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A third case of congenital myasthenic syndrome caused by mutations in SCN4A
Abstracts / Neuromuscular Disorders 25 (2015) S184–S316 2
Bratislava, Slovakia; Comenius University Bratislava, Epidemiology, Medical Faculty, Bratislava, Slovakia
Institute
of
The objective of this study is to analyse the epidemiological data and clinical features in patients (p.) with very late-onset myasthenia gravis (VLOMG) > 70 yrs in Slovakia. In the Slovak MG Register 1950 (p.) are registered (1978–2014). We analysed p. with MG onset > 70 yrs. Collected data for descriptive longitudinal study were age at onset, sex, year of MG onset, year of MG diagnosis, AChR and MuSK antibodies, thymoma, clinical symptoms, and comorbidities. We found VLOMG in 353 p. (18.1%), 181 females (F) 51.3%, 172 males (M) 48.7%. The mean age at onset was 75.2 yrs, F 75.7, M 74.5. 289 p. had MG onset between 70 and 79 yrs (142 F, 147 M). At the age >80 yrs 64 p. (39 F, 25 M) had their onset. Overall incidence of VLOMG had an increase from 0.32/105 in 1978 to 4.29/105 in 2014 (mean 2.52/105). 163 p. were alive on Dec. 31, 2014, giving an overall prevalence of 33.58/105, 71 M (41.29/105), 92 F (29.35/105). In the presentation we will give also data of age-specific incidence and prevalence for both sexes. Ocular symptoms were initial in 73 p. (20.7%), bulbar symptoms in 159 p. (45.0%). 93.6% p. had AChR positive MG, 0.7% p. MuSK positive MG, 5.7% p. double-seronegative MG. 12 p. (3.4%) had thymoma. VLOMG occurs in 353 p. (18.1%), with almost equal frequency in M and F. The mean age-specific incidence is higher for M in comparison to F due to shorter life-expectancy in M and thereby lower representation of M > 70, mainly in 80–89 yrs. Therefore, also the age-specific prevalence of VLOMG is higher in M, though the majority of surviving patients are F. In VLOMG p. AChR positivity dominates (93.6%), bulbar symptoms are often present at onset, and p. have higher occurrence of age-specific comorbidities. http://dx.doi.org/10.1016/j.nmd.2015.06.090
S209
G.P.77 New SCN4A mutations – unusual clinical phenotypes S. Sandell *,1, J. Palmio 2, S. Penttilä 2, T. Suominen 2, B. Udd 2 1 Seinäjoki Central Hospital, Neurology, Seinäjoki, Finland; 2 Neuromuscular Research Center, Tampere University and University Hospital, Tampere, Finland Sodium channel gene (SCN4A) mutations are known to cause several clinical phenotypes in various disorders: paramyotonia congenita, periodic paralyses, myotonia congenita, congenital myasthenic syndrome, and even lifethreatening laryngospasms. SCN4A, encoding the Nav1.4 voltage-gated sodium channel, is responsible for the depolarizing phase of the action potential. We examined a family with six mutation-positive individuals with R1460Q mutation representing various phenotypes, including mother and daughter, who carry CLCN1 Finnish founder mutation R894Xhez as well, and the daughter in addition carrying SCN4A mutation R1059X. In the R1460Qmutated family one middle-aged individual had remained asymptomatic. Of the symptomatic family members 2/5 had myotonia in EMG, but none had clinical myotonia. Both myotonia-positive members were CLCN1-mutation positive as well, suggesting that R1460Q mutation in SCN4A does not cause myotonia in EMG. 4/5 suffered from laryngeal spasms of some severity. 2/5 had stiffnessmyalgic symptoms, leading to early retirement. The youngest family member, a 24-y old woman, has second mutation in the SCN4A gene, R1059X stop-codon mutation, representing an uncommon clinical phenotype of congenital weakness, ptosis, marked facial weakness and dysphonia. Lack of clinical myotonia and wide spectrum of unspecific symptoms can make the diagnosis of ion channel disorder challenging for the clinician. Segregation studies are undergoing. Likewise, mutation pathogenicity is under investigation. These will be reported in the following poster. http://dx.doi.org/10.1016/j.nmd.2015.06.092
