New mutation of gap junction protein β1 (GJB1) gene in X‐linked hereditary motor and sensory neuropathy

Dear Editor, Charcot-Marie-Tooth disease (CMT) or hereditary motor and sensory neuropathy (HMSN) comprises hereditary disorders of the peripheral nervous system with autosomal or X-linked inheritance. The X-linked dominant form of CMT (CMTX) is associated with mutations in the gene for the gap junction protein b1 (GJB1), the gene encoding connexin 32 (Cx32) (Bergoffen et al., 1993). Cx32 has been localized in non-compact peripheral myelin, probably forming gap junctions between adjacent myelin wraps of the same Schwann cells (Scherer et al., 1995). Because the first mutations were reported in 1993, over 200 different mutations in GJB1 associated with CMTX have been identified. These include missense, frameshift, deletion, and non-sense mutations. In this letter, we report a novel 10 base pair (bp) deletion in the GJB1 gene in a patient with CMTX. A 52-year-old man presented with a 10-year history of progressive gait disturbance due to leg muscle weakness. Since the age of 46, he noticed muscle weakness in upper limbs and finger tremor. The patient’s maternal nephew had similar symptoms. Neurological examinations in the patient revealed normal intelligence. Cranial nerves were intact. Manual muscle strength test revealed distal dominant muscle weakness in the extremities. Postural finger tremor was prominent in the upper limbs. He had pes cavus, atrophy of distal leg muscles, and intrinsic hand muscles. Co-ordination was moderately unskillful. Deep tendon reflexes were absent in all extremities. In the sensory system, vibration was severely disturbed in the lower extremities. Gait was characterized by steppage. Romberg sign was present. Motor nerve conduction study revealed diffuse slowing of motor nerve conduction velocity (MCV) with low-amplitude compound muscle action potentials (CMAPs) (median nerve, MCV 32 m/s, CMAP 3.0 mV, F-wave latency 43.5 ms; tibial nerve, MCV 29 m/ s, CMAP 3.7 mV, F-wave latency 70.0 ms). Sensory nerve action potentials (SNAPs) were decreased, and sensory nerve conduction velocity (SCV) was delayed in all nerves tested (median nerve, SCV 37.8 ms, SNAP 1.8 mV; sural nerve, SCV 34 m/s, SNAP 4.7 mV). Sural nerve biopsy was performed with the patient’s consent. The densities of large and small myelinated fibers were moderately decreased (5,243/mm) (Fig. 1A). The majority of fibers had relatively thin myelin, and many myelinated fibers were aggregated in clusters. Several fibers had excessive myelin folding. In teased fiber analysis, the frequency of fibers with paranodal demyelination was 4%, the frequency of fibers with segmental demyelination with variable myelin thickness between internodes more than 50%, demyelination, and remyelination was 28%, the frequency of axonal degeneration was 4%, and the frequency of fibers with focal myelin thickenings was 8%. Informed consent for conducting GJB1 gene analysis was obtained from the patient. Direct testing for GJB1 sequence was performed by PCR amplification and automated sequencing of both genomic strands which code for the entire mature protein. Sequencing demonstrated a heterozygous 10-bp deletion frameshifting mutation 8 nucleotide position (466–475) (Fig. 1B), which is predicted to result in alteration and truncation of the Cx32 protein structure. This is the report of a patient with CMTX having a new truncating frameshift mutation of GJB1 gene. The clinical features of the present case are consistent with mild form of CMTX (Ionasescu et al., 1996). Sural nerve pathology in the present case showed the following features: (1) prominent clusters of thinly myelinated fibers; (2) frequent alterations of paranodal myelin; and (3) abnormalities of adaxonal and innermost Schwann cell cytoplasm. These changes were previously described in CMTX (Vital et al., 2001). Taken together, this new mutation of GJB1 gene may be the cause of neuropathy in the present case. Address correspondence to: Dr Fujio Umehara, The Department of Neurology and Geriatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, Japan. Tel: þ81-99-275-5332; Fax: þ81-99-265-7164; E-mail: umehara@ m2.kufm. kagoshima-u.ac. jp Journal of the Peripheral Nervous System 11:96–97 (2006)