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Novel CLCN1 Mutation in Carbamazepine-Responsive Myotonia Congenita
Novel CLCN1 Mutation in CarbamazepineResponsive Myotonia Congenita Michael J. Lyons, MD*, Reyna Duron, MD†, Isaac Molinero, BA†, Federica Sangiuolo, PhD‡, and Kenton R. Holden, MD*§
Myotonia congenita is a nondystrophic muscle disorder characterized by muscle stiffness and muscle hypertrophy. The disorder can be inherited in an autosomal-dominant (Thomsen disease) or autosomal-recessive (Becker disease) manner. Both forms of myotonia congenita are attributable to mutations in the CLCN1 gene. Treatment with a variety of medications has led to long-term improvement in the clinical course of affected individuals. We describe a Honduran boy with myotonia congenita and a novel p.L287I mutation in the CLCN1 gene. The patient’s unaffected father carries the same mutation, most likely reflecting autosomal-recessive myotonia congenita, with an inability to find a second mutation. The patient received carbamazepine treatment for 1 year, resulting in decreased muscle stiffness, increased strength, and improved quality of life in school and with peers. Ó 2010 by Elsevier Inc. All rights reserved. Lyons MJ, Duron R, Molinero I, Sangiuolo F, Holden KR. Novel CLCN1 mutation in carbamazepine-responsive myotonia congenita. Pediatr Neurol 2010;42:365-368.
From the *Greenwood Genetic Center, Greenwood, South Carolina; † National Autonomous University of Honduras, Tegucigalpa, Honduras; ‡ Department of Biopathology, Tor Vergata University, Rome, Italy; and § Division of Neurology, Department of Neurosciences and Pediatrics, Medical University of South Carolina, Charleston, South Carolina.
Ó 2010 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2010.01.014 0887-8994/10/$—see front matter
Introduction Myotonia congenita is a muscle disorder that can be inherited in an autosomal-dominant (Thomsen disease) or autosomal-recessive (Becker disease) manner [1,2]. Myotonia is defined as impaired skeletal muscle relaxation after voluntary contraction or mechanical stimulation [3]. A warm-up phenomenon is typically observed in which the myotonia is worse after rest and improves with exercise [1,3]. Muscle stiffness and muscle hypertrophy are evident in both forms of myotonia congenita. Certain clinical features, such as generalized muscle hypertrophy, transient weakness, and depressed deep tendon reflexes, are more common in the recessive form of myotonia congenita [1,4]. Both forms of myotonia congenita are caused by mutations in the skeletal muscle chloride channel (CLCN1) gene on chromosome 7q35 [1,5,6]. Dominant myotonia congenita is attributed to a dominant-negative effect, in which the mutated allele negatively affects the wild-type allele [7,8]. Recessive myotonia congenita is typically caused by a loss of function of the mutated alleles [8,9]. A significant number of mutations associated with dominant myotonia congenita were identified in exon 8 [1,4]. However, mutations causing both forms of myotonia congenita have been described throughout the CLCN1 coding region [8]. The CLCN1 gene encodes the chloride channel protein ClC-1. Mutations in CLCN1 lead to decreased chloride conductance of muscle membrane, resulting in muscle hyperexcitability [10]. Myotonia is also associated with other disorders that cause muscle membrane hyperexcitability, including myotonic dystrophy and paramyotonia congenita. Myotonic dystrophy is caused by expanded repeats that lead to altered splicing of ClC-1 pre-messenger ribonucleic acid, resulting in altered chloride conductance and muscle hyperexcitability [11]. Muscle hyperexcitability attributable to a lack of sodium-channel inactivation can also lead to myotonia, as in paramyotonia congenita. This illness is distinguished by a susceptibility to cold weather and stiffness which worsens with repeated muscle contractions [1,2] Medications that increase chloride conductance enough to prevent myotonia are not available, but sodium-channel blockers, including carbamazepine, phenytoin, mexiletine, and procainamide, have been successful in treating myotonia congenita [2,12].
Communications should be addressed to: Dr. Lyons; Greenwood Genetic Center; 3520 West Montague Avenue, Suite 104; North Charleston, SC 29418. E-mail: [email protected] Received July 17, 2009; accepted January 25, 2010.
