Compound Heterozygote Mutation of C12orf65 Causes Distal Motor Neuropathy and Optic Atrophy

The C12orf65 gene is a nuclear gene that encodes a mitochondrial matrix protein contributing to mitochondrial translation. [1] C12orf65 gene-related diseases are rare and present with large heterophenotypes. Most of the reported patients have had optic atrophy with intellectual disability, encephalomyopathy, spastic paraplegia, and ophthalmoplegia. Peripheral neuropathy has been reported in one family. [3] Here, we report a case of a Chinese patient with optic atrophy and distal motor neuropathy due to a novel compound heterozygous mutation in the C12orf65 gene. The girl in this case is an 8-year-old, single offspring of a nonconsanguineous couple. Her delivery was normal, with normal motor and mental development in infancy. At the age of 3 years, she showed insidious progressive loss of visual acuity. Ophthalmic examination revealed 20/100 vision in both eyes. Her visual acuity decreased to 15/100 vision at the age of 5 years. Fundoscopic examination demonstrated bilateral optic atrophy [Figure 1a]. The median value of the latency of flash visual-evoked potentials was delayed, indicating axonal damage of the optic nerves. Optical coherent tomography revealed a general reduction of the retinal nerve fiber layer thickness [Figure 1b]. Ophthalmic examination exposed a temporal visual field defect [Figure 1c]. At the age of 7 years, she had running difficulty due to foot drop and pes cavus. At the age of 8 years, she had a high steppage gait due to a deteriorated foot drop and required the daily use of ankle splints during walking. Neurological examination revealed loss of visual acuity with bilateral optic atrophy. Sensitivity to pinprick, touch, temperature, positioning, and vibration was normal in all the limbs. The muscle strength was normal in the upper limbs, 4/5 in foot flexion (Medical Research Council Scale, Grade 0–5), and 2/5 in foot dorsiflexion. There was wasting of the calves with normal muscle tone in all limbs. Deep tendon reflexes were normal in the upper limbs. In addition to the brisk reflexes of the knee and the ankle, there were no other pyramidal signs. The feet appeared to have a pes cavus deformity with a flexion contracture of the toes. Brain magnetic resonance imaging studies showed bilateral optic atrophy. The other cerebral structures were unremarkable. Nerve conduction velocity studies were consistent with bilateral motor axonal neuropathy in all limbs, sparing the sensory nerves [Table 1]. Motor nerve conduction velocities (MNCVs) were not evoked in the distal lower limbs, while very low amplitudes of compound motor …