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Dantrolene as a treatment option for RYR1-related rhabdomyolysis
S136
Abstracts 2016 / Neuromuscular Disorders 26 (2016) S88–S212
variants confer susceptibility to malignant hyperthermia (MHS) – a life threatening condition. We report the clinical, histopathological and genetic features of a heterogeneous group of 16 RYR1-related paediatric and adult myopathic patients (11 families) from our centre. Patients were grouped according to three distinctive clinical characteristics: extraocular muscle (EOM) weakness (n = 5), predominant axial muscle weakness (n = 2) and excessive joint laxity (n = 5). The remaining four patients had less disabling tetraparesis with or without facial weakness. There was no significant association between EOM weakness and clinical severity. Muscle biopsy performed in 13 patients revealed four different histopathological patterns: centronuclear (n = 4), central core (n = 4), type 1 fibre predominance as the only feature (n = 4) and congenital fibre type disproportion (n = 1) myopathy. Each index case had a different mutation and three had not been previously reported. Three genetic variants known to confer MHS were detected. The compound heterozygote cases with more dispersed mutations along the RYR1 gene and autosomal recessive inheritance were more frequently found within the group with EOM involvement; all cases with a centronuclear histopathological pattern were found in this group. In the remaining patients, there was a higher incidence of mutations in hotspot 3 (exons 93–106) accompanied by AD inheritance; all patients with a central core histopathological presentation were found in this group. Although we have some clinical features to assist diagnosis of RYR1-related congenital myopathy, there is a great variability in clinical presentation and muscle biopsy findings. A multidisciplinary effort is thus particularly important in these cases. http://dx.doi.org/10.1016/j.nmd.2016.06.182
P.164 A new phenotype of RYR1-myopathy: Mild dominant calf myopathy with core pathology M. Jokela 1, P. Isohanni 2, S. Penttilä 1, B. Udd 1 1 Neuromuscular Research Center, Tampere University Hospital and University of Tampere, Tampere, Finland; 2 Helsinki University Hospital, Helsinki, Finland Mutations in the ryanodine receptor (RYR1) gene cause an expanding variety of muscle disorders, including susceptibility to malignant hyperthermia and/or exertional rhabdomyolysis, congenital central core disease (CCD) and multicore disease, among others. Besides the classical CCD phenotype, atypical and later onset phenotypes of RYR1-myopathy are increasingly being recognized. We report a family with dominantly inherited distal myopathy in the proband and her daughter, sister and two brothers segregating with a novel RYR1 mutation. The female patients reported difficulty in running since childhood and all had some degree of ankle contractures. All patients showed fatty infiltration on muscle MRI in the calf muscles, particularly medial gastrocnemius muscles. Creatine kinase values were 2–6× elevated and muscle biopsies displayed mild core-minicore pathology. No malignant hyperthermia episodes were reported. Disease course was very slowly progressive without major disability in late adulthood. A complex deletion-insertion mutation in RYR1 (c.11710_11712delACAinsTGTCCGTCTGTGTCCTGTCTGTGT p.R3903_Q3905delTinsCPSVSCLC) was shown to segregate with the phenotype in two generations. Our findings expand the spectrum of RYR1myopathies to include a mild distal myopathy phenotype due to a previously unreported deletion-insertion mutation in the RYR1 gene. http://dx.doi.org/10.1016/j.nmd.2016.06.184
P.163 Expanded King–Denborough phenotype and congenital myopathy in two brothers with RYR1 mutation F. Munell 1, A. Sanchez-Montáñez 1, S. Quijano-Roy 2, M. Gratacos 1, E. Martinez-Saez 1, S. Ferrer Aparicio 3, M. Gomez Garcia de la Banda 1, R. Urreizti 4, D. Grinberg 4 1 Vall Hebron University Hospital Barcelona, Barcelona, Spain; 2 Hôpital Raymond Poincaré, Garches, Paris, France; 3 Vall Hebron Institute of Research, Barceloba, Spain; 4 University of Barcelona, Barcelona, Spain