Lyons et al: Myotonia Congenita Therapy 365
Figure 1. Patient demonstrates generalized muscle hypertrophy at age 11 years (A,B), with persistent hypertrophy of the calves at age 13 years (C).
We describe a case of myotonia congenita in a family from Honduras, Central America. The patient demonstrated characteristic clinical features of myotonia congenita that negatively affected his quality of life, with a clinically significant response to carbamazepine treatment over the past year. A novel p.L287I mutation in the CLCN1 gene was identified in the patient and in his clinically unaffected father.
Case Report Our patient was a 14-year-old Honduran boy with a history of muscle hypertrophy and muscle stiffness, presenting as transient muscle weakness. He was born at term after an uncomplicated pregnancy, with a birth weight of 2.7 kg (10th percentile). No complications occurred after the delivery. His psychomotor development was normal for 5 years. At age 6 years, weakness developed in his lower limbs. The weakness then spread to his upper limbs, which led to difficulty walking and writing. There was no family history of muscle stiffness, weakness, muscle hypertrophy, genetic syndromes, or consanguinity. His parents, 8-year-old brother, two maternal half-sisters, and two maternal half-brothers were clinically unaffected. At age 11 years, he underwent a neurologic evaluation because of his long-standing muscle stiffness with transient weakness and calf hypertrophy. Significant concern arose about his long term prognosis because his initial presentation was thought to be consistent with muscular dystrophy. A physical examination revealed a lordotic gait, with generalized muscle hypertrophy (Fig 1). The patient was slow in his initial gross motor responses, but demonstrated a warm-up phenomenon with activity. He did not complain of fatigue, muscle pain, cramps, swelling, redness, or joint pain. His weight was 34.1 kg (45th percentile), his height was 132 cm (5th percentile), and his head circumference was 54 cm (50th percentile). His fingers were hyperextensible. He exhibited generalized increased muscle bulk and tone. His muscle strength was normal. Prominent bilateral percussion myotonia of the thenar eminences was evident, as was a modified Gower sign. Deep tendon reflexes were within normal limits. The Babinski
366 PEDIATRIC NEUROLOGY Vol. 42 No. 5
sign was negative bilaterally. The patient’s coordination and sensation were normal. On follow-up examination at age 13 years, he exhibited transient weakness when initiating gross motor activity, and difficulty keeping up with peers and completing his home chores. His weight was 47.7 kg (55th percentile), his height was 144 cm (5th percentile), and his head circumference was 55 cm (60th percentile). The generalized muscle hypertrophy persisted. He demonstrated generalized increased tone, and his muscle strength in all limbs was 4.5/5. He exhibited percussion myotonia of the thenar eminences and a modified Gowers’ sign from a sitting position. His deep tendon reflexes remained normal, and the Babinski sign was negative bilaterally. Laboratory testing of the patient yielded a serum creatine kinase level of 194.5 U/L (normal range, up to 160 U/L). Electrolytes and liver function tests produced normal results, as did an electrocardiogram. Routine needle electromyography indicated frequent myotonic discharges of varying amplitude and frequency, along with the classic ‘‘dive-bomber’s sound’’ typical of myotonia. His DNA was extracted using standard procedures. Polymerase chain reaction amplification and direct sequencing of the entire CLCN1 coding sequence were performed. Testing of CLCN1 revealed a previously unreported p.L287I heterozygous mutation. The mutation was absent in 100 healthy control subjects analyzed by direct sequencing. The patient’s mother and brother demonstrated normal results of CLCN1 testing. The same p.L287I CLCN1 mutation was identified in the patient’s asymptomatic 69-year-old Honduran father, who works without limitations as a manual laborer. His history included no muscle stiffness, weakness, cramps, pain, or swelling. His gait has always been normal. A neurologic examination revealed normal strength, bulk, and muscle tone. He yielded no evidence of percussion myotonia, and no Gowers’ sign from a sitting position. His deep tendon reflexes in all limbs were within normal limits, and the Babinski sign was negative bilaterally. After laboratory confirmation of the diagnosis, our patient began receiving low-dose carbamazepine (100 mg twice a day orally) 1 year ago. Within the first month of treatment, his ability to climb stairs and walk at a faster pace improved. He became less fatigued. His school performance improved, especially because he could write more easily. He continues to manifest percussion myotonia. For optimum performance, his dose of carbamazepine has been gradually increased to 900 mg/day, with close monitoring, as he grows.
