Multiple Cranial Mononeuropathies With Acetylcholine Receptor Antibody in Mitochondrial Diabetes

In 1997, we reported the first identified case of mitochondrial diabetes caused by a T-to-C transition at position 3264 (1). The patient had type 2 diabetes, lipoma, facial palsy, ophthalmoplegia, and hearing loss. His unique profile suggests the heterogeneity of mitochondrial (mt)DNA-related diabetes. Among the characteristics, bilateral facial palsy and ophthalmoplegia (right eye) were noteworthy because they have not been reported in mitochondrial diabetes associated with other pathogenetic mutations. At age 59 years, facial palsy appeared first on the right side and 6 months later on the left side. It occurred without pain and became persistent. At age 64 years, ophthalmoplegia occurred with transient ocular pain with ptosis and pupillary sparing. Interestingly, during the follow-up we observed that serum acetylcholine receptor antibody was positive at age 65 years (0.6 nmol/l; the titer is considered to be positive at >0.2 nmol/l, which is 2 SD above the mean of 170 normal control subjects). Edrophonium chloride (Tensilon) test was negative. Repetitive nerve stimulation was negative, and GAD antibody was negative.

Disordered autoimmunity such as islet cell antibody (ICA) and GAD antibody has been described in several case reports of mitochondrial diabetes or MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) (2–4). As for acetylcholine receptor antibody, it has been reported in two elderly women with external ophthalmoplegia; one of the two women had diabetes (5). Because ragged-red fibers and elevated lactic acid were observed in the patients, Mitsikostas et al. pointed out that ophthalmoplegia and acetylcholine receptor antibody are correlated with mitochondrial myopathies. Therefore, in this case, the association of cranial nerve palsies and positive acetylcholine receptor antibody may not be a fortuitous coincidence. It was speculated that mitochondrial DNA abnormality causes not only diabetes but also the immune destruction associated with acetylcholine receptor antibody, which develops bilateral facial nerve palsy and ophthalmoplegia.

However, as for ophthalmoplegia, this patient’s condition was complicated with ocular pain at onset and did not respond to the tensilon test. Because pain is not a manifestation of myasthenia gravis, vascular factors may be involved, overlapping on the pathogenesis of autoimmune factor. Since the report of Asbury et al. (6) in 1970, the etiology to understand ophthalmoplegia in diabetes has been hypothesized to result from diabetic microvascular injury involving small vessels that supply nerves. This patient had strongly succinate dehydrogenase reactive vessels that contained proliferation of abnormal mitochondria in the smooth muscle cells (1). Therefore, the ophthalmoplegia might be triggered by vascular events associated with a proliferation of abnormal mitochondria in vascular smooth muscle cells. Thus, this case suggests that cranial mononeuropathies in diabetes could possibly be caused by the synergistic effects of mitochondrial genetic abnormality, disordered autoimmunity, and/or microvascular abnormality.