New mutation in a patient with Charcot-Marie-Tooth disease

Dear Editor:

Charcot-Marie-Tooth disease (CMT) is a type of hereditary sensorimotor polyneuropathy which may be caused by a great variety of genetic alterations¹; new alterations continue to be identified.

We present the case of a 39-year-old patient diagnosed with CMT type 1 during childhood. His mother also has the disease but with mild clinical symptoms.

Examination of the patient revealed distal amyotrophy with weakness, steppage gait, and arreflexia. Neurophysiological studies have always shown decreased conduction velocity and amplitudes of motor potentials; sensory potentials could not be elicited. At the time, the patient and his partner were trying to conceive.

A genetic study was conducted in 2015. Proceeding gradually, the study began with genotyping with polymerase chain reaction and allele-specific oligonucleotide of a battery of polymorphisms distributed throughout the CMT1/HNPP region (17p11.2), with no evidence of duplication or deletion. Massively parallel sequencing was performed for 7 genes from the panel associated with autosomal dominant CMT type 1; this did not reveal any clearly pathogenic variant associated with the disease. The study was subsequently expanded to 42 genes, which revealed a mutation of the SBF1 gene (c577C>T [pArg193Trp]) in heterozygosis and a mutation of the GJB1 gene (c.476_481del [pGly159_Tyr160del]) in hemizygosis; since these are not pathogenic variants clearly associated with CMT disease, we conducted a Sanger confirmation and a cosegregation study in the patient's mother.

We confirmed presence of the mutation (c.476_481del [pGly159_Tyr160del]) and the mother was found to be a carrier of the mutation in heterozygosis.

We describe a new mutation of the GJB1 gene, located at Xq13.1 and coding for gap junction beta-1 protein (or connexin 32),² in a patient with demyelinating CMT with an X-linked dominant inheritance pattern. Variations of this gene are the second most frequent genetic alteration observed, following duplication of the PMP22 gene at chromosome 17p11.2-p12.^2,3

Curiously, in these X-linked forms, motor conduction velocities are not homogeneous in different nerves; nor are they as decreased as in autosomal dominant forms.^3,4 These forms can also be associated with disorders of the central nervous system⁵; we therefore requested a brain magnetic resonance imaging scan in our patient, which yielded normal results.

In conclusion, we deem it important to characterise and communicate these alterations, both for the purpose of genetic counselling (as illustrated by our patient) and with a view to the potential prognostic and therapeutic implications of future research.