Novel missense mutation in the caveolin-3 gene in a Belgian family with rippling muscle disease.

Rippling muscle disease (RMD) is a rare muscle disorder characterised by muscle stiffness, exercise induced myalgia, and cramp-like sensations. It is genetically heterogeneous and can be acquired, but most cases show autosomal dominant inheritance due to mutations in the caveolin-3 (CAV3) gene. We report a novel heterozygous missense mutation in CAV3 in a Belgian family with autosomal dominant RMD. A 40 year old woman complained of fatigue, exercise induced muscle pain, and muscle cramps since the age of 35. Neurological examination revealed percussion induced rapid muscle contractions (PIRCs) and localised muscle mounding on percussion; muscle rippling was not observed. Creatine kinase (CK) was elevated but electromyography and nerve conduction studies were normal. Fluorescence immunohistochemistry revealed reduced caveolin-3 and dysferlin staining in a quadriceps muscle biopsy. Western blot analysis confirmed severely reduced caveolin-3 levels, whereas dysferlin was normal. Sequence analysis of the two coding exons of CAV3 revealed a hitherto unreported heterozygous C82A transversion in the first exon, predicting a Pro28Thr amino acid exchange. Thr patient's first degree relatives did not present with neuromuscular complaints, but PIRCs, muscle mounding, and muscle rippling were found in the mother, who also carried the CAV3 mutation.

Directional tuning of speed-related activation for reaching in the vertical plane in cerebellar ataxia.

The role of the cerebellum in the spatial tuning of goal-directed multi-joint movements in human is unknown. We analyzed the directional tuning of phasic EMG activities associated with upper limb reaching movements (12 targets) in the vertical plane in healthy subjects and in patients exhibiting cerebellar ataxia. Tuning of phasic EMG activities was investigated in seven muscles (brachioradialis, biceps, medial and long head of triceps, anterior and posterior deltoid, latissimus dorsi). We digitally compressed the EMG activities corresponding to slow reaches to the same targets into the time frame of the fast EMG traces. Estimates of gravity-related components were subtracted. Peaks of EMG activities in the resulting phasic traces were identified for each muscle and each target. Aberrant privileged directions of M Peak EMG (directions associated with the maximal peak of EMG amongst the 12 peaks of EMG activity in the sagittal plane) were found in all ataxic patients. Directional dominance, defined as the ratio of the M Peak EMG divided by the peak EMG in the opposite direction, was significantly higher in controls than in ataxic patients for one distal muscle (brachioradialis) and one proximal muscle (anterior deltoid). The spreading of EMG activities assessed by the global areas of the polar plots of phasic traces was broader in patients for the biceps and medial head of triceps. The distribution of densities of EMG activities (DDEMG) amongst the four quarters of the vertical plane, an index of the contrast in the intensities between quarters in polar plots, revealed increased values in control subjects for the brachioradialis, the biceps and the anterior deltoid as compared to ataxic patients. Representation of Net Vectors obtained from polar plots of peaks of EMG activities demonstrated an abnormal directional tuning in ataxic patients. In the majority of the cases, the Net Vector was outside the normal range for the following muscles: brachioradialis, biceps, anterior deltoid, posterior deltoid. This study reveals that cerebellar ataxia is associated with defective spatial properties of EMG activity during multiple joint movements. Privileged directions associated with M Peak EMG and Net Vectors are erroneous. We demonstrate that the cerebellum plays a determinant and unsuspected role in the spatial modulation of activation during speed-related action for reaching.

Invariability of the privileged direction of the maximal EMG activity during speed-related activation for reaching in the vertical plane.

