Intermediate nerve conduction velocities define X-linked Charcot-Marie-Tooth neuropathy families

Three genetic loci for the Charcot-Marie-Tooth (CMT) syndromes with slow motor nerve conduction velocities (hereditary motor and sensory neuropathy: HMSN type I) have been mapped to chromosomes 1 (CMT1B), 17 (CMT1A), and the X chromosome (CMTX). The clinical features of these three CMT subgroups are similar. To determine whether any clinical features distinguish CMTX families, the range of clinical findings and motor nerve conduction velocities were examined in two large CMTX families, the range of clinical findings and motor nerve conduction velocities were examined in two large CMTX families with CMTX proven by linkage to X-chromosome markers. CMTX males had more wasting and weakness than CMTX females or individuals with CMT1A. Patellar reflexes were more often retained in CMTX. Motor nerve conduction velocities were faster than in CMT1A. Intermediate-range median nerve conduction velocities were present in CMTX females (45 +/- 9 m/sec; range, 26 to 61 m/sec). These velocities were significantly faster than those for CMT1A females (22 +/- 8 m/sec, p < 0.0001). Median nerve conduction velocities in CMTX males (31 +/- 6 m/sec) were significantly slower than in CMTX females and faster than in CMT1A males (20 +/- 6 m/sec, p < 0.0001). The combination of slow conduction velocities in affected males (< 40 m/sec) and intermediate-range median motor conduction velocity results (> 40 m/sec) in affected or obligate carrier females is a useful distinguishing feature to separate CMTX from CMT1A, as intermediate conduction velocities are not present in autosomal-dominant dominant CMT1A families. This feature defines possible CMTX families for linkage studies. Families with no male-to-male inheritance of the syndrome, slow motor nerve conductions in affected males, and normal or intermediate-range conduction velocities in carrier females should be considered to be X-linked CMT families.     

Connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease show two distinct behaviors: loss of function and altered gating properties

The X-linked form of Charcot-Marie-Tooth disease (CMTX) is associated with mutations in the gene encoding connexin32 (Cx32), which is expressed in Schwann cells. We have compared the functional properties of 11 Cx32 mutations with those of the wild-type protein by testing their ability to form intercellular channels in the paired oocyte expression system. Although seven mutations were functionally incompetent, four others were able to generate intercellular currents of the same order of magnitude as those induced by wild-type Cx32 (Cx32wt). In homotypic oocyte pairs, CMTX mutations retaining functional activity induced the development of junctional currents that exhibited changes in the sensitivity and kinetics of voltage dependence with respect to that of Cx32wt. The four mutations were also capable of interacting in heterotypic configuration with the wild-type protein, and in one case the result was a marked rectification of junctional currents in response to voltage steps of opposite polarity. In addition, the functional CMTX mutations displayed the same selective pattern of compatibility as Cx32wt, interacting with Cx26, Cx46, and Cx50 but failing to do so with Cx40. Although the functional mutations exhibited sensitivity to cytoplasmic acidification, which induced a >/=80% decrease in junctional currents, both the rate and extent of channel closure were enhanced markedly for two of them. Together, these results indicate that the functional consequences of CMTX mutations of Cx32 are of two drastically distinct kinds. The presence of a functional group of mutations suggests that a selective deficit of Cx32 channels may be sufficient to impair the homeostasis of Schwann cells and lead to the development of CMTX.     

Gaucher disease: four families with previously undescribed mutations

A large-scale sequencing project requires a tool to control the quality of the input data because a sizable number of trace data may be of low quality. If these data are allowed to enter the sequence assembly pipeline, harm will be done. Hence, it is important to detect such data as soon as possible. MTT (Move-Track-Trim) is a software package analyzing the quality of the lanes. It subjects each lane to a series of tests, and if a lane does not pass all tests, it is flagged as a "bad" lane. The use has a chance to examine both the "good" and the "bad" lanes and reclassify a "bad" lane as "good," or vice versa. Alternatively, the user may decide to retrack the gel or get rid of some lanes altogether. As a by-product of the analysis, MTT performs other useful functions. It trims the lanes and compresses the lane files and moves them to the directories where assembly is carried out. It also generates some useful statistics describing the quality of the gel.     