Discussion This clinical report describes a Honduran boy with characteristic features of myotonia congenita, including muscle stiffness and muscle hypertrophy. His clinical diagnosis was confirmed by the identification of a novel p.L287I mutation in the CLCN1 gene. The significance of this previously unreported mutation is supported by the finding that the same mutation was not identified in 100 healthy control subjects. In addition, the mutation is located in a highly conserved region [8]. Functional expression studies have not been performed to further support the pathogenicity of the mutation. The p.L287I CLCN1 mutation was also identified in our patient’s unaffected father. This lack of symptomatology may be attributable to incomplete penetrance, which was reported in other families with dominant myotonia congenita [13]. The p.L287I mutation is located in exon 8 of the CLCN1 gene, which was identified as a potential hotspot for dominant myotonia congenita mutations. However, recessive myotonia congenita can also be caused by mutations in exon 8 of the CLCN1 gene [4]. Moreover, certain CLCN1 mutations can function as either dominant or recessive [8]. Recessive myotonia congenita is more commonly reported than dominant myotonia congenita [3,4]. Recessive myotonia congenita has been associated with a later age of onset and an initial lower limb involvement spreading to the upper limbs [14]. However, Fialho et al. observed no difference in age of onset or lower limb involvement [4]. Recessive myotonia congenita was associated with more severe myotonia than dominant myotonia congenita. In addition, transient weakness, generalized muscle hypertrophy, and depressed deep tendon reflexes were more common in recessive myotonia congenita [1,4]. Although our patient manifests normal deep tendon reflexes, his generalized muscle hypertrophy, transient weakness, and clinically unaffected parents are consistent with recessive myotonia congenita. Therefore, we think that our patient most likely exhibits recessive myotonia congenita attributable to compound heterozygosity, with an inability to identify the second CLCN1 mutation. Other cases of recessive myotonia congenita were described in which only one CLCN1 mutation was identified [1]. Individuals with myotonia congenita have responded to treatment with multiple different sodium-channel blockers, because these medications can increase the threshold for muscle membrane depolarization [12,15]. Carbamazepine is a sodium-channel blocker that has been used effectively in individuals with either dominant or recessive myotonia congenita [15]. Our patient demonstrated dramatic improvement in his stiffness and transient weakness after beginning a low dose of carbamazepine. Myotonia congenita can exert a significant impact on an individual’s activities of daily living. Confirmation of the mode of inheritance improves genetic counseling, because establishing the risk of recurrence and the prognosis is
more accurate. Testing of the CLCN1 gene can help confirm the clinical diagnosis and determine the mode of inheritance. However, one or more mutations may not be detected with the available molecular testing [1,3]. Furthermore, prediction of whether a mutation is dominant or recessive is not possible based on the location of the mutation in the CLCN1 gene [8]. In our patient, a definitive mode of inheritance could not be determined, but the clinical presentation and identification of a novel p.L287I CLCN1 mutation in the patient and his asymptomatic father indicate that the patient most likely manifests recessive myotonia congenita because of compound heterozygosity, with an inability to identify the second CLCN1 mutation. The clinical findings of muscle stiffness and muscle hypertrophy in a patient should raise suspicions for a possible diagnosis of myotonia congenita. Our patient initially presented with clinical features suggestive of muscular dystrophy. Confirming the clinical diagnosis of myotonia congenita allowed for prompt investigation of potential treatments and the initiation of carbamazepine, which resulted in significant improvement in his stiffness and transient weakness. Early recognition and treatment should improve the long-term quality of life of individuals with myotonia congenita. We thank the patient’s family for their participation in this study, Cindy Skinner, RN, for help in sample preparation and handling, Giuseppe Novelli, PhD, for assistance in the coordination of CLCN1 testing, and Dario Zuniga, MD, for his involvement in clinical care.
