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00019616-200105000-00011ReportThe EndocrinologistThe Endocrinologist© 2001 Lippincott Williams & Wilkins, Inc.11May 2001 p 233-235Cerebellar Ataxia Associated with High Levels of Anti-Glutamic Acid Decarboxylase AntibodiesCase ReportsBell, David S.H. M.B., FACE; Ovalle, Fernando M.D.; Shadmany, Shahzad M.D.The University of Alabama at Birmingham, School of Medicine, Birmingham, Alabama.Address correspondence to: David S.H. Bell, M.B., F.A.C.E., 1808 7th Avenue South, Birmingham, AL 35294. Phone: 205-975-2404; Fax: 205-975-9304.AbstractWe present, with a review of the relevant literature, the case of a 27-year-old woman with type 1 diabetes mellitus free of long-term complications who presented with vertigo and imbalance. Clinical exam showed evidence of cerebellar dysfunction, and magnetic resonance imaging demonstrated cerebellar atrophy. Anti-glutamic acid decarboxylase antibodies were detected in very high titers, and with all other causes of cerebellar atrophy being ruled out, the diagnosis of cerebellar atrophy associated with glutamic acid decarboxylase autoantibodies as previously described in the literature was made. After a review of the literature, we believe that this is the first report of this unusual condition in a young patient with type 1 diabetes mellitus.IntroductionGlutamic acid decarboxylase (GAD) catalyzes the conversion of glutamate to gamma amino butyric acid (GABA) and is the dominant antigen in stiff-man syndrome (SMS) and type 1 diabetes [1]. A link between GAD autoimmunity and cerebellar dysfunction has previously been shown in older patients with recent onset of type 1 diabetes mellitus and polyendocrine autoimmunity with Hashimoto’s thyroiditis and pernicious anemia [2]. We de-scribe a young patient with established autoimmune type 1 diabetes, Hashimoto’s thyroiditis, and pernicious anemia who presented with cerebellar ataxia and magnetic resonance imaging (MRI) found cerebellar atrophy and a very high titer of anti-GAD antibodies.Case ReportA 27-year-old, white woman with well-controlled type 1 diabetes (A1c’s between 5.5% and 6.6%) of 16 years duration without long-term diabetic complications presented with true vertigo and balance problems. On physical examination, she had difficulty with the heel-knee shin test on the left but not the right side and difficulty with tandem gait. A diagnosis of cerebellar dysfunction was made, and an MRI showed cerebellar parenchymal loss on the left side, which had not been seen on an MRI performed 3 years earlier. An antibody screen for paraneoplastic antigens was negative for antibodies to calcium channels type N and type PQ, and YO antibody was negative. The anti-GAD antibody titer was 3558 n mol/liter (normal less than 0.02 n mol/liter). Within 2 years of the development of cerebellar atrophy, she developed hypothyroidism secondary to Hashimoto’s thyroiditis and pernicious anemia.DiscussionThis case of cerebellar ataxia and high anti-GAD antibodies adds to the series of cases of cerebellar atrophy associated with high anti-GAD antibody levels previously de-scribed by Saiz et al. [2]. The three patients in the paper by Saiz et al., however, ranged in age from 52–76 years and had recent onset autoimmune diabetes. Abele et al. [3] have reported a 68-year-old patient with progressive cerebellar ataxia, insulin-dependent diabetes, and GAD autoantibodies who responded to intravenous immunoglobulins. Our patient had the onset of diabetes at age 5 and the onset of Hashimoto’s thyroiditis and pernicious anemia shortly after developing cerebellar ataxia. She is, therefore, the youngest patient in whom cerebellar ataxia associated with a high anti-GAD antibody has been described.High levels of anti-GAD antibodies have been associated with SMS [1]. Two diabetic patients with cerebellar ataxia included in a control group for comparison with SMS were found to have high anti-GAD antibody titers [4,5]. In addition, a cerebellar disorder has been described in a nondiabetic patient in association with the SMS [6,7], and a nondiabetic patient with cerebellar atrophy and peripheral neuropathy was also found to have high levels of anti-GAD antibodies [8].Why would high levels of anti-GAD antibody be associated with cerebellar ataxia? GAD