Spatial tuning of goal-directed movements is a critical phenomenon for the central nervous system. The use of reliable models is a necessary step for the understanding of the neural mechanisms governing reaching movements. We analysed phasic electromyographic (EMG) activities associated with upper limb reaching movements in the vertical plane (12 targets) in seven healthy subjects during three successive sessions. We tested the hypothesis that one of the fundamental parameters of the directional tuning of phasic EMG activities is the peak of EMG activity. To characterize the tuning of phasic EMG activities for the seven recorded muscles (brachioradialis, biceps, medial and long head of triceps, anterior and posterior deltoid, latissimus dorsi), we digitally compressed the EMG activities corresponding to slow reaches to the same targets into the time frame of the fast EMG traces. Estimates of gravity-related components were subtracted. Peak of EMG activities in the resulting phasic traces were identified for each muscle and each target. The maximal peak EMG amongst the 12 peaks of EMG activity in the sagittal plane was called M Peak EMG. We defined the directional dominance as the ratio of the M Peak EMG divided by the Peak EMG in the opposite direction. The M Peak EMG for each muscle was always found in the same privileged direction of the movement, except for the latissimus dorsi. The directional dominance remained unchanged across recording sessions for the brachioradialis, anterior deltoid and posterior deltoid. However, the directional dominance increased across sessions for the biceps, medial head of triceps, long head of triceps and latissimus dorsi. The invariability of the privileged direction of the M peak EMG was thus observed for six of the seven muscles investigated. Therefore, we suggest that the selection of the privileged direction of the M Peak EMG represents a robust parameter to study the neuromuscular control strategy underlying the specification of movement direction.

Shift from hypermetria to hypometria in multiple system atrophy: analysis of distal and proximal movements.

Dysmetria is a classical sign which designates the overshoot, also called hypermetria, and the undershoot, or hypometria, when the patient attempts to reach rapidly an aimed target. Dysmetria is typically observed in patients presenting a cerebellar dysfunction. Dysmetria of distal movements is associated with an imbalance between the timing and/or the intensity of agonist and antagonist EMG activities. So far, 1. there is only one description in human of a shift from hypermetria to hypometria for fast goal-directed single-joint movements during an aberrant recovery following a cerebellar infarction, and 2. such a shift has not been described for proximal movements. We report a patient presenting a multiple system atrophy (MSA). Initially, he exhibited a marked cerebellar syndrome. Fast wrist flexions and fast upper limb reaches in the sagittal plane were hypermetric. The distal hypermetria was associated with a delayed onset latency of the antagonist EMG activity and reduced intensities of both the agonist and the antagonist EMG activities. The proximal hypermetria was associated with a defect in the phasic spatial tuning of the EMG activities. He developed progressively severe extra-pyramidal signs. Distal hypermetria turned into hypometria, as a result of a decrease in the intensity of the agonist muscle. Proximal hypermetria turned into hypometria, as a result of the loss of directional preference of the EMG activities in proximal muscles. MSA is the second human model of a shift from hypermetria to hypometria.

Effects of hyperventilation on fast goal-directed limb movements in spinocerebellar ataxia type 6.

It has been shown previously that hyperventilation modifies the features of the nystagmus in cerebellar patients (Walker and Zee, 1999). It has been hypothesized that hyperventilation influences the oculomotor control through a metabolic effect on cerebellar calcium channels, which play a critical role in the firing behaviour of neuronal populations in the cerebellum. This hypothesis has been tested here by analysing fast goal-directed limb movements before and after hyperventilation in spinocerebellar ataxia type 6 (SCA-6), a disease associated with a polyglutamine expansion in the alpha 1-A voltage-dependent calcium channel. Cerebellar hypermetria associated with fast distal single-joint movements was found to be increased following hyperventilation in patients presenting SCA-6 but remained unchanged in patients with idiopathic late-onset cerebellar degeneration (ILOCA). This is a new provocative test to enhance distal dysmetria in SCA-6. The present results strengthen the hypothesis of Walker and Zee. It is suggested that hyperventilation enhances the defective calcium transfers in SCA-6, resulting in an impairment of the calcium influx in particular into Purkinje cells involved in the control of fast goal-directed voluntary movements.

