Identification of heterozygous and homozygous individuals with the novel RYR1 mutation Cys35Arg in a large kindred.

BACKGROUND: Malignant hyperthermia (MH) is a potentially fatal, often autosomal dominant, disorder of skeletal muscle and is triggered in susceptible people by all commonly used inhalational anesthetics. In this article, the authors describe a malignant hyperthermia susceptible (MHS) kindred in which both parents of the proband are MHS and are first-degree cousins. Haplotype analysis in this kindred with chromosome 19 linked markers revealed that the proband and another sibling were homozygous for the affected RYR1 allele. METHODS: Eighteen members of this large pedigree were investigated, with a clinical examination for signs of a myopathy, a caffeine halothane contracture test, a histo-enzymologic study on the muscle biopsies, and linkage analysis on genomic DNA isolated from family blood samples. RYR1 cDNA was amplified by polymerase chain reaction and was cloned and sequenced, facilitating mutation detection. RESULTS: Linkage analysis demonstrated linkage between RYR1-linked markers and MH susceptibility in this family. DNA sequencing identified a T to C transition at nucleotide position 103, resulting in the substitution of an arginine for cysteine 35, representing the most N-terminal mutation reported to date in the RYR1 gene. This mutation segregates fully with the MHS trait, generating a lod score of 4.65 in favor of linkage to MHS at a recombination frequency of 0.0. CONCLUSIONS: The proband in this kindred is the first reported homozygote to have presented with an MH episode. The homozygotes in this pedigree do not have an overt myopathy. The sensitivity of muscle samples to caffeine clearly distinguished the two homozygotes from other heterozygous-susceptible individuals. No clear differentiation was observed with the halothane contracture results.

In vitro human masseter muscle hypersensitivity: a possible explanation for increase in masseter tone.

To determine whether a difference in fiber-type caffeine and Ca2+ sensitivities exists between human masseter and vastus lateralis skeletal muscle, we compared the fiber-type caffeine sensitivities in chemically skinned muscle fibers from 13 masseter and 18 vastus lateralis muscles. Caffeine sensitivity was defined as the threshold concentration inducing > 10% of the maximal tension obtained after the fiber was loaded with a 1.6 x 10(-2) mM Ca2+ solution for 30 s. Significant difference in the mean caffeine sensitivity was found between type I masseter fibers [2.57 +/- 1.32 (SD) mM] vs. type I (6.02 +/- 1.74 mM) and type II vastus lateralis fibers (11.25 +/- 3.13 mM). Maximal Ca(2+)-activated force per cross-sectional area was significantly different between masseter and vastus lateralis fibers. However, the Ca2+ concentration corresponding to half-maximal tension (pCa50) was not significantly different between type I masseter (pCa50 5.9 +/- 0.02) and type I vastus lateralis muscle (pCa50 6.01 +/- 0.08). These results suggest that the increase in caffeine sensitivity of masseter muscle reflects the presence of a low reactivity threshold of the sarcoplasmic reticulum.

[Cranio-cerebral dermoid and epidermoid cysts. Classification and pathogenesis]. / Les kystes dermoïdes et épidermoïdes crânio-encéphaliques. Classification et pathogénie.

The pathogenesis of cranial dermoids and epidermoids is still controversial, owing to the multiple etiologies and locations of these lesions. We reviewed 25 cases, classified as follows: extradural lesion of the calvarium; of the occipital squama; dysraphic occipital lesions; and strictly intradural lesions. In the latter group, all lesions but one were in a paramedian, prenevraxial situation, and could be classified according to their situation relative to the tentorium cerebelli. In our series, strictly intradural dermoids are more often in a rostral situation, and epidermoids in a more caudal situation. Dermoids appear earlier in life than epidermoids, suggesting a more rapid growth due to eccrine secretion. For each group of lesions, the pathogenic hypotheses are studied. Inclusion of epidermal nests at different levels might result from traumatism, dysraphism, or developmental trouble in the lamination of the different layers of the meninges. Most intradural lesions trent to be related to the formation of Rathke's pouch and closure of the anterior neuropore.

Mutation screening of the RYR1 gene in malignant hyperthermia: detection of a novel Tyr to Ser mutation in a pedigree with associated central cores.

