd antigen found in the brain, but less intensely stained, was found in extracts of rat testis, ovaries, and adrenal gland, but not in liver, kidney, submandibular gland, pancreas, lung, skeletal muscle, heart, spleen, or mammary gland (data not shown).
The 128-kd antigen was not detected in either the cancerous or the normal breast tissue of Patient 3 (Figure 4AFigure 4
Expression of the 128-kd Antigen in Human and Rat Tissues., lanes 2 and 3). In addition, the 128-kd antigen was not found in any of the 45 abnormal human tissues tested, including the 12 ductal breast carcinomas (Figure 4B, lanes 5 and 6), except for the 2 cystic ovarian teratomas (Figure 4B, lanes 3 and 4),21 which on histologic examination were found to contain several foci of well-differentiated neural tissue. The two patients from whom these tumors were removed had no signs of neurologic dysfunction, and their serum did not contain autoantibodies against the 128-kd antigen.Discussion
We detected a humoral autoimmune response against a neuronal protein of 128 kd in three women with the stiff-man syndrome and breast cancer. The 128-kd antigen was concentrated at synapses and had a highly restricted distribution outside the nervous system.
None of the serum samples from the three patients contained glutamic acid decarboxylase antibodies. Glutamic acid decarboxylase is the main target of humoral autoimmunity in the majority of patients with the stiff-man syndrome3-6. Our results indicate that the 128-kd antigen and glutamic acid decarboxylase3,7 have different but partially overlapping distributions in the brain and are the only major central nervous system autoantigens concentrated at synapses. Neither the 128-kd antigen nor glutamic acid decarboxylase22-25 is expressed selectively in the nervous system, but their distribution outside the nervous system is highly restricted. This study shows that the 128-kd antigen, similar to glutamic acid decarboxylase,22 is localized in the cytoplasmic compartment and is not an intrinsic membrane protein.
The presence of autoantibodies against the 128-kd antigen in the serum of all three patients and in the cerebrospinal fluid of two patients, as well as the presence of oligoclonal IgG bands in the cerebrospinal fluid16 of two of the patients, suggests the occurrence of an active autoimmune process within the central nervous system. Other studies have provided evidence of the activation of an autoimmune response within the central nervous system of patients with the stiff-man syndrome who had serum glutamic acid decarboxylase autoantibodies3,4.
Since both the 128-kd antigen and glutamic acid decarboxylase are cytoplasmic antigens, antibodies to these proteins are not likely to have a direct pathogenetic role, although such a role cannot be excluded26,27. It is also unlikely that autoantibodies directed against the 128-kd antigen and glutamic acid decarboxylase represent epiphenomena caused by the destruction of nervous tissue, because the same autoantibodies were not found in control patients with neurologic disorders, including patients with degenerative diseases of the nervous system4. A close relation between autoimmunity to the two proteins and the pathogenesis of the neurologic symptoms appears likely. The occurrence of each of the two antibodies in distinct groups of patients with the stiff-man syndrome who have different associated diseases suggests two mechanisms of autoimmunity.
In addition to the three patients described here, five other patients with the stiff-man syndrome and cancer have been described in the literature, but none had breast cancer11-15. Autoantibodies to nervous system components were detected in two of these patients, but the reactivity of the antibodies differed from that in our three patients13,15. In a third patient (referred to as Patient 1 in the report by Piccolo et al.12), no such autoantibodies were found (Solimena M, et al.: unpublished data). Autoantibodies were not sought in the remaining two patients.
Each of the three patients had some clinical features that are not typical of classic stiff-man syndrome, including localization of the stiffness to the proximal musculature of the limbs and the absence of fixed trunk rigidity (in Patients 1 and 2), and a remission of the neurologic symptoms after steroid therapy (in Patients 1 and 3). A similar striking response to glucocorticoid therapy was reported in two of the other five patients described previously who had the stiff-man syndrome and cancer11,12.
The syndrome affecting the three patients bears some similarity to previously described paraneoplastic disorders of the central nervous system that are thought to have an autoimmune pathogenesis: paraneoplastic cerebellar degeneration, cancer-associated retinopathy, paraneoplastic sensory neuropathy-encephalomyelitis, and paraneoplastic opsoclonus-myoclonus28-32. In these disorders as well, strong and highly specific humoral responses directed against cytoplasmic or nuclear neuronal antigens are present. In some cases, the tumor tissue of patients with paraneoplastic neurologic diseases expressed the autoantigen (or autoantigens),29,30 and it has been proposed that abnormal expression of the autoantigen (or autoantigens) by the tumor may trigger the autoimmune response29,30. We did not find evidence of the expression of the 128-kd antigen in the only one of the three breast-cancer specimens that we studied. In addition, no neurologic symptoms were present in the two patients affected by ovarian teratomas whose tumors contained the 128-kd antigen. These results, together with the normal expression of the 128-kd antigen in a few nonneuronal tissues, rule out the possibility that the expression of the antigen outside the blood-brain barrier might be a factor, or the only factor, responsible for triggering the autoimmune response.
In conclusion, our findings identify a distinct paraneoplastic disease: stiff-man syndrome associated with ductal breast adenocarcinoma and the presence of autoantibodies directed against a neuronal protein concentrated at synapses. These observations further support an autoimmune pathogenesis of the stiff-man syndrome. They also raise new questions about the relation between humoral autoimmunity and neurologic symptoms. The close association of specific autoantibodies with a given paraneoplastic neurologic condition is considered an indication to search for occult tumors31,32. The detection of autoantibodies against the 128-kd antigen in patients affected by motor-neuron hyperactivity should lead to a careful search for breast cancer.
Supported by grants (AI 30248-01, DK 43078-01, and MH 45191-01) from the National Institutes of Health, the Klingenstein Foundation, the McKnight Endowment for the Neurosciences (to Dr. De Camilli), the Muscular Dystrophy Association (to Dr. Solimena), and a Dottorato di Ricerca, Hospitale Raffaele, University of Milan (to Dr. Folli).
We are indebted to Dr. B. Giometto for performing laboratory studies on the serum and cerebrospinal fluid of Patient 3 and for discussion, to Dr. R. Cameron for helpful advice and discussion, to Dr. C.R. Kahn for critical reading of the manuscript, to Dr. R.K. Donabedian, Dr. T.S. Ravikumar, S. Distasio, R.N., and J. Hanne, R.N., for providing serum samples from patients with cancer, to Dr. D. Spencer and Dr. D. McCormick for providing surgical specimens of human cerebral cortex, to Dr. J. Rosai for providing other human tissues, and to Ms. J. McNally for skillful technical assistance.
Source Information
From the Departments of Cell Biology (F.F., M.S., P.D.C.) and Pathology (G.T.), and Howard Hughes Medical Institute (R.C., P.D.C.), Yale University School of Medicine, New Haven, Conn.; Istituto di Semeiotica Medica, Universita di Padova, Padua, Italy (M.A.); Divisione Neurologica, Ospedale di Belluno, Belluno, Italy (G.F.); the Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom (D.B., N.C.); the Department of Immunology, London Hospital Medical College, London (G.F.B.); and Istituto Neurologico Mondino, Universita di Pavia, Pavia, Italy (G.P.).
Address reprint requests to Dr. De Camilli at Howard Hughes Medical Institute, Department of Cell Biology, Boyer Center for Molecular Medicine, 295 Congress Ave., New Haven, CT 06510.
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