References [1] Matthews E, Fialho D, Tan SV, et al. The non-dystrophic myotonias: Molecular pathogenesis, diagnosis and treatment. Brain 2010;133: 9-22. [2] Lossin C, George AL Jr. Myotonia congenita. Adv Genet 2008;63: 25-55. [3] Sun C, Tranebjaerg L, Torbergsen T, Holmgren G, Van Ghelue M. Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia. Eur J Hum Genet 2001;9:903-9. [4] Fialho D, Schorge S, Pucovska U, et al. Chloride channel myotonia: Exon 8 hot-spot for dominant-negative interactions. Brain 2007;130: 3265-74. [5] Koch MC, Steinmeyer K, Lorenz C, et al. The skeletal muscle chloride channel in dominant and recessive human myotonia. Science 1992;257:797-800. [6] George AL Jr, Crackower MA, Abdalla JA, Hudson AJ, Ebers GC. Molecular basis of Thomsen’s disease (autosomal dominant myotonia congenita). Nat Genet 1993;3:305-10. [7] Steinmeyer K, Lorenz C, Pusch M, Koch MC, Jentsch TJ. Multimeric structure of ClC-1 chloride channel revealed by mutations in dominant myotonia congenita (Thomsen). EMBO J 1994;13:737-43. [8] Meyer-Kleine C, Steinmeyer K, Ricker K, Jentsch TJ, Koch MC. Spectrum of mutations in the major human skeletal muscle chloride channel gene (CLCN1) leading to myotonia. Am J Hum Genet 1995;57: 1325-34. [9] Dunø M, Colding-Jørgensen E, Grunnet M, Jespersen T, Vissing J, Schwartz M. Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype. Eur J Hum Genet 2004;12:738-43.
Lyons et al: Myotonia Congenita Therapy 367
[10] Beck CL, Fahlke C, George AL Jr. Molecular basis for decreased muscle chloride conductance in the myotonic goat. Proc Natl Acad Sci USA 1996;93:11248-52. [11] Mankodi A, Takahashi MP, Jiang H, et al. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell 2002;10:35-44. [12] Kurihara T. New classification and treatment for myotonic disorders. Intern Med 2005;44:1027-32.
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[13] Koty PP, Pegoraro E, Hobson G, et al. Myotonia and the muscle chloride channel: Dominant mutations show variable penetrance and founder effect. Neurology 1996;47:963-8. [14] Mailander V, Heine R, Deymeer F, Lehmann-Horn F. Novel muscle chloride channel mutations and their effects on heterozygous carriers. Am J Hum Genet 1996;58:317-24. [15] Sheela SR. Myotonia congenita: Response to carbamazepine. Indian Pediatr 2000;37:1122-5.
Myotonia congenita is a nondystrophic muscle disorder characterized by muscle stiffness and muscle hypertrophy. The disorder can be inherited in an autosomal-dominant (Thomsen disease) or autosomal-recessive (Becker disease) manner. Both forms of myotonia congenita are attributable to mutations in the CLCN1 gene. Treatment with a variety of medications has led to long-term improvement in the clinical course of affected individuals. We describe a Honduran boy with myotonia congenita and a novel p.L287I mutation in the CLCN1 gene. The patient’s unaffected father carries the same mutation, most likely reflecting autosomal-recessive myotonia congenita, with an inability to find a second mutation. The patient received carbamazepine treatment for 1 year, resulting in decreased muscle stiffness, increased strength, and improved quality of life in school and with peers. Ó 2010 by Elsevier Inc. All rights reserved. Lyons MJ, Duron R, Molinero I, Sangiuolo F, Holden KR. Novel CLCN1 mutation in carbamazepine-responsive myotonia congenita. Pediatr Neurol 2010;42:365-368.
From the *Greenwood Genetic Center, Greenwood, South Carolina; † National Autonomous University of Honduras, Tegucigalpa, Honduras; ‡ Department of Biopathology, Tor Vergata University, Rome, Italy; and § Division of Neurology, Department of Neurosciences and Pediatrics, Medical University of South Carolina, Charleston, South Carolina.