antibodies must enter the cytoplasm of the cell to cause damage. Saiz et al. [2] proposed that in these patients the levels of anti-GAD antibodies in the cerebrospinal fluid are so high that they are taken up in excess by Purkinje cells from where they are transferred to the neurone where they interact with the GAD antigen and cause neuronal dysfunction. Ishida et al. [9] have shown in vitro that immunoglobulins from the cerebrospinal fluid of an ataxic GAD antibody positive patient acted presynaptically to cause a selective suppression of GABA-ergic transmission [8] Another possibility is that high levels of GAD antibody are simply a marker for damage to GAD antigen-containing neurons by a T cell-mediated immune attack on the GAD antigens in the central nervous system (CNS) in the same way that T-lymphocytes attack the GAD antigen in the pancreatic beta cell [8]. Whatever the pathophysiology, multiple autoimmune endocrine syndromes accompanied the high anti-GAD antibody levels in these patients, which is highly suggestive of an immune response to an antigen unique to the CNS, and GAD is only found in the CNS and the pancreatic beta cell.Another unlikely explanation is that the ataxia in this patient was due to pernicious anemia or hypothyroidism [10]. However, this patient was euthyroid, and although investigations for pernicious anemia were not performed at the time of presentation, there was no peripheral neuropathy, anemia, or other indications of a vitamin B12 deficiency.Because GAD is only found in the CNS and the pancreatic beta cell, why do so few GAD antibody positive patients with type 1 diabetes not develop more CNS problems? Comparing patients with SMS and type 1 diabetes provides some answers [11]. First, the HLA antigen types differ with the DQB1 0201 type in SMS and the DR 34 DQ302 type in type 1 diabetes being most prevalent [12,13]. Second, in type 1 diabetes, the GAD antibodies are directed against the GAD 1661 to 243 and 473 to 455 segments of the GAD antigen and to the 81 to 171 and 323 to 403 segments with SMS. Furthermore, both GAD 65 and 67, which predominate in the CNS, are antigenic in SMS; and only GAD 65, which predominates in the pancreatic beta cell is antigenic in type 1 diabetes [14]. In addition, the antibodies are conformational and mostly IGg1 with type 1 diabetes, and although IGg1 predominates in the SMS, patients with SMS were more likely to have in addition to IGg1, IgG4, and IgE antibodies with the formation of the antibodies being both linear and conformational [14]. Third, in type 1 diabetes there is a Th1 response where T-helper cells secrete gamma interferon and interleukin 2 (not interleukins 4, 5, or 6), and this inhibits type 2 T-helper cells that are involved in cell-mediated immunity by activating macrophages and cytotoxic T (CD8) cells, which recognize complexes of peptides and major histocompatibility-complex molecules on the target cell membrane. On the other hand, in SMS, there is a Th2 response where helper T cells secrete interleukins 4, 5, 6, and 10 (not interleukin 2 or gamma interferon), which inhibits type 1 T-helper cells that are chiefly involved in humoral immunity by stimulating B-lymphocytes to produce antibodies [15]. Last, and probably the most important, the levels of GAD antibodies are much higher in SMS, and at these levels, the antibodies have the ability to enter the CNS and to interfere with the synthesis of gamma-amino butyric acid (GABA).ConclusionIn conclusion, we have described a case of cerebellar atrophy associated with high levels of anti-GAD antibodies in a young patient with long-standing type 1 diabetes. This is the first report of this unusual condition in a young diabetic patient and in a patient with long-standing type 1 diabetes.References1. Solimena M, Folli F, Denis-Donini S, et al.: Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type 1 diabetes mellitus. N Engl J Med 1988; 318: 1012–20.[Context Link][CrossRef][Medline Link]2. Saiz A, Arpa J, Sagasta A, et al.: Autoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, late-onset insulin-dependent diabetes mellitus and polyendocrine autoimmunity. 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M.B. FACE; Ovalle, Fernando M.D.; Shadmany, Shahzad M.D.Case ReportsCase Reports311p 233-235