A novel synonymous mutation in the MPZ gene causing an aberrant splicing pattern and Charcot-Marie-Tooth disease type 1b.

Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy with a heterogeneous genetic background. Here, we describe two CMT1B families with a mild sensory-motor neuropathy and a novel synonymous variant (c.309G > T, p.G103G) in exon 3 of the MPZ gene. Next generation sequencing analysis on a 94 CMT gene panel showed no mutations in other disease genes. In vitro splicing assay and mRNA expression analysis indicated that the c.309T variant enhances a cryptic donor splice site at position c.304 resulting in the markedly increased expression of the r.304_448del alternative transcript in patients' cells. This transcript is predicted to encode a truncated P0 protein (p.V102Cfs11*) lacking the transmembrane domain, thus suggesting a possible haploinsufficiency mechanism for this mutation. This is the third reported synonymous MPZ variant associated with CMT1 and affecting splicing. These data confirm the functional impact of synonymous variants on MPZ splicing and their possible role as disease-causing mutations rather than silent polymorphisms.

Intermittent photic stimulation affects motor cortex excitability in photosensitive idiopathic generalized epilepsy.

PURPOSE: To assess the effect of intermittent photic stimulation (IPS) at a common activating frequency, i.e. 20Hz, on motor cortex excitability by means of transcranial magnetic stimulation (TMS) in photosensitive patients with idiopathic generalized epilepsy (IGE). METHODS: We studied 15 photosensitive IGE patients showing a photoparoxysmal response (PPR) to IPS at 20Hz. Nineteen normal subjects of similar age and sex acted as controls. After the resting motor threshold (rMT) was measured, we studied the corticomotor excitability in two conditions randomly delivered, during IPS (5s) at 20Hz and without IPS. Motor evoked potentials (MEPs) were recorded from the right first dorsal interosseous muscle (FDI). We determined the cortical silent period (cSP), the short-latency intracortical inhibition (SICI) at the interstimulus interval (ISI) of 3 and 4ms and the intracortical facilitation (ICF) at ISIs of 12 and 14ms. Data were analyzed by means of rmANOVAs. RESULTS: IPS at 20Hz is significantly shortening the cSP in normal subjects, while no significant changes were detected in patients. The rMT was significantly higher in patients than controls, as expected by the concurrent antiepileptic treatment. Other corticomotor excitability measures were unaffected. CONCLUSIONS: We confirm that IPS has a weak influence on the motor cortical output in patients with IGE and PPR. The loss of the normal shortening of the cSP, otherwise present in healthy subjects in response to IPS, may have a possible protective nature.

Progressive multifocal leucoencephalopathy after autologous bone marrow transplantation: a treatment option.

A patient with multiple myeloma was treated with high-dose chemotherapy followed by two autologous bone marrow transplantations (ABMTs). Nine months after the second ABMT the patient complained of severe left hemiparesis, paraesthesias, left homonymous visual field defects and gait ataxia. She was diagnosed with progressive multifocal leucoencephalopathy (PML) confirmed by detection of JC virus (JCV) DNA and prescribed cidofovir every other week and mirtazapine daily. Her symptoms and signs remained stable and after 6 months the JCV DNA was undetectable in the cerebrospinal fluid. Repeated MRI scans demonstrated the stabilisation of demyelinating lesion volume; after more than 2 years of follow-up the patient's neurological examination does not show significant variations. Combination of cidofovir and mirtazapine may be helpful in the treatment of PML in HIV-negative patients.

Cortical inhibition in Parkinson's disease: new insights from early, untreated patients.

Transcranial magnetic stimulation (TMS) has opened important perspectives on the pathophysiological bases and potential targets of treatment strategies for idiopathic Parkinson's disease (IPD). Studies have been mainly focusing on motor cortical inhibitory phenomena. However, differences in patients and methods caused several discrepancies, particularly on the so-called long-latency cortical inhibition (LICI). We wanted to challenge such controversies by studying early, drug-naïve patients, and by reproducing the original method that detected a pathologic LICI in IPD. We studied the motor potentials evoked in the first dorsal interosseous muscle on the more and the less parkinsonian side of the body in 18 asymmetrical untreated IPD patients in the early stages of their disease. We had 12 healthy controls. The TMS variables were the active motor threshold, the size of the motor-evoked potential, the cortical silent period and LICI. Average active motor threshold was similar in patients and controls, but its variability was significantly higher among patients (P<0.05). There was a trend for the cortical silent period to be shorter on the more affected side of the patients (P=0.1). Patients, especially on their more affected side, exhibited a late LICI peak, which was absent among controls (P<0.05). This effect was independent of the silent period duration. However, patients and controls having a short silent period also had a shorter LICI (P<0.05). Changes in LICI had a strong trend to correlate to the severity of the parkinsonian signs (P=0.1). Thus, the present study definitely reinforced several previous TMS findings in IPD as a feature of the "pure" disease pathophysiology. The pathologic enhancement of late LICI can act as a candidate physiological hallmark of IPD, to be tested in various diagnostic or therapeutic circumstances.

