Stiff-person syndrome

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Stiff-person syndrome

Identity

Other names Stiff-man syndrome
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.

Western blots of brain homogenates showing protein antigens recognized by serum and cerebrospinal fluid samples from patients 1,2 and 3, affected by stiff-man syndrome and breast cancer (lane 1,2 and 3) and by serum samples from control patients and normal subjects. The sera from the three patients affected by affected by stiff-man syndrome and breast cancer did not react with the Gad band, which was recognized by a human serum positive for GAD antibodies (lane 4). Lane 5, serum from a control patient with the stiff-man syndrome who did not have GAD antibodies; and lane 6 serum of a normal subject. A band with an apparent molecular mass of 128 kd was recognized by the serum samples of patient 1, 2 and 3. Lane 7 and 8 were both loaded with 20 ug of protein from a homogenate of a rat brain and were labelled with serum and cerebrospinal fluid, respectively, from patient 3. (Reprinted with permission from F. Folli et al, Autoantibodies to a 128 kd protein in three women with the stiff-man syndrome and breast cancer. N Engl J Med 1993; 328: 546-551. Copyright 1993 Massachusetts Medical Society. All rights reserved). Photomicrographs of Sections of Rat Cerebellum and Brain Stem Stained with Serum Samples (Diluted 1:20) from Patients 1, 2, and 3 affected by stiff-man syndrome and breast cancer, and a Control Patient affected by stiff-man syndrome with autoantibodies against glutamic acid decarboxilase and with Rabbit Antibodies to Synaptic-Vesicle Proteins.
Anti-amphiphysin antibody titers during two series of plasma exchanges (filled squares: anti-amphysin titer, arrows: days of plasma exchange) in a patient with anti-amphiphysin associated stiff-person syndrome. Clinical improvement closely correlated with drop in titer. ( Reprinted from Wessig et al, Neurology 2003; 61:195-198, with permission).

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 Name GAD2 (Glutamate decarboxylase 2)

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 Gravešs disease, hypothyroidism, Addisonšs disease and atrophic gastritis.

Gene Name AMPH (Amphiphysin)

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 Name GPHN (Gephyrin)

Location 14q24

Note GPHN is a postsynaptic protein needed for the clustering of glycine receptors.

External links

Orphanet ORPHA3198

Bibliography

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

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

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

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

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

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

REVIEW articles automatic search in PubMed

Last year publications automatic search in PubMed

Contributor(s)

Written 12-2006 Franco Folli, Claudia Sommer

Citation

This paper should be referenced as such :
Folli F, Sommer C . Stiff-person syndrome. Atlas Genet Cytogenet Oncol Haematol. December 2006 .
URL : http://AtlasGeneticsOncology.org/Genes/StiffpersonID10103.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Wed Sep 24 21:08:26 2008

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For comments and suggestions or contributions, please contact us

j.l.huret@chu-poitiers.fr.

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.




	Western blots of brain homogenates showing protein antigens recognized by serum and cerebrospinal fluid samples from patients 1,2 and 3, affected by stiff-man syndrome and breast cancer (lane 1,2 and 3) and by serum samples from control patients and normal subjects. The sera from the three patients affected by affected by stiff-man syndrome and breast cancer did not react with the Gad band, which was recognized by a human serum positive for GAD antibodies (lane 4). Lane 5, serum from a control patient with the stiff-man syndrome who did not have GAD antibodies; and lane 6 serum of a normal subject. A band with an apparent molecular mass of 128 kd was recognized by the serum samples of patient 1, 2 and 3. Lane 7 and 8 were both loaded with 20 ug of protein from a homogenate of a rat brain and were labelled with serum and cerebrospinal fluid, respectively, from patient 3. (Reprinted with permission from F. Folli et al, Autoantibodies to a 128 kd protein in three women with the stiff-man syndrome and breast cancer. N Engl J Med 1993; 328: 546-551. Copyright 1993 Massachusetts Medical Society. All rights reserved). Photomicrographs of Sections of Rat Cerebellum and Brain Stem Stained with Serum Samples (Diluted 1:20) from Patients 1, 2, and 3 affected by stiff-man syndrome and breast cancer, and a Control Patient affected by stiff-man syndrome with autoantibodies against glutamic acid decarboxilase and with Rabbit Antibodies to Synaptic-Vesicle Proteins. Anti-amphiphysin antibody titers during two series of plasma exchanges (filled squares: anti-amphysin titer, arrows: days of plasma exchange) in a patient with anti-amphiphysin associated stiff-person syndrome. Clinical improvement closely correlated with drop in titer. ( Reprinted from Wessig et al, Neurology 2003; 61:195-198, with permission).



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.

Gene Name	GAD2 (Glutamate decarboxylase 2)
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 Gravešs disease, hypothyroidism, Addisonšs disease and atrophic gastritis.

Gene Name	AMPH (Amphiphysin)
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 Name	GPHN (Gephyrin)
Location	14q24
Note	GPHN is a postsynaptic protein needed for the clustering of glycine receptors.

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed