Lipoma and Sensory Neuropathy in Mitochondrial Diabetes Associated With tRNA Mutation at Position 3271

We previously reported the first identified case of mitochondrial diabetes caused by a T-to-C transition at position 3271 (1). At age 32 years, the patient had lower limb paresthesia. Since beginning diet therapy at age 33 years, his glycemic control has generally been good (HbA_1c 6–7%) and the paresthesia has disappeared.

During 12 years of follow-up, we observed two important clinical features: 1) lower limb paresthesia manifesting even with mild hyperglycemia (e.g., HbA_1c ∼7.5%) and 2) lipoma (round, 10-mm diameter) manifesting at age 44 years over the left breast.

Low et al. (2) hypothesized that lipid peroxidation under hyperglycemic conditions causes mitochondrial DNA (mtDNA) mutations that increase oxygen radicals, causing further damage to the mitochondrial respiratory chain, ultimately resulting in sensory neuropathy. Regarding the lower limb paresthesia of this patient, we speculate that lack of an effective mechanism for maintaining mitochondrial function renders sensory nerves susceptible to hyperglycemic toxicity, thereby producing symptoms.

As for the lipoma, several such cases have been described in the literature. Berkovic et al. (3) reported on four patients, two with multiple symmetric lipomatoses and two with lipoma and multisystem disorder, all with mitochondrial dysfunction. Holme et al. (4) suggested that mtDNA mutations may be either a direct or an indirect cause of pertubation of the maturation process of adipocytes. In benign symmetric lipomatosis (Madelung’s disease), functional sympathetic denervation of adipose tissue is thought to cause an abnormal free fatty acid response to epinephrine. Therefore, lipoma may be a manifestation of peripheral nerve system denervation caused by mitochondrial dysfunction.

Thus, our present case raises the possibility of an association between lipoma and sensory polyneuropathy, both of which appear to be manifestations of mitochondrial diabetes caused by the 3271 mtDNA mutation. This case supports the previous observation of Klopstock et al. (5), indicating a high frequency of peripheral neuropathy in multiple symmetric lipomatosis patients with mitochondrial dysfunction.