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Stiff-person syndrome

Written2006-12Franco Folli, Claudia Sommer
Department of Medicine/ Division of Diabetes, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr MC 7886, San Antonio, Texas 78229-3900, USA

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Identity

Other namesStiff-man syndrome
Atlas_Id 10103
Genes implicated inAMPH  GAD2  GPHN  
Inheritance none known

Clinics

Note Stiff-person syndrome is a rare neurological disorder characterized by stiffness of skeletal muscles with superimposed spasms. The syndrome is a putative autoimmune disease occurring as an idiopathic or paraneoplastic condition. It is often associated with antibodies to glutamic acid decarboxylase (GAD) or, less commonly, to the 128 kD synaptic protein later amphiphysin (AMPH) and few other autoantigens.
Phenotype and clinics Diagnosis of GAD-antibody associated stiff-person syndrome is made according to the following criteria: Prodrome of stiffness and rigidity in axial muscles
Progression to include stiffness of limbs, making walking difficult
Increased lumbar lordosis
Presence of superimposed painful spasm, often precipitated by external stimuli (auditory stimulation like hand clapping)
Normal sensation, no paresis
An EMG finding of continuous motor unit activity (CMUA) at rest
Response to benzodiazepines including clinical response and reduction on CMUA
High levels of GAD antibodies
Other features: Less frequently, stiff-person syndrome is associated with antibodies to the 128 kDa synaptic protein amphiphysin. It is then a paraneoplastic condition, most often occurring with breast cancer. The pathogenic role of the antibodies directed against the 128 kDa synaptic protein amphiphysin has been shown by transmission of disease symptoms by passive transfer to rats. One case of stiff-person syndrome associated with antibodies to the synaptic protein gephyrin has been described.
 
 
 
Neoplastic risk GAD-antibody positive stiff-person syndrome has not been described as a paraneoplastic condition. Most cases of amphiphysin antibody associated stiff-person syndrome are paraneoplastic. Cancers described are breast cancer, small-cell lung, and ovarian carcinoma. The one case with anti-gephyrin antibodies was associated with an undifferentiated carcinoma of the mediastinum.
Treatment Patients may respond to symptomatic treatment with benzodiazepines, and to a certain extent baclofen, valproic acid, tiagabine, and other drugs enhancing GABAergic transmission. Given the autoimmune pathogenesis immunosuppression, plasmapheresis, and high dose intravenous immunoglobulins (IVIG) seem to be treatments of choice. The only randomized controlled trial in this disorder showed that IVIG was an efficient treatment in GAD-antibody positive stiff-person syndrome. In the paraneoplastic forms, removal of the cancer is essential. Anti-amphiphysin associated stiff-person syndrome has been successfully treated with plasmapheresis.
Evolution GAD-antibody positive stiff-person syndrome is usually slowly progressive, but can make patients bed-bound in the end. The paraneoplastic types are usually rapidly progressive and may be associated with encephalitis and other paraneoplastic syndromes. The prognosis of the neurological disorder depends on tumor treatment.

Genes involved and Proteins

 
Gene NameGAD2
Alias GAD65
Location 10p12
Note GAD2 isthe rate limiting enzyme of GABA synthesis. Stiff-person syndrome with autoantibodies directed against GAD is associated with type 1 diabetes mellitus and polyendocrine autoimmune diseases, including Grave's disease, hypothyroidism, Addison's disease and atrophic gastritis.

 
Gene NameAMPH
Location 7p14
Note AMPH is a 128 kd synaptic protein. It supports endocytosis at synapses by the formation of dynamin-rings around clathrin vesicles. Stiff.person syndrome, with autoantibodies directed against Amphiphysin, is associated with breast cancer.

 
Gene NameGPHN
Location 14q24
Note GPHN is a postsynaptic protein needed for the clustering of glycine receptors.

Bibliography

Antiamphiphysin antibodies are associated with various paraneoplastic neurological syndromes and tumors.
Antoine JC, Absi L, Honnorat J, Boulesteix JM, de Brouker T, Vial C, Butler M, De Camilli P, Michel D
Archives of neurology. 1999 ; 56 (2) : 172-177.
PMID 10025422
 
Autoimmunity to gephyrin in Stiff-Man syndrome.
Butler MH, Hayashi A, Ohkoshi N, Villmann C, Becker CM, Feng G, De Camilli P, Solimena M
Neuron. 2000 ; 26 (2) : 307-312.
PMID 10839351
 
High-dose intravenous immune globulin for stiff-person syndrome.
Dalakas MC, Fujii M, Li M, Lutfi B, Kyhos J, McElroy B
The New England journal of medicine. 2001 ; 345 (26) : 1870-1876.
PMID 11756577
 
The synaptic vesicle-associated protein amphiphysin is the 128-kD autoantigen of Stiff-Man syndrome with breast cancer.
De Camilli P, Thomas A, Cofiell R, Folli F, Lichte B, Piccolo G, Meinck HM, Austoni M, Fassetta G, Bottazzo G
The Journal of experimental medicine. 1993 ; 178 (6) : 2219-2223.
PMID 8245793
 
Autoantibodies to a 128-kd synaptic protein in three women with the stiff-man syndrome and breast cancer.
Folli F, Solimena M, Cofiell R, Austoni M, Tallini G, Fassetta G, Bates D, Cartlidge N, Bottazzo GF, Piccolo G
The New England journal of medicine. 1993 ; 328 (8) : 546-551.
PMID 8381208
 
Stiff man syndrome and related conditions.
Meinck HM, Thompson PD
Movement disorders : official journal of the Movement Disorder Society. 2002 ; 17 (5) : 853-866.
PMID 12360534
 
Stiff-person syndrome.
Murinson BB
The neurologist. 2004 ; 10 (3) : 131-137.
PMID 15140273
 
Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin.
Sommer C, Weishaupt A, Brinkhoff J, Biko L, Wessig C, Gold R, Toyka KV
Lancet. 2005 ; 365 (9468) : 1406-1411.
PMID 15836889
 
Neuropathology and binding studies in anti-amphiphysin-associated stiff-person syndrome.
Wessig C, Klein R, Schneider MF, Toyka KV, Naumann M, Sommer C
Neurology. 2003 ; 61 (2) : 195-198.
PMID 12874398
 
The amphiphysin family of proteins and their role in endocytosis at the synapse.
Wigge P, McMahon HT
Trends in neurosciences. 1998 ; 21 (8) : 339-344.
PMID 9720601
 

Citation

This paper should be referenced as such :
Sommer, C ; Folli, F
Stiff-person syndrome
Atlas Genet Cytogenet Oncol Haematol. 2007;11(2):141-144.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Tumors/StiffpersonID10103.html


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