P.165 Dantrolene as a treatment option for RYR1-related rhabdomyolysis R. Scalco 1, N. Voermans 2, R. Piercy 3, H. Jungbluth 4, R. Quinlivan 1 1 University College London, London, UK; 2 Radboud University Medical Center, Nijmegen, Netherlands; 3 Royal Veterinary College, London, UK; 4 King’s College London, London, UK
RYR1 mutations cause a wide range of conditions including congenital myopathies, malignant hyperthermia susceptibility and King–Denborough syndrome. We here present two brothers, aged 7 and 5 yo, with features associated with King–Denborough syndrome and congenital myopathy. The patients were born from non-consanguineous and healthy parents. Both pregnancies were complicated by reduced fetal movements and polyhydramnios. Common findings on physical examination at birth were as follows: hypotonia, arthrogryposis, knee contractures, cryptorchidism, and dysmorphic features including trigonocephaly with prominent metopic suture, hypoplasia of superior orbital fissure, broad nasal bridge, epicanthus, high arched palate, defects of enamel, short neck, low set thumb and toes, single palmar crease and small membrane interdigitorum. On follow-up, both patients showed proximal limb weakness with areflexia, muscle atrophy and early-onset, rapidly progressive kyphoscoliosis. They reach head control and independent sitting, but no independent standing. Cognitive development and head growth were normal. Blood analysis revealed normal creatine kinase levels and EMG showed a myopathic pattern. Whole body MRI showed a pattern consistent with RYR1 congenital myopathy except that Sartorius was spared at the first MRI and involved thereafter. Muscle biopsy was obtained but was not informative since it contained mostly adipose tissue. Exome sequencing revealed the presence of two mutations in RYR-1 gene in both brothers, one maternally inherited missense change predicted to be severely damaging and previously associated with malignant hyperthermia, and one paternally inherited nonsense mutation. We propose that these children serve to expand the phenotype of RYR1-related disorders.
Mutations in RYR1 lead to various neuromuscular phenotypes including rhabdomyolysis (RM). We recently reported the use of oral dantrolene as a prophylactic treatment for RYR1-related RM. Here we will report updated data on safety of dantrolene in the reported patients and report the dantrolene use in RM-susceptible thoroughbred racehorses. Case series. Three patients presenting with severe recurrent episodes of RYR1-related RM were prescribed 25 mg of oral dantrolene up to a maximum of three times a day to be taken as required with symptom onset in order to stop progression of RM episodes. P1 and P2 were on dantrolene for 18 months while P3 continued treatment for 7 years. P1 reported complete abatement of symptoms within 20–30 minutes of taking dantrolene soon after onset of myalgia/cramps. P2 was able to resume symptom-free exercise by taking 25 mg of dantrolene prior to physical activity. P3 started using dantrolene after the second episode of RM. Over a 7-yearperiod, P3 has suffered fewer additional episodes of RM, but with less markedly elevated CK levels. No significant side-effects were reported and the liver function remained normal in all 3 patients. Dantrolene is highly efficacious for rhabdomyolysis-susceptible Thoroughbred racehorses (2 to 3 mg/kg) in training, administrated orally 60–90 minutes prior to exercise. Typically, the drug is used in RM-susceptible animals, when training levels are increasing in intensity or following a period of rest and its use is withdrawn prior to racing. Short term intermittent use of low dose dantrolene appeared to be beneficial in three patients with recurrent RYR1-related rhabdomyolysis without undue sideeffects. Benefits of dantrolene therapy have also been reported in RM-susceptible thoroughbred racehorses. Undertaking a RCT to assess risks and benefits of dantrolene in this group of patients more systematically could help to evaluate the role of Dantrolene in RYR1-related RM.