Discrepancy between dysmetric centrifugal movements and normometric centripetal movements in psychogenic ataxia.

A method to unravel an aberrant motor behaviour in psychogenic ataxia is reported. The kinematic features of fast reaching movements in the vertical plane are described in a patient presenting a psychogenic ataxia. The procedure compared centrifugal and centripetal movements. Path ratios were computed for each phase, as well as the ratios of the paths for centrifugal and centripetal directions. Trajectories of centrifugal phases were erratic but centripetal movements were very regular, whereas both centripetal and centrifugal movements were irregular in patients presenting an organic cerebellar syndrome. A similar incongruity between movements in opposite directions is also shown for a second patient exhibiting psychogenic ataxia. Discrepancies between the centrifugal phase and the centripetal phase of multi-joint reaching movements support the diagnosis of a psychogenic movement disorder.

[Interobserver reliability of a new horizontal pointing manoeuvre: comparison with conventional tests]. / Etude de la reproductibilité inter-observateur de l'évaluation d'une nouvelle manoeuvre de pointage horizontal: comparaison avec les tests cliniques conventionnels.

Finger-to-nose test, fine finger movements, to maintain arms against gravity, alternate movements of hands, Barany's test, muscle tone evaluation, Stewart-Holmes test and handwriting are the conventional clinical tests most frequently used in daily practice to evaluate voluntary movements of the upper limb. We describe a new clinical manoeuvre consisting of a horizontal pointing movement of one upper limb (the moving limb) towards the contralateral motionless limb. We have analyzed the reliability of our new test and of the conventional tests between 2 observers using kappa statistics in a group of 34 right-handed neurological patients. Agreement is very good for our test, since k has a value of 0.63 for left upper limb and a value of 0.64 for right upper limb. The only conventional test characterized by a higher interobserver reliability is handwriting. Furthermore, our manoeuvre is original, as attested by partial association coefficients analysis between our test and conventional tests. This might be due to the fact that our manoeuvre is the sole test investigating rapid proximal movements towards a fixed area in space. In conclusion, our horizontal pointing manoeuvre has a very good reliability between 2 observers and appears original.

Rhythmic cortical and muscle discharges induced by fatigue in corticobasal degeneration.

We describe a patient presenting clinical features of corticobasal degeneration (CBD), including reflex myoclonus in the left upper limb. This patient complained of a marked worsening of involuntary movements in the left upper limb after exercise. We analysed the electrophysiological characteristics of myoclonus in the basal state and after a fatiguing exercise in the left upper limb. In the basal condition, single trials recording EEG showed a cortical complex occurring 20 ms after stimulation of the left median nerve. Surface EMG recordings of the left first dorsal interosseous (FDI) revealed an isolated biphasic C1 response 49 ms after stimulation. After exercise, single trials recording EEG following shocks to the left median nerve showed rhythmic complexes with a duration of approximately 80 ms. EEG complexes were made of a series of 3 bursts, with intervals between bursts tending to cluster at approximately 22 ms. These rhythmic complexes were associated with repetitive activity in the left FDI. We conclude that rhythmic cortical and muscle discharges can be induced by fatigue in CBD.

Resetting of orthostatic tremor associated with cerebellar cortical atrophy by transcranial magnetic stimulation.

OBJECTIVES: To investigate the resetting effects of transcranial magnetic stimulation over motor cortex on orthostatic tremor, characterized by high-frequency electromyographic discharges in weight-bearing muscles, particularly orthostatic tremor (OT) associated with cerebellar cortical atrophy; and to compare our results with those obtained in primary OT, for which transcranial magnetic stimulation does not reset tremor. DESIGN: Study of 3 patients who clinically exhibited a sporadic pancerebellar syndrome associated with isolated cerebellar atrophy and features of OT. SETTING: Research hospital. MAIN OUTCOME MEASURES: Electromyograms and transcranial magnetic stimulation studies with a resetting index calculated on the basis of the timing of measured bursts and predicted bursts for a magnetic stimulus given at increasing delays. RESULTS: Surface electromyographic recordings in weight-bearing muscles showed tremor with a frequency of 14, 15, and 14 Hz in the 3 patients. Transcranial magnetic stimulus was able to reset OT. Resetting index was 0.72. CONCLUSIONS: Transcranial magnetic stimulus resets OT associated with cerebellar cortical atrophy, emphasizing the role of motor cortex in the genesis of OT associated with a cerebellar dysfunction. Our results argue in favor of a distinct pathophysiological mechanism of primary OT and OT associated with cerebellar cortical atrophy.

