Stiff-man syndrome: GABA, GAD, and mechanisms of disease

Stiff-man syndrome (SMS) is a rare disease of progressive muscle stiffness, most common in middle age, often associated with autoimmunity to glutamic acid decarboxylase (GAD) and responsive to treatment with GABA agonists. Diagnosis is established by clinical characteristics and confirmed by EMG or antibody testing. Anti-GAD antibodies are present in 60% of those with SMS and antiamphiphysin antibodies are found in fewer than 10%. The production of antibodies has an unclear relationship to the pathological processes of the disease. GABA receptors and GABA receptor mRNAs are found in high density in the spinal cord laminae and identify possible sites of dysfunction in SMS. At some spinal cord synapses, GABA co-localizes with glycine, a neurotransmitter implicated in hyperekplexia. Failure of spinal cord reflexes explains the symptoms of SMS, but electrophysiological studies have not yet identified a single locus of inhibitory failure. Immunomodulation may alter the disease course, but consistently effective treatments for SMS await development.