The ryanodine receptor gene (RYR1) has been shown to be mutated in a small number of malignant hyperthermia (MH) pedigrees. Missense mutations in this gene have also been identified in two families with central core disease (CCD), a rare myopathy closely associated with MH. In an effort to identify other RYR1 mutations responsible for MH and CCD, we used a SSCP approach to screen the RYR1 gene for mutations in a family exhibiting susceptibility to MH (MHS) where some of the MHS individuals display core regions in their muscle. Sequence analysis of a unique aberrant SSCP has allowed us to identify a point mutation cosegregating with MHS in the described family. The mutation changes a conserved tyrosine residue at position 522 to a serine residue. This mutation is positioned relatively close to five of the six MHS/CCD mutations known to date and provides further evidence that MHS/CCD mutations may cluster in the amino terminal region of the RYR1 protein.

Stroke, hemiparesis and deficient mitochondrial beta-oxidation.

We describe on a 3-year-old child referred for evaluation and therapy of a cerebral vascular accident with residual hemiplegia and partial epilepsy. Metabolic investigations initially showed normal urinary organic acids as well as normal blood and urinary amino acids. Blood carnitine fractions had been pathological and a secondary carnitine deficiency was diagnosed and treated by oral L-carnitine supplementation. During carnitine treatment, abnormal urinary acylcarnitine profiles were noticed with excessive amounts of several carnitine esters including propionylcarnitine, butyryl- and/or isobutyryl-carnitine, isovaleryl- and/or 2-methylbutyryl-carnitine, hexanoylcarnitine and octanoylcarnitine. Subsequently, an urinary organic acid profile suggestive of glutaric aciduria type II was recorded during a clinical decompensation crisis. Morphological and biochemical studies on skeletal muscle and skin fibroblasts were performed and confirmed the existence of a defect of the mitochondrial beta-oxidation pathways with lipidic myopathy, reduced palmitate and octanoate oxidation rates in cultured fibroblasts. Glutaric aciduria type II increases the list of metabolic disorders characterized by hemiplegia and other sequelae of brain ischaemia such as stroke-like episode, seizures, aphasia, ataxia and myoclonia, similar to those seen in MELAS.

[Enzyme histochemical study of tha atrioventricular junction area. Correlation with slow and fast atrial pathways]. / Etude histo-enzymologique de la région pré-tawarienne. Essai de corrélation avec les voies auriculaires lente et rapide.

It was traditionally admitted that junctional tachycardia was based on an intranodal reentry pathway. However, lesions created at a distance from the atrioventricular node by surgery or other physical means (fulguration or radiofrequency energy ablation) demonstrated that the reentry circuit could use the slow and fast atrial pathways. This study performed in 6 human hearts less than 1 hour after death was undertaken to perform enzyme histochemical analysis of the atrial pre-nodal region. The specimens were rapidly frozen in liquid nitrogen and sliced with a cryostat. After localisation of the different regions by routine staining methods, histochemical reactions were performed using the semi-permeable membrane method for weakly bound enzyme. Ten enzymes were studied covering the principal metabolic pathways. Though routine histological stain did not show any particular structures, the enzyme histochemical reactions showed a band of myocardium following the septal insertion of the tricuspid valve, joining the orifice of the coronary sinus to the posterior part of the compact atrioventricular node. This zone of myocardium had an enzymatic make-up similar to that of the sinus node. An analogous structure was also observed above the insertion of the anterior mitral leaflet. These two regions could constitute the trajectory of the slow conduction pathways.

Viability criterion of muscle bundles used in the in vitro contracture test in patients with neuromuscular diseases.

We have compared the viability criteria of muscle bundles used in the in vitro contracture test for susceptibility to malignant hyperthermia (MH) in a group of 28 patients with various neuromuscular diseases (NMD) and 93 MH-related family patients. In the patients with NMD, this standard test gave one positive, six equivocal and 21 negative results. Compared with MH-related family patients, muscle bundles used had significantly smaller resting membrane potentials and smaller predrug twitch tension amplitudes. Some results from the group with NMD were obtained with muscles which were damaged, more rapidly deteriorating, non-standard or both, and should not be taken to indicate that the patients have the genetic trait for MH. The in vitro contracture test is not always relevant for myopathic muscle (especially dystrophic muscle) and this could explain the lack of specificity for MH.

[Emery-Dreifuss muscular dystrophy with major conduction disorders and cardiac excitability]. / Dystrophie musculaire d'Emery-Dreifuss avec troubles majeurs de la conduction et de l'excitabilité cardiaque.

