Towards the molecular elucidation of congenital myasthenic syndromes: identification of mutations in MuSK.

Congenital myasthenic syndromes (CMS) are rare genetic diseases affecting the neuromuscular junction (NMJ) and characterized by a dysfunction of the neurotransmission. They are heterogeneous at the pathophysiological level and can be classified in three categories according to their origin: presynaptic, synaptic or postsynaptic. The strategy for the diagnosis and characterization of CMS relies on the clinic, EMG, muscle biopsy, identification of mutations in genes known to be responsible for CMS and the demonstration that the gene mutations are the cause of the disease by using experimental approaches. As an example of such strategy, we report briefly here the characterization of 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 marked pre- and postsynaptic structural abnormalities of the neuromuscular junction as well as a severe decrease in acetylcholine receptor epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The results obtained strongly suggested that the missense mutation, in the presence of a null mutation on the other allele, was responsible for the severe synaptic changes observed in the patient and, hence, is causing the disease. However the molecular origin of a large number of CMS is still unknown. There are hundreds of molecules known to be present at the NMJ and mutations in the genes coding for these synaptic molecules are likely to be responsible for a neuromuscular block.

Congenital myasthenic syndrome due to rapsyn deficiency: three cases with arthrogryposis and bulbar symptoms.

We report the cases of 3 children with postsynaptic congenital myasthenic syndrome with acetylcholine receptor deficiency due to rapsyn deficiency. Symptoms began at the neonatal period with hypotonia, arthrogryposis, bulbar symptoms, and respiratory distress. Two of the 3 children needed tracheostomy and gastrostomy. Electromyograms showed a decremental response to repetitive stimulation. Muscle biopsies were normal or showed type I fiber preponderance. Genetic studies identified mutations in the rapsyn gene (RAPSN). The 3 patients were heterozygous for N88 K and a second mutation (either Y86X, 1083_1084 dupCT or IVS4-2 A > G). The patients responded favorably to anticholinesterase treatment, with a clear improvement of clinical symptoms, especially the bulbar symptoms of apneas and swallowing disturbances. This paper underlines the importance of anticholinesterase medication in patients with congenital myasthenic syndrome due to rapsyn deficiency.

[Congenital myasthenic syndromes due to mutations in the rapsyn gene]. / Syndromes myasthéniques congénitaux dus à des mutations du gène de la rapsyne.

Congenital myasthenic syndromes (CMS) are genetic diseases characterized by dysfunctional neuromuscular transmission and usually start during the neonatal period. Most are due to postsynaptic abnormalities, specifically to mutations in the acetylcholine receptor (AChR) genes. In 2002, the group of A Engel reported the first cases of CMS with mutations in the gene coding rapsyn, a postsynaptic molecule which stabilizes AChR aggregates at the neuromuscular junction. Since this first publication, more than 30 other cases, including six in France, have been reported. Study of these published cases allows us to distinguish three classes of phenotypes: 1) severe neonatal cases; 2) more benign cases, starting during infancy; 3) cases with facial malformations, involving Jewish patients originating from the Near-East. Comparison of the observations of other groups with our own has led us to the following conclusions: the N88K mutation is frequent (homozygous in 50% of cases); besides the N88K mutation, the second mutation varies considerably; heterozygous allelic cases (N88K + another mutation) are severe; there is probably a founder effect in the European population. There is phenotypic variability in the homozygous N88K cases, with benign cases and severe cases of early expression. A Engel and colleagues report that the seven cases of benign CMS with facial malformation, previously described in the Jewish population of Iraq and Iran, were caused by mutation in the promoter region of the rapsyn gene.

Identification of seven novel mutations in the GAN gene.

Giant axonal neuropathy (GAN) is a severe early onset neurodegenerative disorder affecting both the peripheral nerves and the central nervous system. The diagnosis is based on the presence of characteristic giant axons on nerve biopsy. In GAN, the integrity of the intermediate filament network is altered. Indeed, abnormal accumulation of the intermediate filaments has been reported in different cell types, including in the swollen axons, which are filled with neurofilaments. We identified the defective protein, gigaxonin, of unknown function, and reported fourteen distinct mutations in twelve families of various origins. Two additional mutations have been recently reported. In the present study, we analysed the GAN gene in 6 families, and identified seven novel mutations: three nonsense and two missense mutations and two deletions. In addition, the molecular result for an already reported family was re-evaluated. In this family, the R269Q "polymorphism" is in fact the pathogenic mutation.

Sleep disorders caused by brainstem tumor: case report.

Few studies concerning sleep disorders in brainstem lesions or tumors have been published. We report the case of a girl who was operated on for a brainstem tumor at the age of 4 years. In postsurgery, she had hemiparesis of the left side, swallowing difficulties, and severe apneas requiring a tracheotomy with nocturnal ventilation. The child's health improved progressively. Two sleep recordings were performed at 7 and 9 years without nocturnal ventilation. These recordings showed sleep disorders with a decrease in total sleep time and rapid eye movement (REM) sleep. Several central apneas were observed. The apneas were more frequent during REM sleep in the first recording and were associated with desaturation and microarousals.

