Morvan’s syndrome and myasthenia gravis related to familial Mediterranean fever gene mutations

A 40-year-old woman had experienced ptosis and double vision with daily fluctuations for 1 year and was admitted to our hospital in August 2012. She also had insomnia, hyperhidrosis, and progressive weakness of the extremities. She had experienced recurrent fever, arthralgia, abdominal pain, and oral aphtha since childhood; her mother, older sister, and son also had self-limiting periodic fever. Neurologically, she had ptosis, double vision, mild dysphagia, neck flexor weakness (Medical Research Council (MRC) scale grade 4), symmetrical weakness of her deltoids (MRC grades: right 4/left 4), triceps (right 4/left 4), digit flexors (right 3/left 3), quadriceps (right 4/left 4), and tibialis anterior muscles (right 4/left 4), grip myotonia, and myokymia. Myokymia was most frequently seen in the bilateral first dorsal interosseous muscles and less frequently in the lower leg and trunk muscles. An edrophonium test was positive for ptosis, double vision, and proximal limb muscle weakness but not distal muscle weakness. Blood tests were unremarkable except for hyper-IgDemia (12.2 mg/dL; normal, 0.0–9.0). Anti-acetylcholine receptor antibodies were weakly positive (0.4 nmol/L; normal, <0.2) and anti-muscle-specific receptor tyrosine kinase and anti-low density lipoprotein receptor-related protein 4 antibodies were negative. Anti-voltage-gated potassium channel (VGKC) complex antibodies were elevated to 316 pM (normal, <100), while antibodies against leucine-rich glioma inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (Caspr2) were negative. Cerebrospinal fluid tests including IgG index (0.51; normal, <0.73) were normal and oligoclonal IgG bands were absent. Brain and skeletal muscle magnetic resonance imaging and positron emission tomography/computed tomography of the whole body detected no abnormalities including thymic tumors. Needle electromyography showed neuromyotonic discharges in the left quadriceps and first dorsal interosseous muscles (Fig. 1a) and myokymic discharges in the right thenar muscles (Fig. 1b). Nerve conduction studies in the upper and lower extremities were normal. Repetitive nerve stimulation of the orbicularis oculi, frontalis, and abductor digiti minimi muscles showed no decremental or incremental responses. Electroencephalography revealed intermittent irregular slow waves around 4 Hz in the left temporal region without epileptic discharge. Unrelated word pairs (in Miyake’s Paired-Associate Word Learning Test; a Japanese memory function test) elicited low scores: first task = 0 (normal, 3.2–7.0), second task = 4 (normal, 6.6–10.0), and third task = 7 (normal, 7.7–10.0). Based on these observations, we diagnosed her as having MoS complicated with MG. Intravenous methylprednisolone (IVMP) (1 g/day for 3 days) followed by oral prednisolone (PSL) (40 mg/day) with gradual tapering and five courses of simple plasma exchange (PE) alleviated the ptosis, double vision, memory disturbance, hyperhidrosis, and insomnia. The left temporal slow waves were diminished on electroencephalography. The unrelated word pair scores also improved: first task = 3, second task = 9, and third task = 9. However, her myokymia and muscle weakness persisted. Administration of a choline esterase inhibitor (pyridostigmine 180 mg/day) was effective for the ptosis, double vision, and proximal limb weakness but not the distal muscle weakness. Genetic analyses of MEFV revealed compound heterozygous mutations of L110P/E148Q in exon 2 (Fig. 1c, d), while analyses for mutations associated with tumor necrosis factor (TNF) receptor-associated periodic syndrome and hyper-IgD syndrome were negative. She had an HLA-B51/-52 genotype. Based on these findings, she was also diagnosed with FMF [1].

Her MG symptoms were exacerbated in January 2013 and she was re-admitted to our hospital. Marked elevation of serum interleukin (IL)-6 (353 pg/mL; normal, <8), TNF-α (43 pg/mL; normal, <2.8), and IL-1β (24 pg/mL; normal, <10) was found. She was treated with IVMP followed by oral PSL (40 mg/day) with gradual tapering, which led to limited efficacy for the ptosis and double vision. Although oral colchicine (1 mg/day) resolved her recurrent fever, arthralgia, and oral aphtha, her MG symptoms frequently recurred from July 2013 to October 2014. PE and IVIg (0.4 g/kg/day for 5 days) were required repeatedly every several months, in addition to PSL (5–10 mg/day) and immunosuppressants (tacrolimus 6 mg/day or azathioprine 100 mg/day), which showed transient efficacy for the ptosis, double vision, and proximal limb weakness. However, the limb weakness with myokymia progressively worsened (right 3/left 3), which rendered her wheelchair-bound.

In conclusion, FMF-related auto-inflammation may contribute to the development and augmentation of MG and MoS, suggesting a possible link between auto-inflammation and auto-antibody-mediated diseases.