An 8-generation family with X-linked Charcot-Marie-Tooth: Confirmation Of the pathogenicity Of a 3' untranslated region mutation in GJB1 and its clinical features.

INTRODUCTION: Mutations in gap junction protein beta 1 (GJB1) on the X chromosome represent one of the most common causes of hereditary neuropathy. We assessed manifestations associated with a rare 3' untranslated region mutation (UTR) of GJB1 in a large family with X-linked Charcot-Marie-Tooth disease (CMTX). METHODS: Clinical, electrophysiological, and molecular genetic analyses were performed on an 8-generation family with CMTX. RESULTS: There were 22 affected males and 19 symptomatic females, including an 83-year-old woman followed for 40 years. Electrophysiological studies showed a primarily axonal neuropathy. The c.*15C>T mutation in the GJB1 3' UTR was identified in 4 branches of the family with a log of odds (LOD) of 4.91. This created a BstE II enzyme recognition site that enabled detection by restriction digestion. DISCUSSION: The c.*15C>T mutation in the GJB1 3' UTR segregates with CMTX1 in 8 generations. Penetrance in males and females is essentially complete. A straightforward genetic method to detect this mutation is described. Muscle Nerve 57: 859-862, 2018.

Prevalence of Charcot-Marie-Tooth disease in patients who have bilateral cavovarus feet.

It is not uncommon to see a patient with bilateral cavovarus feet in the outpatient setting. A large percentage of these patients are subsequently diagnosed with an associated condition, such as Charcot-Marie-Tooth disease. The purpose of the present report was to determine the prevalence of Charcot-Marie-Tooth disease in children who have bilateral cavovarus feet. A chart review of children with bilateral cavovarus feet was done. Patients were excluded if they had an existing medical problem known to be associated with bilateral cavovarus feet. Charcot-Marie-Tooth disease was diagnosed after a clinical assessment by an orthopaedic surgeon and a neurologist. The diagnosis was confirmed by either standard nerve conduction velocity studies and/or the CMT DNA Duplication Detection Test (Athena Diagnostics Inc, Worchester, MA). A positive family history was noted only if the diagnosis had been confirmed by a nerve conduction velocity study and/or CMT DNA Duplication Detection Test. One hundred forty-eight patients met the study criteria. The probability of a patient with bilateral cavovarus feet being diagnosed with Charcot-Marie-Tooth disease, regardless of family history, was 78% (116 patients). A family history of Charcot-Marie-Tooth disease increased the probability to 91%. It is recommended that all patients with bilateral cavovarus feet, especially with a known family history, be investigated for Charcot-Marie-Tooth disease.

T118M PMP22 mutation causes partial loss of function and HNPP-like neuropathy.

OBJECTIVE: To determine the clinical consequences of the PMP22 point mutation, T118M, which has been previously considered to either cause an autosomal recessive form of Charcot-Marie-Tooth (CMT) disease or be a benign polymorphism. METHODS: We analyzed patients from five separate kindreds and characterized their peripheral nerve function by clinical and electrophysiological methods. RESULTS: All heterozygous patients had clinical and/or electrophysiological features of a neuropathy similar to hereditary neuropathy with liability to pressure palsies (HNPPs). The homozygous patient had a severe axonal neuropathy without features of demyelination. INTERPRETATION: These findings suggest that T118M PMP22 retains some normal PMP22 activity, allowing the formation of compact myelin and normal nerve conduction velocities in the homozygous state. Taken together, these findings suggest that T118M is a pathogenic mutation causing a dominantly inherited form of CMT by a partial loss of PMP22 function.

Correction of cavovarus foot deformity in Charcot-Marie-Tooth disease.

Operative correction of cavovarus foot deformity in Charcot-Marie-Tooth disease (CMT) is challenging. This progressive peripheral sensory and motor neuropathy commonly involves the forefoot, midfoot, hindfoot, and toes. The authors present a new imaging technique that allows the surgeon to assess the flexibility of the hindfoot in patients with CMT to determine the best operative procedure to correct the deformity. Twenty-five patients (41 feet) with CMT and cavovarus foot deformity were evaluated and a new radiographic technique was studied in some of these patients to determine the usefulness of this imaging modality. The authors believe that this new imaging method will aid in determining the optimal operation for correcting this complex deformity.

Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation.

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous disorder that has been associated with alterations of several proteins: peripheral myelin protein 22, myelin protein zero, connexin 32, early growth response factor 2, periaxin, myotubularin related protein 2, N-myc downstream regulated gene 1 product, neurofilament light chain, and kinesin 1B. To determine the frequency of mutations in these genes among patients with CMT or a related peripheral neuropathy, we identified 153 unrelated patients who enrolled prior to the availability of clinical testing, 79 had a 17p12 duplication (CMT1A duplication), 11 a connexin 32 mutation, 5 a myelin protein zero mutation, 5 a peripheral myelin protein 22 mutation, 1 an early growth response factor 2 mutation, 1 a periaxin mutation, 0 a myotubularin related protein 2 mutation, 1 a neurofilament light chain mutation, and 50 had no identifiable mutation; the N-myc downstream regulated gene 1 and the kinesin 1B gene were not screened for mutations. In the process of screening the above cohort of patients as well as other patients for CMT-causative mutations, we identified several previously unreported mutant alleles: two for connexin 32, three for myelin protein zero, and two for peripheral myelin protein 22. The peripheral myelin protein 22 mutation W28R was associated with CMT1 and profound deafness. One patient with a CMT2 clinical phenotype had three myelin protein zero mutations (I89N+V92M+I162M). Because one-third of the mutations we report arose de novo and thereby caused chronic sporadic neuropathy, we conclude that molecular diagnosis is a necessary adjunct for clinical diagnosis and management of inherited and sporadic neuropathy.