G.P.76 A third case of congenital myasthenic syndrome caused by mutations in SCN4A N. Witting *,1, U. Werlauff 2, M. Ballegaard 3, J. Vissing 1 1 Rigshospitalet, Copenhagen Neuromuscular Center, 2100 Copenhagen, Denmark; 2 The Danish National Rehabilitation Center for Neuromuscular Diseases, Aarhus, Denmark; 3 Rigshospitalet, Neurophysiology, 2100 Copenhagen, Denmark
G.P.78 A Finnish mutation in SCN4A gene causes predominantly myalgic phenotype J. Palmio *,1, S. Sandell 2, S. Penttilä 1, B. Udd 1 1 Tampere University Hospital, Neuromuscular Research Center, Tampere, Finland; 2 Seinäjoki Central Hospital, Neurology, Seinäjoki, Finland
Only two cases with congenital myasthenic syndrome (CMS) due to mutations in SCN4A have been described. We report a third case and elaborate on the clinical phenotype, electrophysiology and treatment response. A 35 year old woman was born in breech position as a floppy infant. Walking was acquired at 18 months, and in the two first years of life there were episodes where she turned cyanotic and stopped breathing. Since then, no episodic cyanosis or weakness has occurred and her disease has been non-progressive. On exam, she has no ptosis, but has ophthalmoplegia and an elongated face with facial palsy and a high-arched palate. Stature and limbs are slender with MRC 3–4 proximal weakness and 5- at the ankles. Neck flexion, abdominal and paraspinal musculature are MRC 2–3. FVC is 83% of normal, echocardiography and Holter normal. No myotonia is present and no worsening occurs in cold surroundings. CK is normal and muscle biopsy showed unspecific myopathic changes. For a long time, she was considered to have congenital myopathy, but targeted exome sequencing revealed that she is compound heterozygote for c.673C>T (p.(Arg225Trp)) and c.3626G>T (p.(Cys1209Phe) in the SCN4A gene. The first mutation was previously described in paramyotonia congenita and both mutations affected conserved amino acids. Electrophysiology showed no myopathy, but a 60% decrement after 10 Hz stimulation. We conclude that she has a very rare form CMS, and suggest that CMS should be considered in cases of suspected congenital myopathy. Results of the treatment will be presented at the poster.
Mutations in the sodium channel gene, SCN4A, are well-known causes of channelopathies: paramyotonia congenita, other forms of mytonia and periodic paralyses. Rare SCN4A mutations have been associated with myasthenia and malignant hyperthermia. The different phenotypes depend on the type and location of the mutations. The p.A1156T mutation in the SCN4A gene was originally reported in a dominant family of Finnish origin showing features of both hyperkalemic periodic paralysis (HyperPP) and paramyotonia congenita. We examined 20 Finnish patients from 11 different families with this particular p.A1156T mutation. The age of onset of symptoms varied considerably from four to 45 years of age. The main clinical manifestation was not myotonia or HyperPP but exercise and cold induced muscle cramps, muscle stiffness and myalgia. Some had a previous diagnosis of fibromyalgia. Several patients experienced muscle weakness or fatigue during and shortly after exercise. EMG myotonic discharges were detected in most, but not in all. Some patients showed increased insertional activity only. Half of the patients underwent ion channel EMG studies (Fournier protocol) with variable results. Clinical myotonia or typical paramyotonia was not evident on clinical examination in any of the patients. Periodic paralysis was not diagnosed in any of them. The unspecific symptoms of myalgia and exercise intolerance with normal clinical findings in our patients make the diagnosis challenging, and the symptoms may be confused with other similar myalgic syndromes including fibromyalgia and myotonic dystrophy type 2.