Myelographic evidence for nerve root enlargement in a case of Charcot-Marie-Tooth disease

The myelographic findings of enlarged nerve roots in a patient with Charcot-Marie-Tooth disease is found to be identical to those of Hypertrophic Interstitial Neuritis and Neurofibromatosis. The hypertrophy of the roots may represent a single response to different noxious stimuli. Clinical and laboratory differentiation are given for the diseases.     

Coordinated activation of muscle fibres by different conduction velocities in branches of a crustacean motor axon

Higher conduction velocities in branches of the fast excitor axon to distal muscle fibres ensure that these fibres are activated almost simultaneously with proximal fibres in the claw closer muscle of lobsters, producing a contraction of maximal force.     

Molecular characterization of germline mutations in neurofibromatosis 2 in two families

Neurofibromatosis 2 (NF2) is an autosomal dominant disorder that predisposes patients to central nervous system tumors. It is caused by mutations in the NF2 tumor suppressor gene, which is located on chromosome 22q12. We studied 2 multigenerational NF2 families (three members of family 1 and the proband of the family) by gene mutation analysis and clinical assessment. One member of family 1 had a 169 C-->T point mutation at codon 57 of exon 2 and had a severe phenotype. His father had a silent 1113 C-->T point mutation at codon 371 of exon 11 and had a normal phenotype. The proband of family 2 had a deletion at nucleotide 720 G (codon 240) of exon 8. This led to a frameshift and termination at codon 250, and a severe NF2 phenotype. Our results indicate that clinical abnormalities can be present in carriers. Nonsense and frameshift mutations in the NF2 tumor suppressor gene are associated with phenotypes. The clinical abnormalities can develop at a young age.     

Polyneuropathy caused by tuberculostatics. Study of motor nerve conduction in 29 patients

This paper presents the reconstruction of an unusual case of suicide. After raiding a branch-bank a robber fled shooting with his Sauer-Western revolver caliber .44 magnum at the pursuing policemen and succeeded in wrestling a pistol Walther caliber 7,65 mm from them. Under the fire of sub-machine guns he destroyed himself by a shot to the neck. Our investigations concerned a textile damage at the front of the sweater of the deceased surrounded by primer residue, showing characteristics of a close-up shot. The damage was identified as effect of explosion gases exhausting far-off the muzzle. The distance between this injury and the bullet hole corresponded with the length of the barrel of the Sauer-Western revolver and could be used for identification; it confirmed the diagnosis of a close-up shot at the neck, too. Collateral experiments with shots from distant ranges developed spadiceous melt figures of textile fibers around the bullet hole, the appearance of which is considered proof for a close-up shot commonly.     

Nerve conduction velocities of single thenar motor axons based on the automated analysis of F waves in amyotrophic lateral sclerosis

OBJECTIVE: To determine effects of i.v. medetomidine administration on selected clinicopathologic variables in dogs. ANIMALS: 6 healthy adult Beagles. PROCEDURE: Dogs were randomly assigned to each of 3 treatments in a crossover study design. Serum osmolality, urine osmolality, urine pH, and fractional clearances of sodium, chloride, potassium, and glucose were determined before and 20, 40, 60, 120, 180, 240, 300, 360, 420, and 480 minutes after i.v. administration of 0.9% NaCl (saline) solution (control) or medetomidine (10 or 20 micrograms/kg of body weight). The urinary bladder was emptied prior to saline or medetomidine administration, and urine volume was determined at the same posttreatment times as those described previously. Free water clearance was calculated for all posttreatment times. RESULTS: After medetomidine administration, serum osmolality, urine volume, free water clearance, and fractional clearance of potassium and glucose increased; urine osmolality decreased. Initially, urine pH and fractional clearance of chloride decreased, then subsequently increased. Fractional clearance of sodium did not change. CONCLUSIONS AND CLINICAL RELEVANCE: Because i.v. administration of medetomidine to dogs at dosages of 10 and 20 micrograms/kg induces a diuretic effect that lasts up to 4 hours, the drug should be used with discretion in hypovolemic or dehydrated dogs, and its use should be avoided in those with urinary tract obstruction.     