The case of a 53-year-old patient with scapulo-humero-peroneal wasting, early flexion contractures of the elbows and ankles, abnormal cardiac conduction and probable X-related heredity is reported. Histology was suggestive of a primary and very slowly progressive muscular disorder. CT scan revealed fatty muscle degeneration which was more extensive than suggested by clinical findings. Electrophysiological studies revealed right atrial paralysis, left atrial tachycardia and supra and, above all, infra-His block. Sustained episodes of ventricular tachycardia, an anomaly described only rarely in pathology of this type, occurred some time after the fitting of a permanent pacemaker. The originality of this case of Emery-Dreifuss progressive muscular dystrophy lies in the usefulness of muscle CT scan and the existence of life-threatening arrhythmias.

Fiber-type caffeine sensitivities in skinned muscle fibers from humans susceptible to malignant hyperthermia.

BACKGROUND: The response to contracture tests may depend upon the relative proportion of muscle fiber types within the muscle specimen. To determine whether a difference in fiber-type caffeine sensitivities exists between malignant hyperthermia susceptible (MHS) and malignant hyperthermia-nonsusceptible (MHN) skeletal muscle, we compared the fiber-type caffeine sensitivities in chemically skinned muscle fibers dissected from vastus lateralis muscle from 15 MHS and 16 MHN patients. METHODS: Muscle fiber type was determined in each fiber by the difference in strontium-induced tension measurements and in 36 fibers, after contracture testing, by ATPase enzyme histochemistry. Caffeine sensitivity was defined as the threshold concentration inducing more than 10% of the maximal tension obtained with a calcium 1.6 x 10(-2) mM solution. RESULTS: Significant difference in the mean (+/- SD) caffeine sensitivity was found between type I MHS fibers (2.63 +/- 0.85 mM) versus type II MHS fibers (3.47 +/- 1.2 mM) and between type I MHN fibers (5.89 +/- 1.8 mM) versus type II MHN fibers (10.46 +/- 2.6 mM). The mean (+/- SD) caffeine sensitivities for a given muscle fiber type (I or II) were different between groups of MHS and MHN patients. Both type I and II MHS fibers had significantly lower caffeine sensitivities, and this increase in caffeine sensitivity was significantly smaller in type I than in type II fiber. CONCLUSIONS: The current study indicates that a truly MHS patient cannot have a false-negative result solely related to abnormal type II fibers contained in a given muscle strip. Although the occurrence of a very high proportion of type I fibers in MHN human muscle could result in a false-positive contracture outcome, such an occurrence is expected to be rare.

[Diagnosis of susceptibility to malignant hyperthermia in children]. / Diagnostic de la sensibilité à l'hyperthermie maligne chez l'enfant.

The realisation and reliability of the halothane-caffeine contracture tests in children to detect the susceptibility to malignant hyperthermia (MH) is still controversial. The present study concerned 26 children aged 2 to 13 years, (mean 9.5 +/- 1.3 years) who were tested either because of a personal symptomatology (14 cases) or as a member of a susceptible MH family (12 cases). Half of the children had a positive test (MHS and MHE) as is found in adults. Furthermore comparison of threshold concentrations of halothane and caffeine as well as the 32 nmol caffeine-induced contractures dit not show significant differences related to age. These results support the possibility to perform under good conditions and with good reliability the diagnostic test of susceptibility to malignant hyperthermia in children from 2 years on.

[Natural history and current surgical prognosis of intracranial arterial aneurysms]. / Histoire naturelle et pronostic chirurgical actuel des anévrysmes artériels intracrâniens.

The abrupt flow of blood in the meninges or in the brain after fissure or rupture of an arterial aneurysm still remains a medico-surgical emergency which includes the mobilisation of important technical and financial means which justifies itself by the reduction of the occurrence of a more severe accident and to give the patient its best chances. The cure of a cerebral aneurysm and its intracranial consequences must not be dissociated from its clinical context. Surgical indication must take into account the cause of the vascular lesion, the background on which it has evoked, its natural outcome which is characterised by rebleeding and vasospasm. Surgical cure of intracranial aneurysm is one of the great achievement of modern surgery. A better understanding of the malformation, the improvement of neuro-anesthesia and intensive care, and the use of pre-operatoire adjuvants have considerably improved the surgical results over the years. At the moment, alternative treatment start to emerge such as selective vascular catheterism with ejectable balloon which become more feasible and seductive.