http://dx.doi.org/10.1016/j.nmd.2016.06.183
http://dx.doi.org/10.1016/j.nmd.2016.06.185
Abstracts 2016 / Neuromuscular Disorders 26 (2016) S88–S212
variants confer susceptibility to malignant hyperthermia (MHS) – a life threatening condition. We report the clinical, histopathological and genetic features of a heterogeneous group of 16 RYR1-related paediatric and adult myopathic patients (11 families) from our centre. Patients were grouped according to three distinctive clinical characteristics: extraocular muscle (EOM) weakness (n = 5), predominant axial muscle weakness (n = 2) and excessive joint laxity (n = 5). The remaining four patients had less disabling tetraparesis with or without facial weakness. There was no significant association between EOM weakness and clinical severity. Muscle biopsy performed in 13 patients revealed four different histopathological patterns: centronuclear (n = 4), central core (n = 4), type 1 fibre predominance as the only feature (n = 4) and congenital fibre type disproportion (n = 1) myopathy. Each index case had a different mutation and three had not been previously reported. Three genetic variants known to confer MHS were detected. The compound heterozygote cases with more dispersed mutations along the RYR1 gene and autosomal recessive inheritance were more frequently found within the group with EOM involvement; all cases with a centronuclear histopathological pattern were found in this group. In the remaining patients, there was a higher incidence of mutations in hotspot 3 (exons 93–106) accompanied by AD inheritance; all patients with a central core histopathological presentation were found in this group. Although we have some clinical features to assist diagnosis of RYR1-related congenital myopathy, there is a great variability in clinical presentation and muscle biopsy findings. A multidisciplinary effort is thus particularly important in these cases. http://dx.doi.org/10.1016/j.nmd.2016.06.182
P.164 A new phenotype of RYR1-myopathy: Mild dominant calf myopathy with core pathology M. Jokela 1, P. Isohanni 2, S. Penttilä 1, B. Udd 1 1 Neuromuscular Research Center, Tampere University Hospital and University of Tampere, Tampere, Finland; 2 Helsinki University Hospital, Helsinki, Finland Mutations in the ryanodine receptor (RYR1) gene cause an expanding variety of muscle disorders, including susceptibility to malignant hyperthermia and/or exertional rhabdomyolysis, congenital central core disease (CCD) and multicore disease, among others. Besides the classical CCD phenotype, atypical and later onset phenotypes of RYR1-myopathy are increasingly being recognized. We report a family with dominantly inherited distal myopathy in the proband and her daughter, sister and two brothers segregating with a novel RYR1 mutation. The female patients reported difficulty in running since childhood and all had some degree of ankle contractures. All patients showed fatty infiltration on muscle MRI in the calf muscles, particularly medial gastrocnemius muscles. Creatine kinase values were 2–6× elevated and muscle biopsies displayed mild core-minicore pathology. No malignant hyperthermia episodes were reported. Disease course was very slowly progressive without major disability in late adulthood. A complex deletion-insertion mutation in RYR1 (c.11710_11712delACAinsTGTCCGTCTGTGTCCTGTCTGTGT p.R3903_Q3905delTinsCPSVSCLC) was shown to segregate with the phenotype in two generations. Our findings expand the spectrum of RYR1myopathies to include a mild distal myopathy phenotype due to a previously unreported deletion-insertion mutation in the RYR1 gene. http://dx.doi.org/10.1016/j.nmd.2016.06.184
P.163 Expanded King–Denborough phenotype and congenital myopathy in two brothers with RYR1 mutation F. Munell 1, A. Sanchez-Montáñez 1, S. Quijano-Roy 2, M. Gratacos 1, E. Martinez-Saez 1, S. Ferrer Aparicio 3, M. Gomez Garcia de la Banda 1, R. Urreizti 4, D. Grinberg 4 1 Vall Hebron University Hospital Barcelona, Barcelona, Spain; 2 Hôpital Raymond Poincaré, Garches, Paris, France; 3 Vall Hebron Institute of Research, Barceloba, Spain; 4 University of Barcelona, Barcelona, Spain
