A number sign (#) is used with this entry because of evidence that demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I) is caused by heterozygous mutation in the POLR3B gene (614366) on chromosome 12q23.

Demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I) is a neurologic disorder characterized predominantly by delayed motor development in the first years of life associated with gait abnormalities, sensory ataxia, hyporeflexia, and distal sensory impairment due to a sensorimotor peripheral neuropathy that mainly affects the lower limbs. The disorder is progressive, and some may have upper limb involvement. A subset of patients has central nervous system involvement that manifests as global developmental delay with impaired intellectual development and speech difficulties. Other features may include spasticity, hyperreflexia, tremor, dysmetria, seizures, or cerebellar findings. Brain imaging may be normal or show nonspecific abnormalities, such as white matter signal changes and delayed myelination (summary by Djordjevic et al., 2021).

For a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (118200).

Djordjevic et al. (2021) reported 6 unrelated patients, ranging from 4 to 22 years of age, with a complex neurologic disorder. They presented in the first years of life with motor delay and walking between 18 months and 3.5 years of age. Walking was impaired by wide-based gait, awkward in-toed gait, or ataxia. Five patients had impaired intellectual development with speech delay and dysarthria. IQ, when measured, ranged in the 50s. One patient (patient 3) had normal cognitive development and attended school. Four patients had progressive spasticity of the upper and lower limbs associated with hyperreflexia and extensor plantar responses. Five patients had EMG evidence of a peripheral sensorimotor neuropathy, usually demyelinating, but sometimes with secondary axonal features. Clinical muscle strength and sensory examinations were difficult to perform. A few showed signs of cerebellar dysfunction, including ataxia, tremor, and dysmetria. Three patients had onset of various types of seizures in the first months or years of life; seizures were refractory in 2 patients. Brain imaging showed nonspecific findings in 3 patients, including cerebellar atrophy, white matter abnormalities, and delayed myelination. A fourth patient had a Chiari I malformation that was thought to be coincidental. Patient 2 had gross motor delay, abnormal gait, and speech delay with dysarthria. He developed seizures at age 3 years, but did not have electrophysiologic evidence of peripheral neuropathy at age 4; the authors suggested that neuropathy may develop with age, as he was the youngest patient in the group.

Xue et al. (2021) reported a 19-year-old Chinese man who developed classic features of CMT beginning around 5 years of age. He had progressive lower limb weakness and atrophy with walking difficulties, including a steppage gait. He developed pes cavus; ankle reflexes were absent. The upper limbs became involved showing claw hands and distal muscle atrophy. He also had distal sensory impairment. Electrophysiologic studies were consistent with a sensorimotor demyelinating polyneuropathy with secondary axonal loss. Sural nerve biopsy showed loss of myelinated nerve fibers. He had normal cognition, no evidence of central nervous system involvement, and normal brain imaging.

The heterozygous mutations in the POLR3B gene that were identified in patients with CMT1I by Djordjevic et al. (2021) occurred de novo.

In 6 unrelated patients with CMT1I, Djordjevic et al. (2021) identified de novo heterozygous missense mutations in the POLR3B gene (see, e.g., 614366.0009-614366.0012). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Affinity purification coupled with mass spectrometry performed on HEK293 cells transfected with the variants showed that 5 of the 6 impaired the association of POLR3B with 1 or more of the other RNA pol III subunits; the sixth variant showed disrupted association of POLR3B with multiple proteins. These findings suggested that the most of the mutations would render the enzyme inactive. All of the variants localized properly to the nucleus. Western blot analysis of fibroblasts from 1 patient showed normal protein expression. The authors postulated a dominant-negative effect, but noted that more studies were needed to confirm the pathogenetic mechanism.

In a 19-year-old Chinese man with CMT1I, Xue et al. (2021) identified a de novo heterozygous R1046H mutation at a highly conserved residue in the POLR3B gene. The mutation, which was found by exome sequencing, was absent from public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed. He had normal cognition and no evidence of central nervous system involvement.