Neurological disorders associated with anti-glutamic acid decarboxylase autoantibodies
(anti-GAD Abs) include stiff-person syndrome (SPS) and its variants (stiff-trunk syndrome,
stiff-limb syndrome, progressive encephalomyelitis with rigidity and myoclonus [PERM],
or “SPS plus”, and paraneoplastic SPS) as well as epilepsy, abnormal eye movements,
limbic encephalitis and cerebellar ataxia[1],[2]. These syndromes are often found in association with other autoimmune disorders,
such as type 1 diabetes mellitus, Addison’s disease, thyroiditis, vitiligo, hemolytic
anemia, myasthenia gravis, vitamin B12 deficiency due to autoimmune destruction of
parietal cells (pernicious anemia) and polyglandular autoimmune syndromes[1],[2],[3],[4]. GAD is a cytoplasmic enzyme that produces GABA (γ-aminobutyric acid), the main
inhibitory neurotransmitter in the central nervous system (CNS). It is expressed predominantly
in CNS GABAergic neurons and pancreatic islet β-cells and has two isoforms, GAD 65,
which is more involved in neurological diseases, and GAD 67[1],[2],[3],[4]. GAD is also found in the liver, kidneys, adrenal glands, ovaries and testes, but
in lower concentrations. Anti-GAD Abs inhibit GAD activity and synthesis of GABA[1],[2],[3],[4]. Anti-GAD 65 autoantibodies were described initially in type 1 diabetes mellitus
patients and are considered a biomarker for this disease[3]. In 1956, Moersch and Woltman[5] published a case report of a 49-year-old man with progressive fluctuating muscular
rigidity and spasm (“stiff-man syndrome”) along with observations of thirteen other
cases. More recently, the term “stiff-man syndrome” was replaced by “stiff-person
syndrome” (SPS), and anti-GAD autoantibodies were found to be associated with this
disorder and its variants[4]. Immune-mediated cerebellar ataxias include gluten ataxia, paraneoplastic cerebellar
degeneration, ataxia associated with systemic lupus erythematosus, Hashimoto’s encephalopathy
(cerebellar type), primary autoimmune cerebellar ataxia and cerebellar ataxia associated
with GAD autoantibodies (GAD Abs-CA)[4]. This last condition was described in 1997 by Saiz et al.[6] in three patients who also had late-onset insulin-dependent diabetes mellitus and
polyendocrine autoimmunity. Since then, several case reports and a study of a small
series of patients have been published[2],[7],[8], as well as a study of fourteen patients by Honnorat et al.[9] published in 2001. GAD Abs-CA occurs most commonly in women in their sixth decade,
and the prognosis is usually poor[9],[10]. In 2008, Hadjivassiliou et al.11 published a prospective study on the prevalence
of immune-mediated cerebellar ataxia. Of 400 patients with progressive cerebellar
ataxia, 23 % had idiopathic sporadic ataxia. The prevalence of autoimmune disease
in this group was 47%. Gluten ataxia was diagnosed in 27% of the patients, paraneoplastic
cerebellar degeneration (PCD) in 3% and GAD Abs-CA in 2%.[11] In this issue of Arquivos de Neuro-Psiquiatria, Aguiar et al.[12] describe the clinical characteristics of patients with GAD Abs-CA. In their retrospective
study they evaluate three patients with this condition (one female and two males,
mean age 49.3 years), two of whom also had SPS. All the patients had high GAD-Ab titers
(> 100 IU/mL) without any paraneoplastic neurological syndromes. After treatment with
intravenous immunoglobulin, one patient made a partial recovery but the two others
showed no improvement.12 Associated endocrine disease included latent autoimmune diabetes
in adults (LADA) in two patients, and autoimmune polyglandular endocrinopathy type
2, or Schmidt’s syndrome in one patient[12]. In 2016, Mitoma et al.[10] published a review of guidelines for treatment of immune-mediated cerebellar ataxias.
They concluded that although various types of immunotherapies (including intravenous
methylprednisolone, intravenous immunoglobulins, plasma exchange and rituximab) have
been used in patients with GAD Abs-CA, most patients continue to have significant
disability and a poor prognosis.[10] However, in clinical practice some patients with this disorder show an improvement
in the cerebellar ataxia symptoms[2],[8],[9]. Despite the controversy surrounding treatment of this condition and its prognosis,
it is now imperative that neurologists be able to recognize this form of auto-immune
cerebellar ataxia caused by anti-GAD Abs.
