Mutations in the mitofusin 2 (MFN2) gene, which encodes a mitochondrial GTPase mitofusin protein, have recently been reported to cause both Charcot-Marie-Tooth 2A (CMT2A) and hereditary motor and sensory neuropathy VI (HMSN VI). It is well known that HMSN VI is an axonal CMT neuropathy with optic atrophy. However, the differences between CMT2A and HMSN VI with MFN2 mutations remained to be clarified. Therefore, we studied the phenotypic characteristics of CMT patients with MFN2 mutations. Mutations in MFN2 were screened in 62 unrelated axonal CMT neuropathy families. We calculated CMT neuropathy scores (CMTNSs) and functional disability scales (FDSs) to quantify disease severity. Twenty-one patients with the MFN2 mutations were studied by brain MRI. Ten pathogenic mutations were identified in 26 patients from 15 families (24.2%). Six of these mutations had not been reported, and de novo mutations were observed in five families (33.3%). The electrophysiological patterns of affected individuals with the MFN2 mutations were typical of axonal CMT; however, the clinical and electrophysiological characteristics were markedly different in early (<10 years) and late disease-onset (> or =10 years) groups. All patients with an early onset had severe CMTNS (> or =21) and FDS (6 or 7), whereas most patients with late onset had mild CMTNS (< or =10) and FDS (< or =3). We identified two HMSN VI families with the R364W mutation in the early onset group; however, two other families with the same mutation did not have optic atrophy. In addition, two early onset families with R94W mutations, previously reported for HMSN VI, did not have visual impairment. Interestingly, eight patients had periventricular and subcortical hyperintense lesions by brain MRI. In the late-onset group, three patients had sensorineural hearing loss and two had bilateral extensor plantar responses. We found that MFN2 mutations are the major cause of axonal CMT neuropathy, and that they are associated with variable CNS involvements. Phenotypes were significantly different in the early and late disease-onset groups. Our findings suggest that HMSN VI might be a variant of the early onset severe CMT2A phenotype.

We examined CMT1A duplication of 17p11.2-p12, mutations of PMP22, MPZ (P0), GJB1 (Cx32), EGR2 and NEFL genes in 57 Korean families with patients diagnosed as having Charcot-Marie-Tooth (CMT) disease. The CMT1A duplication was present in 53.6% of 28 CMT type 1 patients. In the 42 CMT families without CMT1A duplication, 10 pathogenic mutations were found in 9 families. The 10 mutations were not detected in 105 healthy controls. Seven mutations ( c.318delT (p.Ala106fs) in PMP22, c.352G>A (p.Asp118Asn), c.449-1G>T (3'-splice site), c.706A>G (p.Lys236Glu) in MPZ, c.408T>C (p.Val136Ala), c.502T>C (p.Cys168Arg) in GJB1, and c.1001T>C (p.Leu334Pro) in NEFL) were determined to be novel. The mutation frequencies of PMP22 and MPZ were similar to those found in several European populations, however, it appeared that mutations in GJB1 are less frequent in East Asian CMT patients than in European patients. We described the identified mutations and phenotype-genotype correlations based on nerve conduction studies.

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This study aimed to clarify the morphologic variations of the Martin-Gruber anastomosis (MGA) by tracing the anastomotic fascicles. We used 102 upper limbs, and MGA was found in 39.2%. Among 12 instances of MGA between the branches innervating the flexor digitorum profundus muscle, eight anastomotic branches solely innervated the muscle without crossover from median to ulnar nerve. The results of the present study showed three morphologic features of MGA that could not be detected by an electrodiagnostic method.

