1/18. Screening of the ryanodine receptor gene in 105 malignant hyperthermia families: novel mutations and concordance with the in vitro contracture test. malignant hyperthermia (MH) in man is an autosomal dominant disorder of skeletal muscle Ca(2 )-regulation. During anesthesia in predisposed individuals, it is triggered by volatile anesthetics and depolarizing muscle relaxants. In >50% of the families, MH susceptibility is linked to the gene encoding the skeletal muscle ryanodine receptor (RYR1), the calcium release channel of the sarcoplasmic reticulum, on chromosome 19q12-13.2. To date, 21 RYR1 mutations have been identified in a number of pedigrees. Four of them are also associated with central core disease (CCD), a congenital myopathy. Screening for these 21 mutations in 105 MH families including 10 CCD families phenotyped by the in vitro contracture test (IVCT) according to the European protocol revealed the following approximate distribution: 9% Arg-614-Cys, 1% Arg-614-Leu, 1% Arg-2163-Cys, 1% Val-2168-Met, 3% Thr-2206-Met and 7% Gly-2434-Arg. In one CCD family, the disease was caused by a recently reported MH mutation, Arg-2454-His. Two novel mutations, Thr-2206-Arg and Arg-2454-Cys were detected, each in a single pedigree. In the 109 individuals of the 25 families with RYR1 mutations cosegregation between genetic result and IVCT was almost perfect, only three genotypes were discordant with the IVCT phenotypes, suggesting a true sensitivity of 98.5% and a specificity of minimally 81.8% for this test. Screening of the transmembraneous region of RYR1 did not yield a new mutation confirming the cytosolic portion of the protein to be of main functional importance for disease pathogenesis. ( info) |
2/18. Central core disease and congenital neuromuscular disease with uniform type 1 fibers in one family. We report a family in which the father had central core disease and his son had congenital neuromuscular disease with uniform type 1 fibers. This is the first report of such a combination. Although they had no recognized mutation in the ryanodine receptor gene, it is highly likely that the son also had central core disease but without core structures. The absence of cores may be due to the muscle sample or the young age of the patient since core structures have been reported to increase with age. Although the prevalence of core structures in individual muscles is unknown, there is a possibility of sampling error. In some patients, congenital neuromuscular disease with uniform type 1 fibers is closely related to or identical with central core disease. ( info) |
3/18. Multicore myopathy: respiratory failure and paraspinal muscle contractures are important complications. Three ambulant males with multicore myopathy, a rare congenital myopathy, are reported with nocturnal hypoventilation progressing to respiratory failure at the age of 9, 13, and 21 years. Deterioration in these individuals occurred over several months without any precipitating event. patients had clinical evidence of nocturnal hypoventilation with hypoxaemia and hypercapnia. Forced vital capacity was significantly reduced (20 to 43% of predicted level). These parameters improved on institution of overnight ventilation using a BiPAP pressure support ventilator with face mask or nasal pillows with O2 saturation maintained above 90% overnight and an increase in forced vital capacity by as much as 100% (0.3 to 0.6 litres). This was matched by a symptomatic and functional improvement. Also present in these patients and not previously reported is the association of multicore myopathy with paraspinal contractures which produce a characteristic scoliosis described as a 'side-sliding' spine. This may be improved by spinal bracing or surgery. ( info) |
4/18. The spectrum of pathology in central core disease. Central core disease is a congenital myopathy with muscle weakness defined pathologically by the presence of extensive areas in muscle fibres that are devoid of oxidative enzyme activity. The gene responsible has been shown to be the ryanodine receptor 1 on chromosome 19q13 and mutations have now been identified in several patients. Some cases with the morphological defect remain molecularly undefined, particularly those studied before molecular studies were available. We have studied three families with congenital onset, each with a dominantly inherited mutation in a C-terminal exon of the ryanodine receptor 1. They illustrate the spectrum of pathology that can be observed in patients with the myopathic features of central core disease. We show that extensive fibrosis and fat may be present, type 1 fibre uniformity may occur in the absence of cores; cores may be central or peripheral, single or multiple; and that an appearance of multiple focal minicores might cause a diagnostic pathological dilemma. In addition, we show the value of immunocytochemistry in identifying cores, in particular the use of antibodies to desmin and gamma-filamin. ( info) |
5/18. The hypotonic infant: case study of central core disease. Causes of hypotonia in the newborn can be broadly categorized into two classifications. Hypotonia with a supraspinal origin may be seen with systemic disease, hypoxic ischemic encephalopathy, cerebral malformations, syndromes (for example: Down, Prader-Willi, Lowe, Zellweger, Smith-Lemli-Opitz), and c-spine injury. Disorders of the motor unit that present with hypotonia in the newborn period include SMA, congenital myotonic dystrophy, congenital myasthenia gravis, and congenital myopathies. Central core disease is one of the classic congenital myopathies that can be differentiated based on characteristic histologic findings. Muscle fiber samples from patients with central core disease possess distinct morphology that can be diagnostic. Many infants may not exhibit muscle weakness in the newborn period, although there have been rare cases of profound hypotonia and respiratory failure. Clearly, muscle biopsy is the gold standard and is indicated for any infant with marked hypotonia that is not thought to be supraspinal in origin. ( info) |
