Neurological disorders associated with glutamic acid decarboxylase antibodies: a Brazilian series

Abstract

Neurological disorders associated with glutamic acid decarboxylase (GAD) antibodies include stiff-person syndrome (SPS) and its variants -stiff trunk syndrome, stiff limbs syndrome, progressive encephalomyelitis with rigidity, SPS-plus and paraneoplastic SPS -as well as epilepsy and ataxia [1][2][3][4][5][6][7][8] . These syndromes are often found in association with other autoimmune disorders, such as diabetes mellitus, in more than one thirds of all cases, and, less commonly, those caused by antithyroid, antinuclear and antiparietal cell antibodies (5-10%) [1][2][3][9][10][11][12][13] . GAD is a cytoplasmic enzyme that accelerates the conversion of glutamic acid to gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter present in the brain and spinal cord. GAD is synthesized mainly in presynaptic GABAergic neurons in the central nervous system and in the b cells in the islets of Langerhans in the pancreas. GAD autoantibodies are found in around 60 to 80% of SPS cases. Although there are two GAD isoforms ¾ GAD65 and GAD67 ¾ the main target for GAD autoantibodies in SPS is GAD65 [9][10][11][12][13][14] . The pathogenetic role of autoantibodies in SPS is unclear. However, all SPS autoantigens identified to date are synaptic proteins involved in inhibitory synaptic transmission, such as GAD and amphiphysin (presynaptic antigens) and GABA(A) receptor-associated protein (GABARAP) and gephyrin (postsynaptic antigens). The autoantibodies anti-amphiphysin and anti-gephyrin have been linked to paraneoplastic SPS [9][10][11][12][13][14][15] . The objective of this study was to present the clinical and laboratory findings of 12 patients with neurological disorders associated with anti-GAD antibodies. ABSTRACT Neurological disorders associated with glutamic acid decarboxylase (GAD) antibodies are rare pleomorphic diseases of uncertain cause, of which stiff-person syndrome (SPS) is the best-known. Here, we described nine consecutive cases of neurological disorders associated with anti-GAD, including nine patients with SPS and three cases with cerebellar ataxia. Additionally, four had hypothyroidism, three epilepsy, two diabetes mellitus and two axial myoclonus.

Clinical characteristics of patients with cerebellar ataxia associated with anti-GAD antibodies

“…The association between SPS and CA-GAD-ab is even more unusual and creates additional challenges to diagnosis and treatment 20,21,22,23,24,25,26 . This overlap emphasizes a possible common mechanism, which is probably related to the widespread distribution of GAD throughout the CNS 1,2,4,6 .…”

“…This overlap emphasizes a possible common mechanism, which is probably related to the widespread distribution of GAD throughout the CNS 1,2,4,6 . A personal or familial history of other autoimmune diseases such as autoimmune diabetes mellitus, Addison's disease, hemolytic anemia or thyroiditis is commonly found in CA-GAD-ab 6,22 . All the patients reported here had an endocrine disorder: two had latent autoimmune diabetes of adults and one had autoimmune polyglandular syndrome type 2, also known as Schmidt syndrome, which is the most common of the immunoendocrinopathy syndromes characterized by the obligatory occurrence of autoimmune Addison's disease in combination with thyroid autoimmune disorders and/or autoimmune diabetes mellitus (type 1 diabetes mellitus or latent autoimmune diabetes of adults) 23 .…”

Cerebellar ataxia associated with anti-glutamic acid decarboxylase (anti-GAD) autoantibodies: a rare and puzzling disease

“…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).…”

“…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.…”

“…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 .…”