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Biomedical subjects

Emmanuel Fournier

Publications and source records attributed to Emmanuel Fournier.

8 recordsLinked to original sources
PubMed2006

Cold extends electromyography distinction between ion channel mutations causing myotonia.

OBJECTIVE: Myotonias are inherited disorders of the skeletal muscle excitability. Nondystrophic forms are caused by mutations in genes coding for the muscle chloride or sodium channel. Myotonia is either relieved or worsened by repeated exercise and can merge into flaccid weakness during exposure to cold, according to causal mutations. We designed an easy electromyography (EMG) protocol combining repeated short exercise and cold as provocative tests to discriminate groups of mutations. METHODS: Surface-recorded compound muscle action potential was used to monitor muscle electrical activity. The protocol was applied on 31 unaffected control subjects and on a large population of 54 patients with chloride or sodium channel mutations known to cause the different forms of myotonia. RESULTS: In patients, repeated short exercise test at room temperature disclosed three distinct abnormal patterns of compound muscle action potential changes (I-III), which matched the clinical symptoms. Combining repeated exercise with cold exposure clarified the EMG patterns in a way that enabled a clear correlation between the electrophysiological and genetic defects. INTERPRETATION: We hypothesize that segregation of mutations into the different EMG patterns depended on the underlying pathophysiological mechanisms. Results allow us to suggest EMG guidelines for the molecular diagnosis, which can be used in clinical practice.

Action Potentials↗
PubMed2005

In vivo and in vitro functional characterization of Andersen's syndrome mutations.

The inward rectifier K(+) channel Kir2.1 carries all Andersen's syndrome mutations identified to date. Patients exhibit symptoms of periodic paralysis, cardiac dysrhythmia and multiple dysmorphic features. Here, we report the clinical manifestations found in three families with Andersen's syndrome. Molecular genetics analysis identified two novel missense mutations in the KCNJ2 gene leading to amino acid changes C154F and T309I of the Kir2.1 open reading frame. Patch clamp experiments showed that the two mutations produced a loss of channel function. When co-expressed with Kir2.1 wild-type (WT) channels, both mutations exerted a dominant-negative effect leading to a loss of the inward rectifying K(+) current. Confocal microscopy imaging in HEK293 cells is consistent with a co-assembly of the EGFP-fused mutant proteins with WT channels and proper traffick to the plasma membrane to produce silent channels alone or as hetero-tetramers with WT. Functional expression in C2C12 muscle cell line of newly as well as previously reported Andersen's syndrome mutations confirmed that these mutations act through a dominant-negative effect by altering channel gating or trafficking. Finally, in vivo electromyographic evaluation showed a decrease in muscle excitability in Andersen's syndrome patients. We hypothesize that Andersen's syndrome-associated mutations and hypokalaemic periodic paralysis-associated calcium channel mutations may lead to muscle membrane hypoexcitability via a common mechanism.

Action Potentials↗
PubMed2005

[Pathophysiological characterization of congenital myasthenic syndromes: the example of mutations in the MUSK gene].

Congenital myasthenic syndromes (CMS) are rare genetic diseases affecting the neuromuscular junction (NMJ) and are characterized by a dysfunction of the neurotransmission. They are heterogeneous at their pathophysiological level and can be classified in three categories according to their presynaptic, synaptic and postsynaptic origins. We report here the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding a postsynaptic molecule, the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in acetylcholine receptor (AChR) epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The frameshift mutation led to the absence of MuSK expression. The missense mutation did not affect MuSK catalytic kinase activity but diminished expression and stability of MuSK leading to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction. In electroporated mouse muscle, overexpression of the missense mutation induced, within a week, a phenotype similar to the patient muscle biopsy: a severe decrease in synaptic AChR and an aberrant axonal outgrowth. These results strongly suggest that the missense mutation, in the presence of a null mutation on the other allele, is responsible for the dramatic synaptic changes observed in the patient.

Animals↗
PubMed2004

MUSK, a new target for mutations causing congenital myasthenic syndrome.