Prognostic value of evoked potentials and sleep recordings in the prolonged comatose state of children. Preliminary data.

OBJECTIVES: Sleep recordings and evoked potentials (EPs) were used in five comatose children to evaluate their predictive value for outcome following a severe comatose state. METHODS AND SUBJECTS: The protocol included EEG, Brainstem Evoked Responses (BERs), Somatosensory Evoked Potentials (SEPs) and polysomnography. From 10 to 15 days post-coma (D10 to D15), EEG and clinical examinations were carried out every second day, then one day in four from 15 to 30 days post-coma (D15 to D30), and one day in seven from D30 to six months (M6). Evoked potentials and Polysomnography were recorded on D10-D15 or D30 in the second month (M2) and in M6. Of the five children, three were in anoxic coma and two in traumatic coma. All had extensive lesions and a Glasgow Coma Scale (GCS) score of less than five. The results of the EEG, polysomnographic and EP recordings were compared to the clinical outcome. RESULTS AND CONCLUSION: In the three anoxic comas we observed BER abnormalities and the absence of SEP N20 associated with wide cortical lesions with brainstem extension. Sleep recordings showed major alterations of the wake-sleep cycle without any improvement in M6. Abnormalities included loss of the normal REM-sleep pattern associated with alteration of NREM sleep and periods of increase in motor activity without EEG arousal. This sleep pattern appeared to be associated with involvement of the brainstem. In the two traumatic comas, alterations of the early cortical SEP responses were less severe and the BERs were normal. Some sleep spindles were observed as well as the persistence of sleep cycles in the first weeks post-coma. The combined use of EEG, EPs and polysomnography improved the outcome prediction in comparison with the use of just one modality. EPs and sleep recordings were far superior to clinical evaluation and to GCS in the appreciation of the functional status of comatose children. The reappearance of sleep patterns is considered to be of favorable prognosis for outcome of the coma state, as is the presence of sleep spindles in post-trauma coma. This study showed that EPs and sleep recordings help to further distinguish between patients with good or bad outcomes.

Giant axonal neuropathy locus refinement to a < 590 kb critical interval.

Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder, characterised clinically by the development of chronic distal polyneuropathy during childhood, mental retardation, kinky or curly hair, skeletal abnormalities and, ultrastructurally, by axons in the central and peripheral nervous systems distended by masses of tightly woven neurofilaments. We recently localised the GAN locus in 16q24.1 to a 5-cM interval between the D16S507 and D16S511 markers by homozygosity mapping in three consanguineous Tunisian families. We have now established a contig-based physical map of the region comprising YACs and BACs where we have placed four genes, ten ESTs, three STSs and two additional microsatellite markers, and where we have identified six new SSCP polymorphisms and six new microsatellite markers. Using these markers, we have refined the position of our previous flanking recombinants. We also identified a shared haplotype between two Tunisian families and a small region of homozygosity in a Turkish family with distant consanguinity, both suggesting the occurrence of historic recombinations and supporting the conclusions based on the phase-known recombinations. Taken together, these results allow us to establish a transcription map of the region, and to narrow down the GAN position to a < 590 kb critical interval, an important step toward the identification of the defective gene.

Hot water epilepsy: a benign and unrecognized form.

Hot water epilepsy is a reflex epilepsy. Seizures are provoked by hot water, and result from the association of both cutaneous and heat stimuli. Described mainly in India and Japan, the condition seems to be rare in Europe, where it occurs in young children. We report five infants aged from 6 months to 2 years. They had brief seizures during bathing with activity arrest, hypotonia, and vasoactive modification; clonic movements were observed. A simple treatment-decreasing the bath temperature-can be sufficient. Sometimes an antiepileptic drug is required. Seizure course and psychomotor development are favorable. Hot water epilepsy is a benign form of epilepsy. Its incidence could be underestimated because of confusion with febrile convulsions, vagal fits, or aquagenic urticaria.

[Hot water epilepsy: a benign and underestimated form]. / L'épilepsie à l'eau chaude: une forme bénigne et méconnue.

BACKGROUND: Hot water epilepsy belongs to the group of reflex epilepsies. Seizures are provoked by hot water, due to the association of both cutaneous and heat stimuli. Described mainly in India and Japan, it seems to be rare in Europe where it occurs in young children. CASE REPORTS: Five infants aged between 6 months to 2 years had seizures during bathing with activity arrest, hypotonia and vasoactive modification. Sometimes clonic movements could be observed. The diagnosis was confirmed by EEG recorded during bath in the fives cases, with video for two of them. The course of the seizures and of the psychomotor development were favorable. CONCLUSION: Hot water epilepsy is a benign epilepsy. Its incidence could be underestimated because seizures can be confused with febrile convulsions or vagal fits.