RYR1 mutations are a common cause of congenital myopathies with central nuclei.

OBJECTIVE: Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by prominence of central nuclei on muscle biopsy. CNM has been associated with mutations in MTM1, DNM2, and BIN1 but many cases remain genetically unresolved. RYR1 encodes the principal sarcoplasmic reticulum calcium release channel and has been implicated in various congenital myopathies. We investigated whether RYR1 mutations cause CNM. METHODS: We sequenced the entire RYR1 coding sequence in 24 patients with a diagnosis of CNM from South Africa (n = 14) and Europe (n = 10) and identified mutations in 17 patients. The most common genotypes featured compound heterozygosity for RYR1 missense mutations and mutations resulting in reduced protein expression, including intronic splice site and frameshift mutations. RESULTS: The high incidence in South African patients (n = 12/14) in conjunction with recurrent RYR1 mutations associated with common haplotypes suggested the presence of founder effects. In addition to central nuclei, prominent histopathological findings included (often multiple) internalized nuclei and type 1 fiber predominance and hypotrophy with relative type 2 hypertrophy. Although cores were not typically seen on oxidative stains, electron microscopy revealed subtle abnormalities in most cases. External ophthalmoplegia, proximal weakness, and bulbar involvement were prominent clinical findings. INTERPRETATION: Our findings expand the range of RYR1-related phenotypes and suggest RYR1 mutations as a common cause of congenital myopathies with central nuclei. Corresponding to recent observations in X-linked CNM, these findings indicate disturbed assembly and/or malfunction of the excitation-contraction machinery as a key mechanism in CNM and related myopathies.

Pyloric localisation in 57 dogs of breeds susceptible to gastric dilatation-volvulus in the UK using computed tomography.

OBJECTIVE: Describe the location of the pylorus using CT in dog breeds susceptible to gastric dilatation-volvulus in the UK. METHODS: Descriptive anatomical study. Abdominal CT scans of 57 client-owned dogs were reviewed to assess pyloric position relative to the 9th, 10th, 11th and 13th ribs and 2 and 3 cm caudal to the 13th rib at the 8, 9 and 10 o'clock positions. The angle of the pylorus from the centre of the abdominal cavity relative to the sagittal plane was also determined. RESULTS: In 88 per cent of cases, the pylorus was located in the right cranioventral abdomen with 63 per cent positioned at the 9-10 o'clock position. The overall distance between the pylorus and right abdominal wall (RAW) at the 13th rib 10 o'clock position was equivalent to 29 per cent of ventral abdominal length, significantly greater than the median overall distance of ∼14 per cent of ventral abdominal length between the pylorus and RAW at the 9th or 10th rib 10 o'clock position (P<0.0001). CLINICAL SIGNIFICANCE: Common gastropexy locations may result in considerable displacement of the pylorus relative to its natural anatomic location. Further case-control studies are required to assess the clinical significance of this finding.

Late presentation of canine nasal tumours in a UK referral hospital and treatment outcomes.

OBJECTIVES: To determine the computed tomographic stage of dogs with nasal tumours in a UK referral population, and whether stage, time to referral and treatment correlates with outcome. METHODS: Retrospective review of clinical records and computed tomography scans of dogs with nasal tumours. RESULTS: Dogs (n=78) presented to a referral practice in the UK with suspected nasal tumours are presented with more late stage tumours than dogs in the USA and Japan. Length of time from initial presentation to referral did not correlate with tumour stage at diagnosis. Median survival times for radiotherapy-treated dogs in this population are equivalent to those previously reported for late stage nasal tumours. CLINICAL SIGNIFICANCE: Dogs with nasal tumours are presented late in the course of disease in the North West of England. Dogs with clinical signs consistent with a nasal tumour should have timely imaging and biopsy, in order to make prompt treatment decisions. Although survival times are comparable with previous reports and radiotherapy is a valid treatment option for dogs with late stage disease, better outcomes are likely to be achievable with earlier treatment.

Congenital myopathies--clinical features and frequency of individual subtypes diagnosed over a 5-year period in the United Kingdom.

The congenital myopathies are a group of inherited neuromuscular disorders mainly defined on the basis of characteristic histopathological features. We analysed 66 patients assessed at a single centre over a 5 year period. Of the 54 patients where muscle biopsy was available, 29 (54%) had a core myopathy (central core disease, multi-minicore disease), 9 (17%) had nemaline myopathy, 7 (13%) had myotubular/centronuclear myopathy, 2 (4%) had congenital fibre type disproportion, 6 (11%) had isolated type 1 predominance and 1 (2%) had a mixed core-rod myopathy. Of the 44 patients with a genetic diagnosis, RYR1 was mutated in 26 (59%), ACTA1 in 7 (16%), SEPN1 in 7 (16%), MTM1 in 2 (5%), NEB in 1 (2%) and TPM3 in 1 (2%). Clinically, 77% of patients older than 18 months could walk independently. 35% of all patients required ventilatory support and/or enteral feeding. Clinical course was stable or improved in 57/66 (86%) patients, whilst 4 (6%) got worse and 5 (8%) died. These findings indicate that core myopathies are the most common form of congenital myopathies and that more than half can be attributed to RYR1 mutations. The underlying genetic defect remains to be identified in 1/3 of congenital myopathies cases.

Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis.

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of neuromuscular disease, ranging from various congenital myopathies to the malignant hyperthermia (MH) susceptibility trait without associated weakness. We sequenced RYR1 in 39 unrelated families with rhabdomyolysis and/or exertional myalgia, frequent presentations in the neuromuscular clinic that often remain unexplained despite extensive investigations. We identified 9 heterozygous RYR1 mutations/variants in 14 families, 5 of them (p.Lys1393Arg; p.Gly2434Arg; p.Thr4288_Ala4290dup; p.Ala4295Val; and p.Arg4737Gln) previously associated with MH. Index cases presented from 3 to 45 years with rhabdomyolysis, with or without exertional myalgia (n=12), or isolated exertional myalgia (n=2). Rhabdomyolysis was commonly triggered by exercise and heat and, less frequently, viral infections, alcohol and drugs. Most cases were normally strong and had no personal MH history. Inconsistent additional features included heat intolerance, and cold-induced muscle stiffness. Muscle biopsies showed mainly subtle changes. Familial RYR1 mutations were confirmed in relatives with similar or no symptoms. These findings suggest that RYR1 mutations may account for a substantial proportion of patients presenting with unexplained rhabdomyolysis and/or exertional myalgia. Associated clinico-pathological features may be subtle and require a high degree of suspicion. Additional family studies are paramount in order to identify potentially MH susceptible relatives.

Interfamilial phenotypic heterogeneity in SMARD1.

Spinal muscular atrophy with respiratory distress (SMARD1: mu-binding protein 2 gene mutation) is characterised by low birth weight, progressive distal limb weakness, diaphragmatic paralysis and subsequent respiratory failure manifesting before 13 months of age. Our case report illustrates marked phenotype variability in two siblings with an identical genetic mutation of SMARD1, one of whom died of fulminant respiratory failure aged 6 months, whereas the other shows limb weakness but, only mild sleep hypoventilation aged 12 years. This suggests other compensatory mechanisms may play a role in modifying SMARD1; broadening our perception of phenotype. Therefore, SMARD1 phenotype should be considered in cases of atypical spinal muscular atrophy even in the absence of overt diaphragmatic weakness.