Neurological syndromes associated with antibodies against the glutamic acid decarboxylase (GAD)

This thesis focuses on antibodies against the glutamic acid decarboxylase (GAD-ab) in neurological disorders. GAD-ab were first identified in 1988 in the serum and CSF from one patient with stiff-person syndrome (SPS) and diabetes mellitus (T1DM). Since then, GAD-ab have become excellent biomarkers in several autoimmune conditions affecting the endocrine system, the CNS or both simultaneously. High serum GAD-ab levels have expanded the neurological spectrum and have been described in patients with cerebellar ataxia (CA), epilepsy and limbic encephalitis (LE) of autoimmune origin. Even though all the syndromes share the same autoimmune biomarker, it may well be that GAD-ab have a different role in each syndrome. Whether all GAD-associated syndromes share the same pathogenic mechanisms, or what renders certain brain regions vulnerable to autoantibody attack is not clear. In recent years, other antibodies have been found in patients with neurological syndromes attributed to GAD-ab, such as antibodies directed against the alpha subunit of the glycine receptor (GlyRα1) in patients with syndromes of the stiff-person spectrum, or antibodies against GABA receptors (GABAA in patients with severe epilepsy, and GABAB in patients with limbic encephalitis, GAD-ab and an unknown lung cancer), yielding the possibility of an alternative immunological response coexisting with GAD autoimmunity that might be more relevant in certain neurological conditions. In this thesis we explored the immunological determinants linked to the different neurological phenotypes with state-of-the-art techniques, and investigated the prognostic value of GAD-ab in neurological disorders. After studying the largest cohort of patients (121) with neurological syndromes and GAD-ab, we found that: 1) the presence of additional antibodies against antigens of the inhibitory synapse or a different reactivity against particular GAD isoforms or sites of GAD65 do not explain the diversity of the clinical phenotype in non-paraneoplastic neurological syndromes associated with GAD-ab; 2) the immunological response against GAD is different in serum and CSF, indicating a process of antigen-driven intrathecal maturation in patients with non-paraneoplastic syndromes; 3) patients with cerebellar ataxia and GAD-ab may respond to immunotherapy, and maintain good functional status at long-term. Early initiation of treatment likely offers a greater chance of improvement; 4) neurological syndromes with paraneoplastic criteria in the context of GAD autoimmunity have a different clinical presentation and humoral immunity profile. Patients presenting neurological syndromes not typically associated with GAD-ab should be screened for an underlying cancer; 5) among patients with stiff-person spectrum disorders, the immunological classification is an independent predictor of outcome. Those patients with GAD-ab have worse prognosis than antibody-negative patients and patients with GlyR-ab. Our results confirmed that autoimmunity regarding the humoral response is similar among different neurological syndromes, and that GAD-ab is still the most important biomarker in these diseases. From a clinical perspective we contributed to fill some clinical gaps, like the value of GAD-ab in SPS, the management of patients with GAD-associated CA, and he clues to suspect paraneoplastic neurological syndromes.Esta tesis se centra en síndromes neurológicos asociados a anticuerpos contra el enzima descarboxilasa del ácido glutámico (anti-GAD), descritos asociados a multitud de síndromes neurológicos y enfermedades endocrinológicas. El rol de estos anticuerpos en cada una de estas entidades no está perfectamente establecido. Los resultados de esta tesis contribuyen a clarificar qué valor tiene el hallazgo de anticuerpos anti-GAD en pacientes con determinados síndromes neurológicos y a caracterizar el perfil de algunos de los grupos grupos clínicos asociados a anti-GAD más desconocidos, como son pacientes con ataxia cerebelosa (AC) o síndromes paraneoplásicos. Algunas de las conclusiones más relevantes, recogidas en las 4 publicaciones principales que conforman esta tesis, son: 1) la presencia adicional de anticuerpos contra antígenos de la sinapsis inhibitoria, una reactividad diferente contra alguna de las isoformas de GAD o contra algún epítopo particular de GAD65, no determinan la diversidad fenotípica en síndromes neurológicos asociados a anti-GAD ; 2) la respuesta inmune contra GAD difiere en suero y líquido cefalorraquídeo; 3) los pacientes con AC y anti-GAD pueden responder a la inmunoterapia y mantener un buen estado funcional a largo plazo, pero es importante la instauración del tratamiento de forma precoz; 4) los síndromes neurológicos paraneoplásicos asociados a anti-GAD tienen una presentación clínica y un perfil inmunológico diferente; 5) En pacientes con síndromes del espectro de la persona rígida, la clasificación inmunológica es un factor pronóstico independiente. Aquellos pacientes con anticuerpos anti-GAD tienen un peor pronóstico