6/18. myalgia as the revealing symptom of multicore disease and fibre type disproportion myopathy. BACKGROUND: Multicore disease and congenital fibre type disproportion myopathy are diseases assigned to the heterogeneous group of congenital myopathies. Although hypotonia and muscle weakness appearing in early life are the commonest manifestations of these diseases, distinct phenotypes and late onset cases have been described. OBJECTIVE: To report the occurrence of myalgia as the revealing symptom of multicore disease and fibre type disproportion myopathy. methods: The clinical cases of three patients with fibre type disproportion myopathy and one with multicore disease are described. Skeletal muscle biopsies were processed for routine histological and histochemical studies. RESULTS: The clinical picture was unusual in that the symptoms were of late onset and the predominant complaint was muscle pain exacerbated by exercise. muscle weakness was found in only a single patient, the mother of a patient with fibre type disproportion myopathy. physical examination was unremarkable in the other patients. Muscle biopsies from patients 1 and 2 contained type I fibres that were considerably smaller than the type II fibres, supporting the diagnosis of fibre type disproportion myopathy. Skeletal muscle of patient 4 showed multiple areas, predominantly but not exclusively in the type I fibres, from which oxidative enzyme activities were absent, as seen in multicore disease. CONCLUSIONS: Muscle pain was the main clinical manifestation in our patients. Recognition of the broader clinical expression of these myopathies is important for prognostic reasons and for genetic counselling of the family members. ( info) |
7/18. Dominant and recessive central core disease associated with RYR1 mutations and fetal akinesia. We studied seven patients (fetuses/infants) from six unrelated families affected by central core disease (CCD) and presenting with a fetal akinesia syndrome. Two fetuses died before birth (at 31 and 32 weeks) and five infants presented severe symptoms at birth (multiple arthrogryposis, congenital dislocation of the hips, severe hypotonia and hypotrophy, skeletal and feet deformities, kyphoscoliosis, etc.). Histochemical and ultrastructural studies of muscle biopsies confirmed the diagnosis of CCD showing unique large eccentric cores. Molecular genetic investigations led to the identification of mutations in the ryanodine receptor (RYR1) gene in three families, two with autosomal recessive (AR) and one with autosomal dominant (AD) inheritance. RYR1 gene mutations were located in the C-terminal domain in two families (AR and AD) and in the N-terminal domain of the third one (AR). This is the first report of mutations in the RYR1 gene involved in a severe form of CCD presenting as a fetal akinesia syndrome with AD and AR inheritances. ( info) |
8/18. Familial restrictive cardiomyopathy with skeletal abnormalities. A family is described in which 5 of 9 living children were found to have restrictive cardiomyopathy associated with skeletal muscle and orthopedic abnormalities. In the absence of another identifiable etiology, a genetic cause for restrictive cardiomyopathy in this family is probable. Consistent with the poor prognosis encountered for children with restrictive cardiomyopathy, 2 children in this family died, whereas a third was symptomatic by age 3 years. ( info) |
9/18. Ankylosing spondylitis and central core disease: case report. Ankylosing spondylitis (AS) is an inflammatory disorder of unknown cause that primarily affects the axial skeleton. Neurological manifestations of AS are usually related to spinal deformities. Previous studies of the paraspinal muscles of AS patients showed muscle fiber atrophy, and core fibers. On the other hand, central core disease (CCD) is a genetic condition that primarily involves the skeletal muscles, but can present articular deformities secondary to muscular weakness. We report the case of a 45-year-old man with clinical and radiological diagnosis of AS and proximal muscular weakness in the lower limbs. Needle electromyography showed myopathic features and nerve conduction study was normal. Muscle biopsy disclosed almost complete predominance of type-1 fibers, and fibers with central cores. This is the first report of AS and CCD. Whether central core myopathy is coincidental or a new association with AS is discussed. ( info) |
10/18. Anaesthetic management of coronary artery bypass grafting in a patient with central core disease and susceptibility to malignant hyperthermia on statin therapy. Central core disease and malignant hyperthermia (MH) are both associated with mutations in the RYR1 gene. We report the anaesthetic management of one such patient presenting for coronary artery bypass grafting. Her medication included aspirin 75 mg, atorvastatin 20 mg, isosorbide mononitrate 60 mg, atenolol 25 mg and glyceryl trinitrite sublingual spray as required. The use of aprotinin, statins and moderate hypothermia in patients with central core disease and known susceptibility to MH has not been documented. ( info) |