Charcot-Marie-Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of peripheral neuropathies characterized by progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4. Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles. Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families. Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance. Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cells.
Objectives: To examine whether two cortical processes concerned with spectro-temporal analysis of complex tones, a`C-process' generating CN1 and CP2 potentials at cf. 100 and 180 ms after sudden change of pitch or timbre, and an`M-process' generating MN1 and MP2 potentials of similar latency at the sudden cessation of repeated changes, are dependent on accumulation of a sound image in the long auditory store.Methods: The durations of steady (440 Hz) and rapidly oscillating (440±494 Hz, 16 changes/s) pitch of a synthesized`clarinet' tone were reciprocally varied between 0.5 and 4.5 s within a duty cycle of 5 s. Potentials were recorded at the beginning and end of the period of oscillation in 10 non-attending normal subjects.Results: The CN1 at the beginning of pitch oscillation and the MN1 at the end were both strongly in¯uenced by the duration of the immediately preceding stimulus pattern, mean amplitudes being 3±4 times larger after 4.5 s as compared with 0.5 s.Conclusions: The processes responsible for both CN1 and MN1 are in¯uenced by the duration of the preceding sound pattern over a period comparable to that of the`echoic memory' or long auditory store. The store therefore appears to occupy a key position in spectro-temporal sound analysis. The C-process is concerned with the spectral structure of complex sounds, and may therefore re¯ect the`grouping' of frequency components underlying auditory stream segregation. The M-process (mismatch negativity) is concerned with the temporal sound structure, and may play an important role in the extraction of information from sequential sounds. q
In this study, synthesised instrumental tones were used to examine human auditory cortical processes engaged at the end of a period of w rapid pitch modulation. It was previously S.J. Jones, O. Longe, M. Vaz Pato, Auditory evoked potentials to abrupt pitch and timbre Ž . x change of complex tones: electrophysiological evidence of 'streaming'?, Electroencephalogr. Clin. Neurophysiol., 108 1998 131-142 suggested that the 'change-N1' produced by infrequent changes in pitch or timbre of a continuous complex tone represents the activity of a neuronal population topographically distinct from that responsible for the 'onset-N1' at the beginning of the tone. In the present study a Ž . superficially similar negativity was produced when the tone came to rest on a steady pitch after a period of rapid 8-16 changesrs modulation; its scalp maximum was anterior to that of the two previously identified potentials but similar to that of the mismatch negativity elicited by discontinuous tones. By varying the modulation rate the latency was shown to be relatively constant with respect to the time the next pitch change was expected but failed to occur. The largest responses averaging c. 7 mV were evoked at the end of modulation sequences which were both rhythmic and repetitive, but a potential was still produced when there was no rhythmic pattern or repetition of individual notes. This response to non-occurrence of an expected but not necessarily specified change implies an automatic process for comparing the incoming sound with an extrapolated template of the preceding pattern in which timing as well as pitch information is accurately represented. We suggest this technique offers a robust method for eliciting the mismatch negativity, which may extend the opportunities for electrophysiological investigation of higher auditory processes. q
In order to assess higher auditory processing capabilities, long-latency auditory evoked potentials (AEPs) were recorded to synthesized musical instrument tones in 22 post-comatose patients with severe brain injury causing variably attenuated behavioural responsiveness. On the basis of normative studies, three different types of spectro-temporal modulation were employed. When a continuous 'clarinet' tone changes pitch once every few seconds, N1/P2 potentials are evoked at latencies of approximately 90 and 180 ms, respectively. Their distribution in the fronto-central region is consistent with generators in the supratemporal cortex of both hemispheres. When the pitch is modulated at a much faster rate ( approximately 16 changes/s), responses to each change are virtually abolished but potentials with similar distribution are still elicited by changing the timbre (e.g. 'clarinet' to 'oboe') every few seconds. These responses appear to represent the cortical processes concerned with spectral pattern analysis and the grouping of frequency components to form sound 'objects'. Following a period of 16/s oscillation between two pitches, a more anteriorly distributed negativity is evoked on resumption of a steady pitch. Various lines of evidence suggest that this is probably equivalent to the 'mismatch negativity' (MMN), reflecting a pre-perceptual, memory-based process for detection of change in spectro-temporal sound patterns. This method requires no off-line subtraction of AEPs evoked by the onset of a tone, and the MMN is produced rapidly and robustly with considerably larger amplitude (usually >5 microV) than that to discontinuous pure tones. In the brain-injured patients, the presence of AEPs to two or more complex tone stimuli (in the combined assessment of two authors who were 'blind' to the clinical and behavioural data) was significantly associated with the demonstrable possession of discriminative hearing (the ability to respond differentially to verbal commands, in the assessment of a further author who was blind to the AEP findings). Behavioural and electrophysiological findings were in accordance in 18/22 patients, but no AEPs could be recorded in two patients who had clear behavioural evidence of discriminative hearing. The absence of long-latency AEPs should not, therefore, be considered indicative of complete functional deafness. Conversely, AEPs were substantially preserved in two patients without behavioural evidence of discriminative hearing. Although not necessarily indicative of conscious 'awareness', such AEP preservation might help to identify sentient patients who are prevented by severe motor disability from communicating their perception.
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