Characteristics of clinical and electrophysiological pattern of Charcot-Marie-Tooth 4C.

To describe the clinical and electrophysiological features evoking CMT4C, an autosomal recessive (AR) form of Charcot-Marie-Tooth disease (CMT) due to mutations in the SH3TC2 gene, we screened the coding sequence of SH3TC2 gene in 102 unrelated patients with a demyelinating or intermediate CMT and a family history compatible with an AR transmission. We identified among this cohort 16 patients carrying two mutations in the SH3TC2 gene, but medical records finally analyzed 14 patients. We report clinical, electrophysiological, and molecular data of 14 patients (9 men, 5 women) with CMT4C. Mean age at examination was 43.6 years (median = 42.5). Among the 14 studied cases 6 had scoliosis as the presenting sign. Cranial nerve involvement affecting either the VIIIth, VIIth, XIIth or a combination of the IXth and Xth nerves was noted in 10 patients. Remarkably, 50% of the patients had proximal limb involvement at the time of examination. The hallmark of the electrophysiological study was the presence of probable conduction block and temporal dispersion. Thus the clinical and paraclinical spectrum of CMT4C can guide the clinician to perform analysis of the SH3TC2 gene.

Charcot-Marie-Tooth disease type 2A: from typical to rare phenotypic and genotypic features.

IMPORTANCE: Axonal Charcot-Marie-Tooth disease (CMT) is genetically heterogeneous, with 11 genes identified. Axonal CMT has most frequently been associated with mutations in the MFN2 gene (CMT2A). OBJECTIVES: To describe the clinical and molecular features of CMT2A, to delineate prognostic factors, to understand connections between a certain phenotype and more serious clinical consequences, and to identify interactions among the associated genes. EVIDENCE REVIEW: We describe the clinical, molecular, electrophysiological, and additional features of 43 patients with CMT2A. The degree of physical disability was determined by the CMT neuropathy score and adapted to the CMT neuropathy score gradient to evaluate the clinical course. We evaluated all data within the context of the most recent and important publications concerning this issue. FINDINGS: Twenty-five patients had early-onset CMT2A and severe functional disability, with 9 being wheelchair bound, and 18 had late-onset disease and a milder phenotype. Optic atrophy, vocal cord palsy, and auditory impairment were observed in 5, 6, and 2 patients, respectively. Among the 24 patients who underwent magnetic resonance imaging of the spinal cord, 6 had evidence of spinal atrophy with or without hydromyelia. In 1 patient, magnetic resonance imaging revealed hydrocephalus. Twenty different MFN2 mutations were identified, and 14 were considered new variants. Their transmission was predominantly autosomal dominant, with vertical transmission in 8 and de novo occurrence in 3. However, we also identified rare types of transmission, especially a germinal mosaicism and an autosomal recessive inheritance. One patient carried a rare variant in the GDAP1 gene and another in the OPA1 gene in association with MFN2 mutation. CONCLUSIONS AND RELEVANCE: Charcot-Marie-Tooth disease type 2A associated with MFN2 mutations is clinically very heterogeneous. Ranging from a mild to a severe form, CMT2A exhibits various types of transmission. Optic atrophy and vocal cord palsy were observed in patients with severe disability and an early-onset form and also in patients with later onset. Hydromyelia and spinal cord atrophy support central nervous system involvement in CMT2A.

Detection of genomic rearrangements by DHPLC: a prospective study of 90 patients with inherited peripheral neuropathies associated with 17p11.2 rearrangements.

Large genomic duplications and deletions are increasingly recognized as a cause of human disease. Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsy (HNPP) result, respectively, from a duplication or deletion of a 1.5 Mb genomic region in 17p11.2-12, containing the PMP22 gene. In routine diagnostic analysis, CMT1A status is inferred from the detection of an imbalanced dosage of two alleles or the presence of three alleles of a polymorphic marker flanking the PMP22 gene. HNPP is suspected if only one allele is seen, but hemizygosity must be confirmed by analyzing allele segregation in the family or by other techniques such as Southern blotting or fluorescence in situ hybridization (FISH). PCR-based methodologies have also been developed that allow single-step determination of the PMP22 gene copy number, wherein amplicons are typically labeled and/or separated by gel electrophoresis. We describe here a fast and reliable PCR-based method for the diagnosis of CMT1A and HNPP in which the PMP22 gene is co-amplified with a reference gene, and the amplicons are separated according to their size and quantified by DHPLC. Our results suggest that this method for quantifying gene dosage could be applied to other genomic rearrangements.

Rapid detection of 17p11.2 rearrangements by FISH without cell culture (direct FISH, DFISH): a prospective study of 130 patients with inherited peripheral neuropathies.

Charcot-Marie-Tooth (CMT) disease and hereditary neuropathy with pressure palsies (HNPP) are two frequent hereditary motor and sensory neuropathies. CMT is characterized by slowly progressive weakness and atrophy, primarily in peroneal and distal leg muscles. The most frequent form, CMT1A, is due, in most cases, to the duplication of a 1.5 Mb region on chromosome 17p11.2 containing the peripheral myelin protein 22 gene (PMP22). The phenotype seems to result from dosage of the PMP22 gene. This hypothesis is reinforced by the existence of HNPP, which is clinically characterized by various recurrent truncular palsies or sensory loss precipitated by minor trauma, which is caused by deletion of the same 1.5 Mb region in 17p11.2. In clinical practice, the detection of the duplication or the deletion in 17p11.2, which permits a positive diagnosis, is still performed by time consuming methods (Southern blot or various combinations of molecular tools). We developed a method for the rapid detection of 17p11.2 rearrangements, using "direct FISH" and PRINS analyses, which does not require cell culture. In a prospective study of 92 patients with CMT and 38 with suspected HNPP, we compared this new technique to classical strategies like Southern blot. The results demonstrate the high sensitivity and specificity of the new FISH technique for the diagnosis of CMT1A and HNPP. Moreover, because of its simplicity and rapidity, this technique provides a useful alternative to the molecular approaches that have been used to diagnose segmental aneusomies, especially in the case of duplications that often go undetected.