Repetitive nerve stimulation testing of the ulnar nerve was systematically performed on 21 normal controls and 120 patients with myasthenia gravis (MG). Diagnostic sensitivity increased from 0% in MG in remission and 17.2% in ocular MG to 100% in severe generalized MG. Six types of responses were observed in MG and could be classified into two distinct patterns based upon disease severity: ( 1 ) in mild MG, an abnormal decremental response at low rate of stimulation, normal response at high rate of stimulation, and prominent posttetanic facilitation and exhaustion phenomena; and (2) in severe MG, abnormal decremental responses at low as well as high stimulation rates and less common posttetanic facilitation and rare posttetanic exhaustion phenomena. This difference is most likely due to the severity of the neuromuscular block in MG. Oh Methods and MaterialsFor study of neuromuscular transmission we used the Harvey-Masland method with the surface-recording electrode on the abductor digiti quinti muscle and the surfacestimulating electrode on the transsulcal segment of the ulnar nerve [ 111. For the recording electrode, the active electrode was placed over the belly of the muscle and the reference electrode over the tendon. For stimulation of the nerve, we used the supramaximal 0.2 msec stimulus duration.Each subject lay on a bed with the forearm and hand fixed on a stand with a heavy base (281. The nerve was stimulated at 3isec for 2 seconds, at 5isec for 1 sec-ond, and at 50/sec for I second, using DISA 14 and 1500 EMG machines. There was at least a I-minute interval between each test. Immediately and 4 minutes after tetanic stimulation at 50isec, the nerve was stimulated at S/sec for 1 second each time.The peak-to-peak amplitude of each muscle potential was measured. The percentage of decrement or increment was calculated by comparing the first response with the lowest or highest among the first five responses at the low rate of stimulation and during t h e first second at the high rate of stimulation. When the results differed by 2 standard deviations from the mean in controls, they were considered abnormal.Posttetanic facilitation and exhaustion phenomena were defined as having occurred when the decremental response at Sisec immediately after and 4 minutes after tetanic stimulation showed improvement or aggravation, respectively, compared with the response at 5isec prior to tetanic stimulation.The present analysis is based on 2 1 normal controls a d 120 patients with MG. M G was diagnosed by a combination of clinical examination and consistent reversal of signs and symptoms upon parenteral administration of edrophonium or neostigmine. Among 103 patients with symptomatic MG, the test was performed in 79 before any medication was started (no-anticholinesterase group), in 18 after anticholinesterases had been discontinued for at least 12 hours (anticholinesterase-off group), and in 6 patients with myasthenic crisis within 6 hours after administration of anticholinesterase medication.

Sporadic inclusion body myositis (SIBM) is characterized by vacuolar degeneration of muscle fibers and intrafiber clusters of paired helical filaments with abnormal amyloid deposition. Because of their potential involvement in other degenerative disorders, we have examined the expression of transglutaminases (TGases) in normal and SIBM tissues. We report that at least two different enzymes, the ubiquitous TGase 2 as well as the TGase 1 enzyme, are present in muscle tissues. However, in comparison with normal tissue, the expression of TGases 1 and 2 was increased 2.5-and 4-fold in SIBM, accompanied by about a 20-fold higher total TGase activity. By immunohistochemical staining, in normal muscle, TGase 2 expression was restricted to some endomysial connective tissue elements, whereas TGase 1 and ␤-amyloid proteins were not detectable. In SIBM muscle, both TGases 1 and 2 as well as amyloid proteins were brightly expressed and co-localized in the vacuolated muscle fibers, but none of these proteins colocalized with inflammatory cell markers. Next, we isolated high molecular weight insoluble proteins from SIBM muscle tissue and showed that they were cross-linked by about 6 residues/1000 residues of the isopeptide bond. Furthermore, by amino acid sequencing of solubilized tryptic peptides, they contain amyloid and skeletal muscle proteins. Together, these findings suggest that elevated expression of TGases 1 and 2 participate in the formation of insoluble amyloid deposits in SIBM tissue and in this way may contribute to progressive and debilitating muscle disease.

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N440K causes a gain of function consistent with skeletal muscle hyperexcitability as observed in individuals with the mutation. How the same mutation results in distinct phenotypes in the 2 kindreds remains to be determined.