Ó 2010 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2010.01.014 0887-8994/10/$—see front matter
Introduction Myotonia congenita is a muscle disorder that can be inherited in an autosomal-dominant (Thomsen disease) or autosomal-recessive (Becker disease) manner [1,2]. Myotonia is defined as impaired skeletal muscle relaxation after voluntary contraction or mechanical stimulation [3]. A warm-up phenomenon is typically observed in which the myotonia is worse after rest and improves with exercise [1,3]. Muscle stiffness and muscle hypertrophy are evident in both forms of myotonia congenita. Certain clinical features, such as generalized muscle hypertrophy, transient weakness, and depressed deep tendon reflexes, are more common in the recessive form of myotonia congenita [1,4]. Both forms of myotonia congenita are caused by mutations in the skeletal muscle chloride channel (CLCN1) gene on chromosome 7q35 [1,5,6]. Dominant myotonia congenita is attributed to a dominant-negative effect, in which the mutated allele negatively affects the wild-type allele [7,8]. Recessive myotonia congenita is typically caused by a loss of function of the mutated alleles [8,9]. A significant number of mutations associated with dominant myotonia congenita were identified in exon 8 [1,4]. However, mutations causing both forms of myotonia congenita have been described throughout the CLCN1 coding region [8]. The CLCN1 gene encodes the chloride channel protein ClC-1. Mutations in CLCN1 lead to decreased chloride conductance of muscle membrane, resulting in muscle hyperexcitability [10]. Myotonia is also associated with other disorders that cause muscle membrane hyperexcitability, including myotonic dystrophy and paramyotonia congenita. Myotonic dystrophy is caused by expanded repeats that lead to altered splicing of ClC-1 pre-messenger ribonucleic acid, resulting in altered chloride conductance and muscle hyperexcitability [11]. Muscle hyperexcitability attributable to a lack of sodium-channel inactivation can also lead to myotonia, as in paramyotonia congenita. This illness is distinguished by a susceptibility to cold weather and stiffness which worsens with repeated muscle contractions [1,2] Medications that increase chloride conductance enough to prevent myotonia are not available, but sodium-channel blockers, including carbamazepine, phenytoin, mexiletine, and procainamide, have been successful in treating myotonia congenita [2,12].
Communications should be addressed to: Dr. Lyons; Greenwood Genetic Center; 3520 West Montague Avenue, Suite 104; North Charleston, SC 29418. E-mail: [email protected] Received July 17, 2009; accepted January 25, 2010.
Lyons et al: Myotonia Congenita Therapy 365
Figure 1. Patient demonstrates generalized muscle hypertrophy at age 11 years (A,B), with persistent hypertrophy of the calves at age 13 years (C).
We describe a case of myotonia congenita in a family from Honduras, Central America. The patient demonstrated characteristic clinical features of myotonia congenita that negatively affected his quality of life, with a clinically significant response to carbamazepine treatment over the past year. A novel p.L287I mutation in the CLCN1 gene was identified in the patient and in his clinically unaffected father.
Case Report Our patient was a 14-year-old Honduran boy with a history of muscle hypertrophy and muscle stiffness, presenting as transient muscle weakness. He was born at term after an uncomplicated pregnancy, with a birth weight of 2.7 kg (10th percentile). No complications occurred after the delivery. His psychomotor development was normal for 5 years. At age 6 years, weakness developed in his lower limbs. The weakness then spread to his upper limbs, which led to difficulty walking and writing. There was no family history of muscle stiffness, weakness, muscle hypertrophy, genetic syndromes, or consanguinity. His parents, 8-year-old brother, two maternal half-sisters, and two maternal half-brothers were clinically unaffected. At age 11 years, he underwent a neurologic evaluation because of his long-standing muscle stiffness with transient weakness and calf hypertrophy. Significant concern arose about his long term prognosis because his initial presentation was thought to be consistent with muscular dystrophy. A physical examination revealed a lordotic gait, with generalized muscle hypertrophy (Fig 1). The patient was slow in his initial gross motor responses, but demonstrated a warm-up phenomenon with activity. He did not complain of fatigue, muscle pain, cramps, swelling, redness, or joint pain. His weight was 34.1 kg (45th percentile), his height was 132 cm (5th percentile), and his head circumference was 54 cm (50th percentile). His fingers were hyperextensible. He exhibited generalized increased muscle bulk and tone. His muscle strength was normal. Prominent bilateral percussion myotonia of the thenar eminences was evident, as was a modified Gower sign. Deep tendon reflexes were within normal limits. The Babinski