[Fulminating cryptococcal meningoencephalitis. An anatomo-clinical case]. / Cryptococcose neuro-méningée foudroyante. Un cas anatomo-clinique.

We report a case of cryptococcal meningoencephalitis in a 52 year-old man. The patient had complained of headache and drowsiness for a few hours before he became comatose with a bilateral sixth cranial nerve palsy. The cerebrospinal fluid contained less than one lymphocyte per cubic millimeter, a low glucose level (0.20 g/l) and numerous Cryptococcus neoformans encapsulated yeasts. A neuropathological study showed that the cortex and midbrain were involved. To our knowledge, such an acute case with death within the first 20 hours has not yet been reported.

[Central core disease associated with malignant hyperthermia sensitivity]. / Myopathie à axe central (central core disease) associée à une sensibilité à l'hyperthermie maligne.

The authors report the case of a 57-year old woman who was susceptible to malignant hyperthermia (MH) and also had central core disease (CCD) of muscle. The latter was asymptomatic and was discovered when muscle biopsy was performed for in vitro tests of susceptibility to malignant hyperthermia. This case was compared with the 117 cases of CCD and 33 cases of CCD associated with MH published in the literature. Anaesthesia-induced MH is lethal in 80 per cent of the cases without treatment and in 20 per cent with treatment. CCD and MH are both transmitted as autosomal dominant traits. Susceptibility to MH is a functional abnormality of unknown mechanism. CCD is a disease of muscle fibre structure. One may hope that molecular studies and genetic probes will show whether or not these two diseases are transmitted by genes that are similar but distinct and independent.

[Cervical melanotic neurofibroma. Apropos of a case and a review of the literature]. / Neurofibrome mélanotique cervical. A propos d'un cas et revue de la littérature.

The authors report a case of cervical melanotic neurofibroma hour glass shaped, growing in the extra and intradural spaces. Melanotic aspect of spinal neurofibroma are rarely reported in the literature. Various etiopathologies have already been discussed.

Discectomies of the lower cervical spine using interbody biopolymer (B.O.P.) implants. Advantages in the treatment of complicated cervical arthrosis. A review of 150 cases.

The authors report their experience with 150 cases of discectomies performed with interbody grafts using a copolymer (Biocompatible Orthopedic Polymer or BOP). Made of N-Vinylpyrrolidone-Methylmethacrylate monomers, polyamide fibres and calcium gluconate. BOP is a biocompatible, biodegradable, osteoconductive matrix, easy to use and quite safe. These properties are quite well appreciated for cervical interbody grafting. After discectomy, stabilization of the spine is immediate, and fusion slowly occurs around and through the biopolymer within one year. The biomaterial avoids morbidity inherent in the harvesting of an autograft, as well as any limitations resulting from the use of allografts.

[Tests of contracture and sensitivity to malignant hyperthermia in 27 patients]. / Tests de contracture et sensitilité à l'hyperthermie anesthésique chez vingt-sept sujets suspects.

Twenty-seven patients, four of whom had presented with a crisis of malignant hyperthermia and the 23 other being close relatives of such patients, underwent a muscle biopsy so as to determine their susceptibility to malignant hyperthermia. Halothane-caffeine contracture tests, interpreted in accordance with the criteria of the European Group on Malignant Hyperthermia, yielded the following results: 13 positive (MHS), 10 negative (MHN), 4 equivocal (MHE). The history, clinical examination, CPK level, histoenzymatic morphology and electron microscopic study did not provide information sensitive enough to use for the detection of susceptibility to malignant hyperthermia. This confirmed the literature: the halothane-caffeine contracture test remains the only reliable diagnostic test to detect this susceptibility, despite the search for non invasive tests. If the mechanism of triggering a contracture to increasing doses of caffeine is well known in normal muscle, it is the smaller concentrations required which suggests malignant hyperthermia abnormality. The halothane effect is less well understood. A concentration less than or equal to 2 vol % yields a contracture only in MHS muscle. Differences in protocols used by American authors emphasize the importance of standardization as used by the European Group, which is the only way of collecting and comparing results on well over a thousand patients. This confrontation should reduce the number of equivocal diagnoses and allow a correct classification of patients at risk or their relatives as MHS or MHN.