Electrophysiologic mapping and cadaveric dissection of the lateral foot: implications for tibial motor nerve conduction studies

OBJECTIVE: To clarify, through electrophysiologic mapping and cadaveric dissection of the lateral foot, the previously published "proximal" and "distal" recording sites for tibial motor nerve conduction studies. DESIGN: Observational. SETTING: Electromyography laboratory; anatomy laboratory. PATIENTS OR OTHER PARTICIPANTS: Ten asymptomatic feet; eight cadaveric feet. MAIN OUTCOME MEASURES: (1) Amplitudes and onset latencies of compound muscle action potentials (CMAPs) recorded over a grid on the lateral foot that included the "proximal" and "distal" recording sites; (2) nerve supply and anatomic boundaries of the abductor digiti minimi pedis (ADMP) and nearby muscles, particularly as they relate to the above recording sites. RESULTS: (1) Relatively large CMAPs were recorded at and around the "proximal" and "distal" sites, with significantly shorter "proximal" latencies. (2) In all cadaveric feet, ADMP was innervated by only the inferior calcaneal nerve (ICN) and was located deep to the "proximal" site, with virtually no muscle fibers deep to the "distal" site. The flexor digiti minimi brevis (FDMB) was conspicuously located immediately deep to the "distal" site and was innervated by only the lateral plantar nerve (LPN). CONCLUSIONS: This study strongly suggests that the "proximal" site records predominantly from the ICN-innervated ADMP, whereas the "distal" site predominantly records from the LPN-innervated FDMB.     

Peripheral motor and sensory nerve conduction studies in haemodialysis patients. A study of 54 patients

Peripheral motor and sensory nerve conduction velocities were studied prospectively in 54 chronic haemodialysis patients. The most sensitive parameters for the detection of polyneuropathy were the deep peroneal nerve motor conduction velocity, the sural nerve sensory conduction velocity and the H-reflex latency and H-index of the S1 roots. All patients examined were found to present at least one abnormal nerve conduction parameter. In the present study the side of the arteriovenous shunt had no statistically significant effect on the sensory and motor nerve conduction velocities in the upper extremities. There was a significant correlation between H-reflex latency and H-reflex index, and between H-reflex latency and sural nerve sensory conduction velocity.     

Acoustic streaming: comparison of low-amplitude linear model with streaming velocities measured by 32-MHz Doppler

To further investigate the dependency of fMRI signal changes on echo time TE, we measured T2 and T2* values, obtained from human blood samples at various oxygenation levels and used them in a simple model to calculated signal enhancement in fMRI. In addition, the longitudinal relaxation time T1 of human blood was determined for reference. All measurements were performed at 23 degrees C to reduce blood cell metabolism during the measurement procedure. At 23 degrees C T1 values of 1434 +/- 48 ms for arterial human blood were obtained after correcting for hematocrit content, as hematocrit values ranged fro 28% to 34% only. The T2 relaxation times obtained are 181 +/- 23 ms for venous and 254 +/- 26 ms for arterial human blood, T2* relaxation times corrected for inhomogeneities of the static magnetic field (B0) are 42 +/- 2.8 ms and 254 +/- 32 ms, respectively. Furthermore, absolute and relative signal changes in fMRI experiments are calculated. The results from these model calculations reveal that contrast in fMRI can be optimised by choosing an appropriate echo time.     

Centrotemporal spikes in families with rolandic epilepsy: linkage to chromosome 15q14

