A large kindred (group of related people) of Charcot Marie Tooth disease type 1B (CMT1B) patients revealed an increasing incidence of facial spasms and intense nerve pain with age, two uncommon conditions in the disease.
The study, “A Charcot Marie Tooth Type 1B Kindred Associated with Hemifacial Spasm and Trigeminal Neuralgia,” appeared in the journal Muscle & Nerve.
More than 150 mutations in the MPZ gene are reported to cause CMT1B, a disease subtype with pronounced variability in severity and age of onset. As unusual features such as facial weakness or vocal cord paralysis have been associated with specific mutations across the different CMT types, studies linking genetic alterations to uncommon presentations may help differentiate CMT from other disorders.
Hemifacial spasm (HFS, involuntary muscle twitching on one side of the face) and trigeminal neuralgia (TN, intense pain along a nerve) usually develop in mid- to late adulthood and are caused by alterations in the facial and trigeminal cranial nerves, respectively. Reports of HFS and trigeminal neuralgia in CMT are scarce and not linked to a specific mutation.
A team from Wake Forest School of Medicine and Geisel School of Medicine at Dartmouth identified a kindred from western North Carolina who descended from an 18th century founder from Sussex, England. All 63 people were interviewed regarding symptoms of neuropathy (nerve damage), facial pain, and twitching, and underwent a brief neurologic examination. Some also underwent nerve conduction tests.
The results showed that 25 participants had signs and symptoms of CMT. Two adolescents did not fulfill CMT criteria but had signs suggesting neuropathy as well as an MPZ gene mutation, thereby being included in the analysis.
Among this group of 27 (16 females), the average age was 51.9 years, ranging from 13 to 73. Fifteen people reported onset of neuropathy during childhood or adolescence, but did not give a specific age.
Both of the participants with HFS who underwent facial nerve testing had marked prolongation of latencies (slowed nerve conduction) to facial muscles and blink responses.
Genetic analysis in 22 participants with CMT who provided blood samples showed a point mutation — a change in only one nucleotide, the building blocks of DNA — in exon 4 of the MPZ gene, resulting in an amino acid change from glycine to arginine. Exons are the DNA bits containing the information to make proteins.
This mutation, known as G163R, was associated with CMT in prior studies, but not with HFS or trigeminal neuralgia, the team noted.
The data also showed HFS and/or trigeminal neuralgia in 10 of 27 participants (eight women), three of whom had both conditions, five HFF only and two trigeminal neuralgia only. Three of the CMT patients had bilateral HFS, while one had bilateral trigeminal neuralgia. Patients with HFS and/or trigeminal neuralgia were older than those without CMT alone (mean age 61.7 vs. 46.7 years).
While HFS presented within 35-60 years (mean 48.8), trigeminal neuralgia manifested within 41-56 years (mean 50.8). Patients with HFS who had been treated with botulinum toxin injections reported consistent improvement.
“This kindred exhibits a distinct CMT phenotype characterized by the development of HFS or [trigeminal neuralgia] decades after clinical signs of hereditary neuropathy are manifest,” the scientists stated.
Typical neuropathy signs, as assessed in the tibialis anterior (lower leg) muscle, were similar among CMT patients with or without HFS/trigeminal neuralgia. Only one participant — a 53 year-old woman — without the point mutation had HFS, which was successfully treated with botulinum toxin. Neither this participant nor her two examined first-degree relatives had neuropathy or abnormal nerve conduction.
A magnetic resonance angiography of the brain found tortuous, or twisted, vertebral arteries in the cranial nerve VII/VIII area, a possible explanation for the patient’s HFS, according to the researchers.
“This description extends the spectrum of genotype-phenotype correlation for a gene commonly implicated in CMT,” the investigators said.
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