http://dx.doi.org/10.1016/j.nmd.2015.06.091
http://dx.doi.org/10.1016/j.nmd.2015.06.093
Bratislava, Slovakia; Comenius University Bratislava, Epidemiology, Medical Faculty, Bratislava, Slovakia
Institute
of
The objective of this study is to analyse the epidemiological data and clinical features in patients (p.) with very late-onset myasthenia gravis (VLOMG) > 70 yrs in Slovakia. In the Slovak MG Register 1950 (p.) are registered (1978–2014). We analysed p. with MG onset > 70 yrs. Collected data for descriptive longitudinal study were age at onset, sex, year of MG onset, year of MG diagnosis, AChR and MuSK antibodies, thymoma, clinical symptoms, and comorbidities. We found VLOMG in 353 p. (18.1%), 181 females (F) 51.3%, 172 males (M) 48.7%. The mean age at onset was 75.2 yrs, F 75.7, M 74.5. 289 p. had MG onset between 70 and 79 yrs (142 F, 147 M). At the age >80 yrs 64 p. (39 F, 25 M) had their onset. Overall incidence of VLOMG had an increase from 0.32/105 in 1978 to 4.29/105 in 2014 (mean 2.52/105). 163 p. were alive on Dec. 31, 2014, giving an overall prevalence of 33.58/105, 71 M (41.29/105), 92 F (29.35/105). In the presentation we will give also data of age-specific incidence and prevalence for both sexes. Ocular symptoms were initial in 73 p. (20.7%), bulbar symptoms in 159 p. (45.0%). 93.6% p. had AChR positive MG, 0.7% p. MuSK positive MG, 5.7% p. double-seronegative MG. 12 p. (3.4%) had thymoma. VLOMG occurs in 353 p. (18.1%), with almost equal frequency in M and F. The mean age-specific incidence is higher for M in comparison to F due to shorter life-expectancy in M and thereby lower representation of M > 70, mainly in 80–89 yrs. Therefore, also the age-specific prevalence of VLOMG is higher in M, though the majority of surviving patients are F. In VLOMG p. AChR positivity dominates (93.6%), bulbar symptoms are often present at onset, and p. have higher occurrence of age-specific comorbidities. http://dx.doi.org/10.1016/j.nmd.2015.06.090
S209
G.P.77 New SCN4A mutations – unusual clinical phenotypes S. Sandell *,1, J. Palmio 2, S. Penttilä 2, T. Suominen 2, B. Udd 2 1 Seinäjoki Central Hospital, Neurology, Seinäjoki, Finland; 2 Neuromuscular Research Center, Tampere University and University Hospital, Tampere, Finland Sodium channel gene (SCN4A) mutations are known to cause several clinical phenotypes in various disorders: paramyotonia congenita, periodic paralyses, myotonia congenita, congenital myasthenic syndrome, and even lifethreatening laryngospasms. SCN4A, encoding the Nav1.4 voltage-gated sodium channel, is responsible for the depolarizing phase of the action potential. We examined a family with six mutation-positive individuals with R1460Q mutation representing various phenotypes, including mother and daughter, who carry CLCN1 Finnish founder mutation R894Xhez as well, and the daughter in addition carrying SCN4A mutation R1059X. In the R1460Qmutated family one middle-aged individual had remained asymptomatic. Of the symptomatic family members 2/5 had myotonia in EMG, but none had clinical myotonia. Both myotonia-positive members were CLCN1-mutation positive as well, suggesting that R1460Q mutation in SCN4A does not cause myotonia in EMG. 4/5 suffered from laryngeal spasms of some severity. 2/5 had stiffnessmyalgic symptoms, leading to early retirement. The youngest family member, a 24-y old woman, has second mutation in the SCN4A gene, R1059X stop-codon mutation, representing an uncommon clinical phenotype of congenital weakness, ptosis, marked facial weakness and dysphonia. Lack of clinical myotonia and wide spectrum of unspecific symptoms can make the diagnosis of ion channel disorder challenging for the clinician. Segregation studies are undergoing. Likewise, mutation pathogenicity is under investigation. These will be reported in the following poster. http://dx.doi.org/10.1016/j.nmd.2015.06.092
