Anti-amphiphysin antibody disorders

Introduction
A disorder with antibodies to amphiphysin was first described by De Camilli et al. in 1993 in several woman with breast cancer who developed stiff-person syndrome. Several years later Dropcho et al. reported detection of amphiphysin antibodies in three patients with paraneoplastic encephalomyelitis associated with SCLC. Rosin et al. described another case in a patient with breast cancer in 1998. Schmierer described a case in 1998 that was not clearly associated with any malignancy, but three years later they reported that the patient had been diagnosed with breast cancer.

Several additional case series were subsequently published of patients with symptoms of encephalopathy, neuropathy, and/or opsoclonus-myoclonus. In 2002 Perego et al. published a case of a patient with sensorimotor neuropathy, who had autoantibodies to both amphiphysin I and amphiphysin II. In 2004 a case was reported of a patient with limbic encephalitis with anti-amphiphysin antibodies. A large series of 63 patients was published in 2005.

Pathophysiology
Amphiphysin is an enzyme associated with synaptic vesicles and is produced from the gene AMPH on chromosome 7p13-p14. It has a role in synaptic vessel endocytosis with binding to clathrin. There are actually two types of amphiphysin, amphiphysin I and amphiphysin II. These exist primarily as a heterodimer. A splice variant called muscle amphiphysin 2 is expressed in skeletal muscle.

Antibody may be able to bind to amphiphysin when it is transiently exposed to the cell surface when a vesicle fuses with the cell membrane. Antibodies then bind to the amphiphysin SH3 domain, which blocks its interaction with other proteins. This leads to defective endocytosis, which in turns leads to a reduced number of presynaptic vesicles filled with neurotransmitter, in this case GABA. Thereby it reduces GABAergic transmission.

As the disease progresses, irreversible damage may occur due to inflammatory infiltration which appears to have involvement of CD8+ T cells. Mice injected with amphiphysin antibodies developed muscle spasms similar to human stiff-person syndrome.

Amphiphysin 1 has increased expression in breast cancer tumors compared with normal breast, and is hypothesized to have anti-oncogenetic functions.

Epidemiology
Anti-amphiphysin antibodies are much less common as causes of stiff-person syndrome than anti-GAD antibodies.

Age: average 60-65 (range 39-79)

Female predominance

Of 78,889 patients tested for paraneoplastic antibodies, one or more antibodies were seen in 9,183 patients (12%). Anti-amphiphysin antibodies were found in 39 patients (0.05% of total, 0.4% of all positive paraneoplastic panels).

Of note, anti-amphiphysin antibodies are seen in approximately 2% of patients without paraneoplastic syndromes and in healthy controls.

Symptoms predated cancer diagnosis by 4 months on average (range 2-24 months).

Signs and symptoms

 * Sensory or sensorimotor neuropathy: 53%-60%
 * Sensory: 22%
 * Sensorimotor: 17%
 * Polyradiculopathy: 6%
 * Pruritis: 5%
 * Motor: 3%
 * Neuromyotonia: 3%
 * Brachial plexopathy: case report
 * Encephalitis/encephalopathy: 30%
 * Limbic encephalitis: 6%
 * Several cases of limbic encephalitis reported in children
 * Stiff-person syndrome spectrum disorders: 29%
 * More cervical and arm involvement than in anti-GAD syndrome
 * Stiff-limb: 21%
 * Stiff-person: 8%
 * Dysautonomia: common, 45% of non-stiff-person cases in one series
 * Myelitis/myelopathy: 27%
 * Cerebellar syndrome: 17%
 * Cranial neuropathies: 10%
 * Opsoclonus/myoclonus: 9%
 * Lambert-Eaton myasthenic syndrome: 8%
 * Optic neuritis / retinitis: 5%
 * Brainstem encephalitis
 * Rhabdomyolysis or necrotizing myopathy
 * Sensorineural hearing loss

Associated malignancies
Anti-amphiphysin antibodies are associated with malignancy in 35-79% of cases.
 * Breast cancer: most common in women
 * In one series, this was the second most common paraneoplastic antibody in breast cancer patients (after anti-PCA-1/Yo).
 * Small-cell lung cancer: most common in men
 * Presence of both amphiphysin and either ANNA-1 or CRMP-5 antibodies may suggest SCLC
 * Although SCLC is very common in patients with anti-amphiphysin antibodies, in patients with SCLC these antibodies are very rare.
 * Other malignancies
 * Non-small cell lung cancer
 * Ovarian carcinoma
 * Melanoma
 * Thymoma
 * Hodgkin's lymphoma
 * Colon cancer
 * Cervical cancer
 * Gastric cancer
 * Esophageal cancer
 * Follicular thyroid adenoma
 * Angiosarcoma
 * Neuroendocrine tumor

Other associated autoantibodies
In one series, 74% of cases had one or more coexisting antibodies. Patients with small cell carcinoma have other antibodies (in addition to anti-amphiphysin) in more than 80% of cases, while those with breast cancer tend to have anti-amphiphysin alone.
 * Anti-ANNA-1
 * Anti-CRMP-5:
 * Anti-Hu antibodies
 * Anti-P/Q-type calcium channel
 * Anti-N-type calcium channel
 * Anti-GAD
 * Anti-AChR
 * Anti-PCA2
 * Anti-SOX1
 * Anti-mitochondrial antibodies (M2 type)
 * Anti-VGCC
 * Anti-ANNA-2
 * Anti-VGKC
 * Anti-thyroglobulin
 * Anti-TPO
 * Anti-AGNA1
 * Anti-GABAB
 * Anti-AMPA receptor
 * Anti-AQP4

CSF

 * Elevated WBCs, predominantly lymphocytes
 * Elevated protein
 * Oligoclonal bands

Imaging

 * MRI
 * Often normal
 * Can show intrinsic spinal cord abnormality

Treatment
In one study of 13 patients who received various immunotherapies, 11 (85%) had improvement, even in one patient who was 10 years after onset of symptoms.
 * Removal/treatment of underlying malignancy
 * Steroids
 * IVIG
 * Cyclophosphamide
 * Plasmapheresis
 * Rituximab

Prognosis
In one study of 63 patients, 13 died during the study period, with mean interval from symptom onset to death of 33 months. In this study, 40% of patients were wheelchair bound at 6 months after symptom onset. . In a series of 9 patients with myelopathy from anti-amphiphysin antibodies, at last follow-up 2 were using a walker and 7 were using a wheelchair.

Ini a series of 53 patients with anti-amphiphysin IgG autoimmune neuropathy, 58% of patients were immunotherapy responsive. Patients with additional other antibodies tended to be less immunotherapy responsive.