We report the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in acetylcholine receptor (AChR) epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The frameshift mutation led to the absence of MuSK expression. The missense mutation did not affect MuSK catalytic kinase activity but diminished expression and stability of MuSK leading to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction. In electroporated mouse muscle, overexpression of the missense mutation induced, within a week, a phenotype similar to the patient muscle biopsy: a severe decrease in synaptic AChR and an aberrant axonal outgrowth. These results strongly suggest that the missense mutation, in the presence of a null mutation on the other allele, is responsible for the dramatic synaptic changes observed in the patient.

Adult↗
PubMed2004

Electromyography guides toward subgroups of mutations in muscle channelopathies.

Myotonic syndromes and periodic paralyses are rare disorders of skeletal muscle characterized mainly by muscle stiffness or episodic attacks of weakness. Familial forms are caused by mutations in genes coding for skeletal muscle voltage-gated ion channels. Exercise is known to trigger, aggravate, or relieve the symptoms. Therefore, exercise can be used as a functional test in electromyography to improve the diagnosis of these muscle disorders. Abnormal changes in the compound muscle action potential can be disclosed using different exercise tests. We report the outcome of an inclusive electromyographic survey of a large population of patients with identified ion channel gene defects. Standardized protocols comprising short and long exercise tests were applied on 41 unaffected control subjects and on 51 case patients with chloride, sodium, or calcium channel mutations known to cause myotonia or periodic paralysis. These tests disclosed significant changes of compound muscle action potential, which generally matched the clinical symptoms. Combining the responses to the different tests defined five electromyographic patterns (I-V) that correlated with subgroups of mutations and may be used in clinical practice as guides for molecular diagnosis. We hypothesize that mutations are segregated into the different electromyographic patterns according to the underlying pathophysiological mechanisms.

Action Potentials↗
PubMed2004

Electrophysiological recording of deep tendon reflexes: normative data in children and in adults.

OBJECTIVE: Latency measurement of myoelectric deep tendon (T) reflex responses is not usually performed in EMG laboratories. We investigated the optimal conditions of reliable recording of T reflex in children and adults. METHODS: Two hundred and sixty-eight normal subjects (139 males, 129 females, age rank 2 days-80 years) were studied. T reflexes were recorded from soleus and rectus femoris muscles (children and adults) and from triceps brachialis, biceps brachialis and flexor carpi radialis (adults). Specially devised hammers were used. They were fitted with a spring switch system in order to trigger the trace display on the EMG machine. Distinct technical options for the synchronisation delay assessment were tested. The nerve conduction velocities along reflex pathways were computed by referring the T wave latencies to subject's height. RESULTS: Reliable recordings could be obtained in all cases, with a strong linear correlation of the response latency with height. T reflex conduction velocities increased as the log value of subject age. Normative data from birth to 80 years are provided. CONCLUSION: T reflex recording represents a painless and easily performed technique. It may be helpful for the assessment of proximal conduction velocities, especially in children during maturation of the peripheral nervous system.

Adolescent↗
PubMed1998

Different strategies of modulation can be operative during hypnotic analgesia: a neurophysiological study.

Nociceptive electrical stimuli were applied to the sural nerve during hypnotically-suggested analgesia in the left lower limb of 18 highly susceptible subjects. During this procedure, the verbally reported pain threshold, the nociceptive flexion (RIII) reflex and late somatosensory evoked potentials were investigated in parallel with autonomic responses and the spontaneous electroencephalogram (EEG). The hypnotic suggestion of analgesia induced a significant increase in pain threshold in all the selected subjects. All the subjects showed large changes (i.e., by 20% or more) in the amplitudes of their RIII reflexes during hypnotic analgesia by comparison with control conditions. Although the extent of the increase in pain threshold was similar in all the subjects, two distinct patterns of modulation of the RIII reflex were observed during the hypnotic analgesia: in 11 subjects (subgroup 1), a strong inhibition of the reflex was observed whereas in the other seven subjects (subgroup 2) there was a strong facilitation of the reflex. All the subjects in both subgroups displayed similar decreases in the amplitude of late somatosensory evoked cerebral potentials during the hypnotic analgesia. No modification in the autonomic parameters or the EEG was observed. These data suggest that different strategies of modulation can be operative during effective hypnotic analgesia and that these are subject-dependent. Although all subjects may shift their attention away from the painful stimulus (which could explain the decrease of the late somatosensory evoked potentials), some of them inhibit their motor reaction to the stimulus at the spinal level, while in others, in contrast, this reaction is facilitated.

Adult↗