366 PEDIATRIC NEUROLOGY Vol. 42 No. 5
sign was negative bilaterally. The patient’s coordination and sensation were normal. On follow-up examination at age 13 years, he exhibited transient weakness when initiating gross motor activity, and difficulty keeping up with peers and completing his home chores. His weight was 47.7 kg (55th percentile), his height was 144 cm (5th percentile), and his head circumference was 55 cm (60th percentile). The generalized muscle hypertrophy persisted. He demonstrated generalized increased tone, and his muscle strength in all limbs was 4.5/5. He exhibited percussion myotonia of the thenar eminences and a modified Gowers’ sign from a sitting position. His deep tendon reflexes remained normal, and the Babinski sign was negative bilaterally. Laboratory testing of the patient yielded a serum creatine kinase level of 194.5 U/L (normal range, up to 160 U/L). Electrolytes and liver function tests produced normal results, as did an electrocardiogram. Routine needle electromyography indicated frequent myotonic discharges of varying amplitude and frequency, along with the classic ‘‘dive-bomber’s sound’’ typical of myotonia. His DNA was extracted using standard procedures. Polymerase chain reaction amplification and direct sequencing of the entire CLCN1 coding sequence were performed. Testing of CLCN1 revealed a previously unreported p.L287I heterozygous mutation. The mutation was absent in 100 healthy control subjects analyzed by direct sequencing. The patient’s mother and brother demonstrated normal results of CLCN1 testing. The same p.L287I CLCN1 mutation was identified in the patient’s asymptomatic 69-year-old Honduran father, who works without limitations as a manual laborer. His history included no muscle stiffness, weakness, cramps, pain, or swelling. His gait has always been normal. A neurologic examination revealed normal strength, bulk, and muscle tone. He yielded no evidence of percussion myotonia, and no Gowers’ sign from a sitting position. His deep tendon reflexes in all limbs were within normal limits, and the Babinski sign was negative bilaterally. After laboratory confirmation of the diagnosis, our patient began receiving low-dose carbamazepine (100 mg twice a day orally) 1 year ago. Within the first month of treatment, his ability to climb stairs and walk at a faster pace improved. He became less fatigued. His school performance improved, especially because he could write more easily. He continues to manifest percussion myotonia. For optimum performance, his dose of carbamazepine has been gradually increased to 900 mg/day, with close monitoring, as he grows.
Discussion This clinical report describes a Honduran boy with characteristic features of myotonia congenita, including muscle stiffness and muscle hypertrophy. His clinical diagnosis was confirmed by the identification of a novel p.L287I mutation in the CLCN1 gene. The significance of this previously unreported mutation is supported by the finding that the same mutation was not identified in 100 healthy control subjects. In addition, the mutation is located in a highly conserved region [8]. Functional expression studies have not been performed to further support the pathogenicity of the mutation. The p.L287I CLCN1 mutation was also identified in our patient’s unaffected father. This lack of symptomatology may be attributable to incomplete penetrance, which was reported in other families with dominant myotonia congenita [13]. The p.L287I mutation is located in exon 8 of the CLCN1 gene, which was identified as a potential hotspot for dominant myotonia congenita mutations. However, recessive myotonia congenita can also be caused by mutations in exon 8 of the CLCN1 gene [4]. Moreover, certain CLCN1 mutations can function as either dominant or recessive [8]. Recessive myotonia congenita is more commonly reported than dominant myotonia congenita [3,4]. Recessive myotonia congenita has been associated with a later age of onset and an initial lower limb involvement spreading to the upper limbs [14]. However, Fialho et al. observed no difference in age of onset or lower limb involvement [4]. Recessive myotonia congenita was associated with more severe myotonia than dominant myotonia congenita. In addition, transient weakness, generalized muscle hypertrophy, and depressed deep tendon reflexes were more common in recessive myotonia congenita [1,4]. Although our patient manifests normal deep tendon reflexes, his generalized muscle hypertrophy, transient weakness, and clinically unaffected parents are consistent with recessive myotonia congenita. Therefore, we think that our patient most likely exhibits recessive myotonia