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  • Updated 02.29.2024
  • Released 10.19.2020
  • Expires For CME 03.01.2027

GAD antibody-spectrum disorders



The article describes the clinical phenotypes associated with anti-GAD antibodies as distinctly evolved in the last decade, their underlying pathophysiology, the significance of anti-GAD antibody titers in clinical diagnosis, and the current therapeutic approaches.

Key points

• High levels of GAD antibodies are associated with stiff-person syndrome and a subgroup of patients with cerebellar ataxia, encephalitis, or drug-resistant temporal lobe epilepsy.

• The diagnostic criteria for stiff-person syndrome include (1) stiffness of the axial muscles; (2) superimposed painful spasms; (3) electromyographic evidence of continuous motor unit activity at rest; (4) absence of an alternative diagnosis; and (5) high-titer anti-GAD antibodies.

• It is not clear whether GAD antibodies are pathogenic or a marker of aberrantly activated innate and acquired immunity.

• There is strong evidence that in stiff-person syndrome, as well as in patients with the other GAD-associated neurologic syndromes, there is intrathecal synthesis of GAD antibodies.

• IVIG is the first-line immunotherapy in conjunction with GABA-enhancing drugs.

• Rituximab can be useful for a subset of patients who have failed IVIg.

Historical note and terminology

Glutamic acid decarboxylase (GAD) is a pyridoxal 5’-phosphate-dependent enzyme that catalyzes the conversion of the excitatory neurotransmitter l-glutamate to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The enzyme is widely expressed within the central nervous system and pancreatic beta-cells but is also found in lower amounts in the liver, kidneys, adrenal glands, ovaries, and testes (66). The presence of autoantibodies against GAD was first described in 1988 by Solimena and colleagues in a 49-year-old woman with stiff-person syndrome, epilepsy, and type-1 diabetes mellitus. They detected anti-GAD antibodies in both serum and cerebrospinal fluid and identified for the first time the immunostaining pattern of these antibodies, pointing out the possible immunological connection between stiff-person syndrome and type 1 diabetes mellitus. They concluded that the clinical manifestations of stiff-person syndrome are related to disruption of GABAergic pathways, a notion that it is still valid today (126).

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ISSN: 2831-9125