Accuracy of the ICD-9 codes for identifying TIA and stroke in an Italian automated database.

The object of this study was to evaluate the sensitivity and positive predictive value (PPV) of International Classification of Diseases, 9th revision (ICD-9) codes 430-438 in the Sistema Informativo Sanitario Regionale (SISR), an Italian health care automated database. We compared the SISR with a manual search of all cases of transient ischaemic attack (TIA) and stroke discharged from the Novara Hospital, NW Italy. Results were as follows: SISR list: 1017 patients; manual list 1005. Linked: 896; false negatives: 109; false positives: 121. Sensitivity of codes 430-438: 77% at the primary position only and 89% at either the primary or secondary position; PPV: 93% and 88%. Sensitivity and PPV for specific codes vs. each subcategory (sensitivity at the primary position only/any position; PPV at the primary position only/any position): for 430, subarachnoid haemorrhage (33/35%; 46/43%); for 431, cerebral haemorrhage (57/59%; 77/75%); for 434, cerebral infarction (35/37%; 90/87%); for 436, stroke of unknown type (29/29%; 19/16%); and for 435, TIA (75/82%; 80/78%). The SISR database has a high PPV; sensitivity is high for TIA, but low for specific stroke ICD codes.

Cortical excitability in drug-naive patients with partial epilepsy: a cross-sectional study.

OBJECTIVE: To use paired-pulse transcranial magnetic stimulation (TMS) to investigate cortical excitability in drug-naive patients with partial epilepsy. METHODS: Twenty-one drug-naive patients with partial epilepsy and 15 control subjects were studied. The relaxed threshold to TMS, the central silent period, and the intracortical inhibition/facilitation were measured. Statistics implied cluster analysis methods. Also assessed were the patient interictal EEG epileptiform abnormalities (EAs) on a semiquantitative basis. Then the TMS was contrasted to the clinical and EEG findings, using chi2 or Fisher exact tests. RESULTS: One-third of the patients made up a "pathologic" cluster with a disrupted intracortical inhibition (p < 0.01). Two-thirds had a normal inhibition. Interictal EAs predominated in the pathologic cluster, for frequency (p < 0.04), duration (p < 0.04), and focality (p < 0.02). CONCLUSIONS: Intracortical inhibition, which was impaired in one-third of the patients, reflects gamma-aminobutyric acid (GABA) activity within cortical area 4. Defective GABA inhibition is a typical pathogenic factor in partial epilepsy. Transcranial magnetic stimulation proved able to detect it. The weaker cortical inhibition had a direct relation to the severity of interictal epileptiform abnormalities.

Cortical excitability and sleep deprivation: a transcranial magnetic stimulation study.

The objective was to assess the changes in cortical excitability after sleep deprivation in normal subjects. Sleep deprivation activates EEG epileptiform activity in an unknown way. Transcranial magnetic stimulation (TMS) can inform on the excitability of the primary motor cortex. Eight healthy subjects (four men and four women) were studied. Transcranial magnetic stimulation (single and paired) was performed by a focal coil over the primary motor cortex, at the "hot spot" for the right first dorsal interosseous muscle. The following motor evoked potential features were measured: (a) active and resting threshold to stimulation; (b) duration of the silent period; (c) amount of intracortical inhibition on paired TMS at the interstimulus intervals of 2 and 3 ms and amount of facilitation at interstimulus intervals of 14 and 16 ms. The whole TMS session was repeated after a sleep deprivation of at least 24 hours. After the sleep deprivation, the threshold to stimulation (in the active and resting muscle), as well as the silent period, did not change significantly. By contrast, the paired stimulus study showed a significant (p<0.05) reduction in both intracortical inhibition and facilitation. Thus, TMS showed that sleep deprivation is associated with changes in inhibition-facilitation balance in the primary motor cortex of normal subjects. These changes might have a link with the background factors of the "activating" effects of sleep deprivation.

Effects of a photic input on the human cortico-motoneuron connection.