congenita attributable to compound heterozygosity, with an inability to identify the second CLCN1 mutation. Other cases of recessive myotonia congenita were described in which only one CLCN1 mutation was identified [1]. Individuals with myotonia congenita have responded to treatment with multiple different sodium-channel blockers, because these medications can increase the threshold for muscle membrane depolarization [12,15]. Carbamazepine is a sodium-channel blocker that has been used effectively in individuals with either dominant or recessive myotonia congenita [15]. Our patient demonstrated dramatic improvement in his stiffness and transient weakness after beginning a low dose of carbamazepine. Myotonia congenita can exert a significant impact on an individual’s activities of daily living. Confirmation of the mode of inheritance improves genetic counseling, because establishing the risk of recurrence and the prognosis is
more accurate. Testing of the CLCN1 gene can help confirm the clinical diagnosis and determine the mode of inheritance. However, one or more mutations may not be detected with the available molecular testing [1,3]. Furthermore, prediction of whether a mutation is dominant or recessive is not possible based on the location of the mutation in the CLCN1 gene [8]. In our patient, a definitive mode of inheritance could not be determined, but the clinical presentation and identification of a novel p.L287I CLCN1 mutation in the patient and his asymptomatic father indicate that the patient most likely manifests recessive myotonia congenita because of compound heterozygosity, with an inability to identify the second CLCN1 mutation. The clinical findings of muscle stiffness and muscle hypertrophy in a patient should raise suspicions for a possible diagnosis of myotonia congenita. Our patient initially presented with clinical features suggestive of muscular dystrophy. Confirming the clinical diagnosis of myotonia congenita allowed for prompt investigation of potential treatments and the initiation of carbamazepine, which resulted in significant improvement in his stiffness and transient weakness. Early recognition and treatment should improve the long-term quality of life of individuals with myotonia congenita. We thank the patient’s family for their participation in this study, Cindy Skinner, RN, for help in sample preparation and handling, Giuseppe Novelli, PhD, for assistance in the coordination of CLCN1 testing, and Dario Zuniga, MD, for his involvement in clinical care.
References [1] Matthews E, Fialho D, Tan SV, et al. The non-dystrophic myotonias: Molecular pathogenesis, diagnosis and treatment. Brain 2010;133: 9-22. [2] Lossin C, George AL Jr. Myotonia congenita. Adv Genet 2008;63: 25-55. [3] Sun C, Tranebjaerg L, Torbergsen T, Holmgren G, Van Ghelue M. Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia. Eur J Hum Genet 2001;9:903-9. [4] Fialho D, Schorge S, Pucovska U, et al. Chloride channel myotonia: Exon 8 hot-spot for dominant-negative interactions. Brain 2007;130: 3265-74. [5] Koch MC, Steinmeyer K, Lorenz C, et al. The skeletal muscle chloride channel in dominant and recessive human myotonia. Science 1992;257:797-800. [6] George AL Jr, Crackower MA, Abdalla JA, Hudson AJ, Ebers GC. Molecular basis of Thomsen’s disease (autosomal dominant myotonia congenita). Nat Genet 1993;3:305-10. [7] Steinmeyer K, Lorenz C, Pusch M, Koch MC, Jentsch TJ. Multimeric structure of ClC-1 chloride channel revealed by mutations in dominant myotonia congenita (Thomsen). EMBO J 1994;13:737-43. [8] Meyer-Kleine C, Steinmeyer K, Ricker K, Jentsch TJ, Koch MC. Spectrum of mutations in the major human skeletal muscle chloride channel gene (CLCN1) leading to myotonia. Am J Hum Genet 1995;57: 1325-34. [9] Dunø M, Colding-Jørgensen E, Grunnet M, Jespersen T, Vissing J, Schwartz M. Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype. Eur J Hum Genet 2004;12:738-43.
Lyons et al: Myotonia Congenita Therapy 367
[10] Beck CL, Fahlke C, George AL Jr. Molecular basis for decreased muscle chloride conductance in the myotonic goat. Proc Natl Acad Sci USA 1996;93:11248-52. [11] Mankodi A, Takahashi MP, Jiang H, et al. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell 2002;10:35-44. [12] Kurihara T. New classification and treatment for myotonic disorders. Intern Med 2005;44:1027-32.
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[13] Koty PP, Pegoraro E, Hobson G, et al. Myotonia and the muscle chloride channel: Dominant mutations show variable penetrance and founder effect. Neurology 1996;47:963-8. [14] Mailander V, Heine R, Deymeer F, Lehmann-Horn F. Novel muscle chloride channel mutations and their effects on heterozygous carriers. Am J Hum Genet 1996;58:317-24. [15] Sheela SR. Myotonia congenita: Response to carbamazepine. Indian Pediatr 2000;37:1122-5.