A Family Harboring CMT1A Duplication and HNPP Deletion

Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with duplication of chromosome 17p11.2-p12, whereas hereditary neuropathy with liability to pressure palsies (HNPP), which is an autosomal dominant neuropathy showing characteristics of recurrent pressure palsies, is associated with 17p11.2-p12 deletion. An altered gene dosage of PMP22 is believed to the main cause underlying the CMT1A and HNPP phenotypes. Although CMT1A and HNPP are associated with the same locus, there has been no report of these two mutations within a single family. We report a rare family harboring CMT1A duplication and HNPP deletion.

Effectiveness of Real-Time Quantitative PCR Compare to Repeat PCR for the Diagnosis of Charcot-Marie-Tooth Type 1A and Hereditary Neuropathy with Liability to Pressure Palsies

The majority of cases of Charcot-Marie-Tooth type 1A (CMT1A) and of hereditary neuropathy with a liability to pressure palsies (HNPP) are the result of heterozygosity for the duplication or deletion of peripheral myelin protein 22 gene (PMP22) on 17p11.2. Southern blots, pulsed-field gel electrophoresis (PFGE), fluorescence in situ hybridization (FISH) and polymorphic marker analysis are currently used diagnostic methods. But they are time-consuming, labor-intensive and have some significant limitations. We describe a rapid real- time quantitative PCR method for determining gene copy number for the identification of DNA duplication or deletion occurring in CMT1A or HNPP and compare the results obtained with REP-PCR. Six patients with CMT1A and 14 patients with HNPP [confirmed by Repeat (REP) -PCR], and 16 patients with suspicious CMT1A and 13 patients with suspicious HNPP [negative REP-PCR], and 15 normal controls were studied. We performed REP-PCR, which amplified a 3.6 Kb region (including a 1.7Kb recombination hotspot), using specific CMT1A-REP and real-time quantitative PCR on the LightCycler system. Using a comparative threshold cycle (Ct) method and beta-globin as a reference gene, the gene copy number of the PMP22 gene was quantified. The PMP22 duplication ratio ranged from 1.35 to 1.74, and the PMP22 deletion ratio from 0.41 to 0.53. The PMP22 ratio in normal controls ranged from 0.81 to 1.12. All 6 patients with CMT1A and 14 patients with HNPP confirmed by REP-PCR were positive by real-time quantitative PCR. Among the 16 suspicious CMT1A and 13 suspicious HNPP with negative REP-PCR, 2 and 4 samples, respectively, were positive by real-time quantitative PCR. Real-time quantitative PCR is a more sensitive and more accurate method than REP-PCR for the detection of PMP22 duplications or deletions, and it is also faster and easier than currently available methods. Therefore, we believe that the real-time quantitative method is useful for diagnosing CMT1A and HNPP.

Clinical, Electrophysiological and Pathological Characteristics in Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) with Chromosome 17p11.2-p12 Deletion

BACKGROUND: Hereditary neuropathy with liability to pressure palsies (HNPP) is a peripheral nerve disorder characterized by autosomal dominant inheritance, recurrent pressure palsies, reduced motor and sensory conduction velocities and sausage-like swellings (tomacula) of myelin sheaths in nerve biopsy. A 1.5-Mb deletion in chromosome 17p11.2- p12 is present in the majority but not all cases of HNPP. The aim of the present study was to evaluate the clinical, electrophysiological and morphological aspects of HNPP patients associated with chromosome 17p11.2-p12 deletion. METHODS: To detect the presence of the deletion, the DNA of the patients was analyzed with pVAW409R3 (D17S122). An electrophysiological study was done in all patients. Sural nerve biopsy with teasing was done in three patients. RESULTS: DNA analysis and electrophysiological tests revealed the deletion in 8 families and 16 patients. Nerve conduction studies demonstrated diffuse mild to moderate slowing of nerve conduction velocities especially worse over the common entrapment sites, regardless of clinical manifestations. The long duration of compound muscle and nerve action potentials without conduction blocks or dispersion is characteristic of patients with HNPP. The tomacula of myelin sheaths was found on sural nerve teasing. CONCLUSIONS: We report the clinical, electrophysiological and morphological aspects of the Korean HNPP patients associated with chromosome 17p11.2-p12 deletion. (J Korean Neurol Assoc 19(3):251~259, 2001)

Intraoperative Electrophysiological Monitoring during Microvascular Decompression for Hemifacial Spasm and Surgical Outcome

BACKGROUND: Hereditary neuropathy with liability to pressure palsies (HNPP) is a peripheral nerve disorder characterized by autosomal dominant inheritance, recurrent pressure palsies, reduced motor and sensory conduction velocities and sausage-like swellings (tomacula) of myelin sheaths in nerve biopsy. A 1.5-Mb deletion in chromosome 17p11.2- p12 is present in the majority but not all cases of HNPP. The aim of the present study was to evaluate the clinical, electrophysiological and morphological aspects of HNPP patients associated with chromosome 17p11.2-p12 deletion. METHODS: To detect the presence of the deletion, the DNA of the patients was analyzed with pVAW409R3 (D17S122). An electrophysiological study was done in all patients. Sural nerve biopsy with teasing was done in three patients. RESULTS: DNA analysis and electrophysiological tests revealed the deletion in 8 families and 16 patients. Nerve conduction studies demonstrated diffuse mild to moderate slowing of nerve conduction velocities especially worse over the common entrapment sites, regardless of clinical manifestations. The long duration of compound muscle and nerve action potentials without conduction blocks or dispersion is characteristic of patients with HNPP. The tomacula of myelin sheaths was found on sural nerve teasing. CONCLUSIONS: We report the clinical, electrophysiological and morphological aspects of the Korean HNPP patients associated with chromosome 17p11.2-p12 deletion. (J Korean Neurol Assoc 19(3):251~259, 2001)