OBJECTIVE: To localize a gene predisposing to benign epilepsy of childhood with centrotemporal spikes (BECTS). BACKGROUND: BECTS, or rolandic epilepsy, is the most prevalent idiopathic epilepsy syndrome in childhood. Functional relevant defects in the alpha 4 subunit of the neuronal nicotinic acetylcholine receptor (AChR) have been demonstrated in autosomal dominant nocturnal frontal lobe epilepsy, which, like BECTS, is an idiopathic partial epilepsy. METHODS: A DNA linkage study was conducted screening all chromosomal regions known to harbor neuronal nicotinic AChR subunit genes. Twenty-two nuclear families with BECTS were analyzed. RESULTS: In an "affected-only" study, best p values and lod scores were reached between D15S165 and D15S1010 on chromosome 15q14. In multipoint nonparametric linkage analysis a nominal p value of 0.000494 was calculated by GENEHUNTER. Best parametric results were obtained under an autosomal recessive model with heterogeneity (multipoint lod score 3.56 with 70% of families linked to the locus). These markers are localized in direct vicinity to the alpha 7 subunit gene of the AChR. CONCLUSIONS: We found evidence for linkage of BECTS to a region on chromosome 15q14. Either the alpha 7 AChR subunit gene or a closely linked gene are implicated in pedigrees with BECTS. The disorder is genetically heterogeneous. Surprisingly, the same chromosomal area has been reported to be linked to the phenotype in families with an auditory neurophysiologic deficit as well as in families with juvenile myoclonic epilepsy, another idiopathic but generalized epilepsy syndrome.     

Novel mutations of the endothelin B receptor gene in patients with Hirschsprung's disease and their characterization

Hirschsprung's disease (HSCR) is a congenital intestinal disease, characterized by the absence of ganglion cells in the distal portion of the intestinal tract. Recently, three susceptibility genes have been identified in HSCR, namely the RET protooncogene, the endothelin B (ETB) receptor gene (EDNRB), and the endothelin-3 (ET-3) gene (EDN3). To investigate whether mutations in EDNRB could be related with HSCR in non-inbred populations in Japan, we examined alterations of the gene in 31 isolated patients. Three novel mutations were detected as follows: two transversions, A to T and C to A at nucleotides 311 (N104I) and 1170 (S390R), respectively, and a transition, T to C at nucleotide 325 (C109R). To analyze functions of these mutant receptors, they were expressed in Chinese hamster ovary cells. S390R mutation did not change the binding affinities but caused the decreases in the ligand-induced increment of intracellular calcium and in the inhibition of adenylyl cyclase activity, showing the impairment of the intracellular signaling. C109R receptors were proved to be localized near the nuclei as an unusual 44-kDa protein with the extremely low affinity to endothelin-1 (ET-1) and not to be translocated into the plasma membrane. On the other hand, N104I receptors showed almost the same binding affinities and functional properties as those of the wild type. Therefore, we conclude that S390R and C109R mutations could cause HSCR but that N104I mutation might be polymorphous.     

Genetic analysis of mutations in seven Japanese families with type I antithrombin deficiency

Recently, a new device (Combilith) for electrokinetic lithotripsy (EKL) has become available which is very similar to the well-known device for pneumatic (ballistic) lithotripsy (Swiss Lithoclast). The Lithoclast uses air pressure to push a projectile within the handpiece against the end of a metal probe, which is thereby accelerated and thrown like a jackhammer against the stone. In principle, the same stroking movement of a small metal probe is provided by EKL; the difference is that instead of a projectile, a magnetic core within the handpiece is accelerated by the electromagnetic principle. This paper compares the clinical efficacy and the features of the two devices. Testing the devices on a stone model, taking into account stone propulsion, the systems turned out to equally effective regarding stone disintegration. However, stone displacement was more pronounced with the Lithoclast applied on easily breaking stones. In a second experiment, an optoelectronic movement-measuring apparatus (Zimmer camera) was employed to measure the range and velocity of the movement of the probe tip without any contact. The linear acceleration velocity ranged from 5 to a maximum of 12.5 m/sec with both systems, but the maximum height of the stroke was 2.5 mm with the Lithoclast and 1 mm with EKL. After the initial break-up of soft stones, further impact of the probe tip against the stone resulted merely in propulsion; thus, the greater probe stroke height is the cause of the stone displacement. In a clinical trial, 22 ureteral stones were treated with the Lithoclast and 35 with the EKL. The two devices were equally effective in terms of stone disintegration and safety margin. Fixation using a Dormia basket was necessary in 12 cases (8 Lithoclast, 4 EKL). Although a difference in probe stroke height was noted when comparing pneumatic and electrokinetic lithotripsy, there were no clinically significant differences in the efficacy of stone fragmentation or stone-free rates. At the current time, EKL is less costly.