OBJECTIVES: Disease manifestations such as photic cortical reflex myoclonus or myoclonus due to intermittent light stimulation rely on a pathologic interaction between non-structured visual inputs and the corticospinal system. We wanted to assess the normal interaction, if any, between a prior photic input and the output of the cortico-motoneuron connection. METHODS: In 9 consenting healthy subjects we quantified the changes exerted by a sudden, unexpected bright light flash on (i) the motor potentials (MEPs) evoked in the right first dorsal interosseous muscle (FDI) by transcranial magnetic or electrical stimulation (TMS/TES) of the primary motor cortex, (ii) the FDI F-waves and (iii) the soleus H-wave. Separately, we measured the simple reaction times to the flash itself. All determinations were repeated twice with an interval of 2-24 months. RESULTS: When the flash preceded TMS by 55-70 ms, the MEP size was reduced, while at interstimulus intervals (ISIs) of 90-130 ms it was enlarged. Statistical significance (P<0.05) emerged at ISIs of 55, 70, 100, 105 and 120 ms. Conversely, the MEP latency was prolonged at ISIs of 55-70 ms and shortened at ISIs of 90-130 ms (P<0.05 at ISIs of 55, 110 and 130 ms). Electrical MEPs were enhanced at an ISI of 120 ms. The F-wave size showed a non-significant trend of enhancement at ISIs of 90-130 ms. The soleus H-wave showed significant enlargement at ISIs of 90-130 ms (P<0.05 at ISIs of 100 and 105 ms). The minimum reaction time was on average 120 ms. CONCLUSIONS: An unexpected photic input, to which no reaction is planned, can cause an early inhibition of the responses to TMS. We think its origin lies within the primary motor cortex, since it is not associated with changes in spinal excitability or electrical MEPs. A later facilitation persists using TES and has a temporal relationship with an enlargement of the soleus H-wave. Thus, it likely results from activation of descending (possibly reticulospinal) fibers that excite the spinal motor nucleus.

Cortical excitability in cryptogenic localization-related epilepsy: interictal transcranial magnetic stimulation studies.

PURPOSE: To assess whether single-and paired-pulse transcranial magnetic stimulation (TMS) can measure the interictal brain excitability of medicated patients with cryptogenic localization related epilepsy (CLE). Changes in the balance between excitation and inhibition are the core phenomena in focal epileptogenesis. TMS can assess this balance in the primary motor cortex. METHODS: We selected 18 patients with CLE and similar clinical features in whom we located the epileptogenic area reliably, with 11 age-and sex-matched healthy controls. For both motor cortices, we determined the threshold to TMS, the duration of the cortical silent period, and the corticocortical inhibition and facilitation curve. RESULTS: TMS was safe. The more antiepileptic drugs (AEDs) taken by the patients, the higher their threshold to TMS. The silent period duration failed to show significant changes. On paired TMS, a cluster analysis identified a homogeneous subgroup of patients (n = 7) who showed a significantly defective corticocortical inhibition and excess facilitation. With respect to the epileptogenic area, the phenomenon was bilateral in four of these patients, ipsilateral in two, and contralateral in one. The phenomenon was independent of AEDs and many other clinical variables. However, this patient group had a higher seizure frequency and a higher proportion of electroencephalograms (EEGs) showing interictal generalized epileptic discharges than the rest of the patients. CONCLUSION: Paired TMS provided a valuable pathophysiologic insight into the interictal excitatory state of the cortex in CLE. This method can potentially supply useful prognostic clinical information.

Hemispheric asymmetries of cortico-cortical connections in human hand motor areas.

OBJECTIVE: To evaluate possible functional asymmetries of the motor cortex on the hand-dominant versus the non-dominant hemisphere. METHODS: We assessed the handedness of 15 consenting volunteers using the Edinburgh Inventory. They were divided in two groups: 9 right-handers and 6 left-handers. We used single- and paired-transcranial magnetic stimulation (TMS) to measure the relaxed and active motor threshold and the ipsilateral cortico-cortical inhibition and facilitation curve for both hand motor areas. We looked for hemispheric asymmetries of variables related to the side of stimulation (dominant versus non-dominant) and to handedness. RESULTS: We found no significant intra- or intergroup hemispheric asymmetry for the relaxed and active thresholds. Among the right-handers, the cortico-cortical inhibition and facilitation curve showed an increased amount of facilitation in the dominant as compared with the non-dominant hand area. No such changes were seen among the left-handers. Both the dominant and the non-dominant hand areas of the right-handers showed more inhibition and less facilitation on the cortico-cortical inhibition and facilitation curve than the corresponding areas of left-handers. CONCLUSION: In the right-handers, paired TMS studies showed a functional asymmetry of the motor cortex between the dominant and the non-dominant hand. The left-handers did not show this lateralization. Under TMS investigation their motor cortex function appeared different from that of right-handers.