Cerebellar ataxia following whooping cough.

Bordetella pertussis (BP), the agent of whooping cough, has not been recognized so far as a cause of permanent cerebellar ataxia in human. We describe three patients who developed a disabling and permanent cerebellar syndrome soon after whooping cough. In two patients, diagnosis of BP infection was confirmed by culture of nasopharyngeal secretions. The infection occurred between the age of 13 and 15 years, with neurological symptoms beginning after a delay varying from 3 weeks to 3 months. In our three patients, the cerebellar syndrome was characterized by dysmetria of ocular saccades, scanning speech and ataxic gait. Brain MRI demonstrated a pancerebellar atrophy. The pathogenesis of this cerebellar degeneration is not established. Experimental studies have demonstrated that the cerebellum is particularly vulnerable to lymphocytosis-promoting factor (LPF), one of the exotoxins from BP. The mechanism of this toxicity might be a marked increase in the cellular levels of 3',5'cyclic guanosine monophosphate (cGMP). Since whooping cough is a bacterial exotoxin-mediated disease, this is the first report of a cerebellar syndrome triggered by a bacterial exotoxin.

[Friedreich's ataxia: recent developments and prospects for treatment]. / L'ataxue de Fruedreucg: données récentes et perspectives thérapeutiques.

Friedreich's ataxia (FRDA) is the most frequent cause of recessive ataxias. Neurological examination shows oculo-motor ataxia, dysarthria, limbs ataxia, tendon areflexia, pyramidal signs and sensory deficits. Extra-neurological involvement consists in osteoarticular deformities, cardiomyopathy and diabetes mellitus. Neurological deficits and osteoarticular deformities both contribute to the gait disorder, which is the main disabling deficit. In 98% of the cases, a trinucleotide repeat is found in chromosome 9. Gene implicated in FRDA codes for a protein called frataxin. Experimental studies have revealed iron accumulation in mitochondria of neurons and cardiomyocytes, suggesting that frataxin plays a determinant role in intramitochondrial iron homeostasis. These discoveries are now considered as a clue for new strategies of treatment in this hereditary disease.

[Autosomal dominant spinocerebellar ataxia]. / Les ataxies spino-cérébelleuses (SCA) autosomiques dominantes.

The autosomal dominant spinocerebellar ataxias (SCA) are a heterogeneous group of degenerative diseases presenting with ataxic gait, limbs ataxia, dysarthria and cerebellar oculomotor disturbances. Usually, cerebellar signs are associated with pyramidal signs, extra-pyramidal signs, spinal signs and signs of peripheral neuropathy. Neuropathological studies have disclosed an involvement of the cerebellum and its afferent/efferent pathways, of the brainstem and of the spinal cord. Distinct entities are now recognized: SCA1, SCA2, SCA3/Machado-Joseph disease, SCA4, SCA5,SCA6, SCA7 and dentatorubropillidoluysian atrophy (DRPLA). In most cases, a CAG trinucleotide repeat expansion has been demonstrated by genetic investigations. Moreover, recent studies have shown that autosomal dominant spinocerebellar ataxias are characterized by intra-nuclear inclusions containing polyglutamine in affected cells. These complexes might pl ay a determinant role in the neurodegenerative process. Cell death could be due to accumulation of a polyglutamine as a result of trinucleotide repeats.