P.165 Dantrolene as a treatment option for RYR1-related rhabdomyolysis R. Scalco 1, N. Voermans 2, R. Piercy 3, H. Jungbluth 4, R. Quinlivan 1 1 University College London, London, UK; 2 Radboud University Medical Center, Nijmegen, Netherlands; 3 Royal Veterinary College, London, UK; 4 King’s College London, London, UK
RYR1 mutations cause a wide range of conditions including congenital myopathies, malignant hyperthermia susceptibility and King–Denborough syndrome. We here present two brothers, aged 7 and 5 yo, with features associated with King–Denborough syndrome and congenital myopathy. The patients were born from non-consanguineous and healthy parents. Both pregnancies were complicated by reduced fetal movements and polyhydramnios. Common findings on physical examination at birth were as follows: hypotonia, arthrogryposis, knee contractures, cryptorchidism, and dysmorphic features including trigonocephaly with prominent metopic suture, hypoplasia of superior orbital fissure, broad nasal bridge, epicanthus, high arched palate, defects of enamel, short neck, low set thumb and toes, single palmar crease and small membrane interdigitorum. On follow-up, both patients showed proximal limb weakness with areflexia, muscle atrophy and early-onset, rapidly progressive kyphoscoliosis. They reach head control and independent sitting, but no independent standing. Cognitive development and head growth were normal. Blood analysis revealed normal creatine kinase levels and EMG showed a myopathic pattern. Whole body MRI showed a pattern consistent with RYR1 congenital myopathy except that Sartorius was spared at the first MRI and involved thereafter. Muscle biopsy was obtained but was not informative since it contained mostly adipose tissue. Exome sequencing revealed the presence of two mutations in RYR-1 gene in both brothers, one maternally inherited missense change predicted to be severely damaging and previously associated with malignant hyperthermia, and one paternally inherited nonsense mutation. We propose that these children serve to expand the phenotype of RYR1-related disorders.
Mutations in RYR1 lead to various neuromuscular phenotypes including rhabdomyolysis (RM). We recently reported the use of oral dantrolene as a prophylactic treatment for RYR1-related RM. Here we will report updated data on safety of dantrolene in the reported patients and report the dantrolene use in RM-susceptible thoroughbred racehorses. Case series. Three patients presenting with severe recurrent episodes of RYR1-related RM were prescribed 25 mg of oral dantrolene up to a maximum of three times a day to be taken as required with symptom onset in order to stop progression of RM episodes. P1 and P2 were on dantrolene for 18 months while P3 continued treatment for 7 years. P1 reported complete abatement of symptoms within 20–30 minutes of taking dantrolene soon after onset of myalgia/cramps. P2 was able to resume symptom-free exercise by taking 25 mg of dantrolene prior to physical activity. P3 started using dantrolene after the second episode of RM. Over a 7-yearperiod, P3 has suffered fewer additional episodes of RM, but with less markedly elevated CK levels. No significant side-effects were reported and the liver function remained normal in all 3 patients. Dantrolene is highly efficacious for rhabdomyolysis-susceptible Thoroughbred racehorses (2 to 3 mg/kg) in training, administrated orally 60–90 minutes prior to exercise. Typically, the drug is used in RM-susceptible animals, when training levels are increasing in intensity or following a period of rest and its use is withdrawn prior to racing. Short term intermittent use of low dose dantrolene appeared to be beneficial in three patients with recurrent RYR1-related rhabdomyolysis without undue sideeffects. Benefits of dantrolene therapy have also been reported in RM-susceptible thoroughbred racehorses. Undertaking a RCT to assess risks and benefits of dantrolene in this group of patients more systematically could help to evaluate the role of Dantrolene in RYR1-related RM.
http://dx.doi.org/10.1016/j.nmd.2016.06.183
http://dx.doi.org/10.1016/j.nmd.2016.06.185