G.P.76 A third case of congenital myasthenic syndrome caused by mutations in SCN4A N. Witting *,1, U. Werlauff 2, M. Ballegaard 3, J. Vissing 1 1 Rigshospitalet, Copenhagen Neuromuscular Center, 2100 Copenhagen, Denmark; 2 The Danish National Rehabilitation Center for Neuromuscular Diseases, Aarhus, Denmark; 3 Rigshospitalet, Neurophysiology, 2100 Copenhagen, Denmark
G.P.78 A Finnish mutation in SCN4A gene causes predominantly myalgic phenotype J. Palmio *,1, S. Sandell 2, S. Penttilä 1, B. Udd 1 1 Tampere University Hospital, Neuromuscular Research Center, Tampere, Finland; 2 Seinäjoki Central Hospital, Neurology, Seinäjoki, Finland
Only two cases with congenital myasthenic syndrome (CMS) due to mutations in SCN4A have been described. We report a third case and elaborate on the clinical phenotype, electrophysiology and treatment response. A 35 year old woman was born in breech position as a floppy infant. Walking was acquired at 18 months, and in the two first years of life there were episodes where she turned cyanotic and stopped breathing. Since then, no episodic cyanosis or weakness has occurred and her disease has been non-progressive. On exam, she has no ptosis, but has ophthalmoplegia and an elongated face with facial palsy and a high-arched palate. Stature and limbs are slender with MRC 3–4 proximal weakness and 5- at the ankles. Neck flexion, abdominal and paraspinal musculature are MRC 2–3. FVC is 83% of normal, echocardiography and Holter normal. No myotonia is present and no worsening occurs in cold surroundings. CK is normal and muscle biopsy showed unspecific myopathic changes. For a long time, she was considered to have congenital myopathy, but targeted exome sequencing revealed that she is compound heterozygote for c.673C>T (p.(Arg225Trp)) and c.3626G>T (p.(Cys1209Phe) in the SCN4A gene. The first mutation was previously described in paramyotonia congenita and both mutations affected conserved amino acids. Electrophysiology showed no myopathy, but a 60% decrement after 10 Hz stimulation. We conclude that she has a very rare form CMS, and suggest that CMS should be considered in cases of suspected congenital myopathy. Results of the treatment will be presented at the poster.
Mutations in the sodium channel gene, SCN4A, are well-known causes of channelopathies: paramyotonia congenita, other forms of mytonia and periodic paralyses. Rare SCN4A mutations have been associated with myasthenia and malignant hyperthermia. The different phenotypes depend on the type and location of the mutations. The p.A1156T mutation in the SCN4A gene was originally reported in a dominant family of Finnish origin showing features of both hyperkalemic periodic paralysis (HyperPP) and paramyotonia congenita. We examined 20 Finnish patients from 11 different families with this particular p.A1156T mutation. The age of onset of symptoms varied considerably from four to 45 years of age. The main clinical manifestation was not myotonia or HyperPP but exercise and cold induced muscle cramps, muscle stiffness and myalgia. Some had a previous diagnosis of fibromyalgia. Several patients experienced muscle weakness or fatigue during and shortly after exercise. EMG myotonic discharges were detected in most, but not in all. Some patients showed increased insertional activity only. Half of the patients underwent ion channel EMG studies (Fournier protocol) with variable results. Clinical myotonia or typical paramyotonia was not evident on clinical examination in any of the patients. Periodic paralysis was not diagnosed in any of them. The unspecific symptoms of myalgia and exercise intolerance with normal clinical findings in our patients make the diagnosis challenging, and the symptoms may be confused with other similar myalgic syndromes including fibromyalgia and myotonic dystrophy type 2.
http://dx.doi.org/10.1016/j.nmd.2015.06.091
http://dx.doi.org/10.1016/j.nmd.2015.06.093