Double-trouble in pediatric neurology: Myotonia Congenita combined with Charcot-MarieTooth disease type 1A

Anna Ardissone, MD 1, Raffaella Brugnoni PhD 2, Claudia Gandioli MD 1, Micaela Milani PhD 3, Claudia Ciano, MD 4 , Graziella Uziel, MD 1, Isabella Moroni, MD 1

1

Child Neurology Unit,

2

Neuromuscular Diseases and Neuroimmunology Unit,

3

Genetics of

Neurodegenerative and Metabolic Diseases Unit, 4 Neurophysiopathology and Epilepsy Unit Foundation IRCCS C.Besta Neurological Institute, Milan, Italy

Corresponding author at: Moroni Isabella, MD Child Neurology Unit, Foundation IRCCS C. Besta Neurological Institute Via Celoria 11, 20133, Milan, Italy. Tel: +39 02 23942346; Fax: +39 02 23942181 mail: [email protected] Running title: Myotonia congenita combined with CMT1A

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/mus.24205

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Double-trouble in pediatric neurology: Myotonia Congenita combined with Charcot-MarieTooth disease type 1A

Keywords: Myotonia Congenita; CLCN1 gene; skeletal muscle voltage-gated chloride channel (ClC-1); Charcot-Marie-Tooth disease type1A (CMT1A); Childhood.

Myotonia congenita (MC) is a rare muscle disorder that may be transmitted as either autosomal dominant (Thomsen disease) or recessive traits (Becker disease), due to mutations in the chloride channel voltage-sensitive 1 (CLCN1) gene located on chromosome 7q35.1,2 Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous hereditary neuropathy and CMT1A is the most common form, caused by a duplication of the peripheral myelin protein 22 (PMP22) gene.3 Since the estimated prevalence of MC is between 7 and 10 in 100,000 4,5, and CMT has a prevalence of 40:100,000 3, the theoretical chance of inheriting both diseases is extremely low. We describe a boy, now age 16 years. He was born to apparently unrelated parents and presented with clumsy gait and frequent falls from the first years of life, progressive gait stiffness, running difficulty, and weakness in proximal upper and lower limbs. At age 11 years he showed an unusual association of myopathic and neuropathic signs, including mild distal atrophy, weakness in proximal and distal muscles, reduced tendon reflexes, and evidence of generalized myotonia, with slow and painful muscle relaxation after contraction and a “warm-up” phenomenon with repeated motor activity. Needle electromyography revealed increased insertional and spontaneous activity, marked repetitive discharges of trains of motor unit action potentials, and sustained runs of positive waves or runs of small triphasic potentials consistent with myotonic discharges in proximal and distal muscles (Fig 1a). Mildly reduced motor and sensory conduction velocities (median nerve 42 m/s and sural nerve 40 m/s), increased distal motor latency (median 4.8 ms), and reduced sensory amplitude (sural 7.3 John Wiley & Sons, Inc.

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µV) were also present. Electrodiagnostic studies in both asymptomatic parents disclosed a demyelinating polyneuropathy in the father and mild myotonia in the mother. Direct sequencing of the CLCN1 gene

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in the proband revealed the presence of 2 known

heterozygous mutations7: a splice mutation c.180+3A>T in intron 1, and a missense mutation c.1970T>C in exon 17 (Fig. 1b). PMP22 gene analysis8 disclosed the presence of a 17p11.2-12 duplication. We thus demonstrated the CLCN1 gene c.180+3A>T mutation in the mother and the p.L657P mutation in the father, who also carried the 17p11.2-12 duplication in the PMP22 gene (Fig. 1c). These results allowed us to confirm the diagnosis of 2 combined diseases, recessive Becker MC and dominant CMT1A. Two separate gene mutations in different neuromuscular disorders, including CMT, have been reported in a limited number of cases 9-13, and we now report the association of MC with CMT1A. There are too few “double trouble” cases to define whether concomitant genetic conditions modify the severity and progression of the 2 diseases to produce more severe phenotypes, and we cannot predict whether this condition in our patient could lead to more severe clinical impairment with age. We suggest that clinicians consider that, in the presence of unusual clinical features and a negative family history, there is possibly a combination of 2 rare neuromuscular diseases. This can have a significant impact on medical care and genetic counselling.

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Myotonia congenita combined with CMT1A Consent Written informed consent for DNA storage and use for genetic analysis and research purposes was obtained from the patient and his relatives, as required by the Ethical Committee of Foundation Neurological Institute “Carlo Besta”.

Abbreviations : Charcot-Marie-Tooth disease: CMT; Myotonia congenita: MC; chloride channel voltage-sensitive 1 gene: CLCN1; peripheral myelin protein 22 gene: PMP22; human skeletal muscle chloride channel: ClC-1.

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REFERENCES

1) Lossin C, George AL Jr. Myotonia congenita. Adv Genet 2008; 63:25-55. 2) Lorenz C, Meyer-Kleine C, Steinmeyer K, Koch MC, Jentsch TJ. Genomic organization of the human muscle chloride channel CIC-1 and analysis of novel mutations leading to Becker-type myotonia. Hum Mol Genet 1994; 3(6):941-6. 3) Pareyson D, Marchesi C. Diagnosis, natural history and management of Charcot-MarieTooth disease. Lancet Neurol 2009 7: 654-667. 4) Matthews E, Fialho D, Tan SV, Venance SL, Cannon SC, Sternberg D et al. The nondystrophic myotonia: molecular pathogenesis, diagnosis and treatment. Brain 2010 133; 922 . 5) Lehmann-Horn F, Jurkat-Rott K and Rüdel R. Diagnostics and Therapy of Muscle Channelopathies – Guidelines of the Ulm Muscle Centre. Acta Myologica 2008;XXVII: 98-113. 6) Brugnoni R, Kapetis D, Imbrici P, Pessia M, Canioni E, Colleoni L et al. A large cohort of myotonia congenita probands: novel mutations and a high-frequency mutation region in exons 4 and 5 of the CLCN1 gene. J Hum Genet 2013; 58(9):581-7. 7) Leiden Open Variation Database. Chloride channel 1, skeletal muscle (CLCN1). http://chromium.liacs.nl/LOVD2/ . 2012 8) Aarskog NK, Vedeler CA. Real-time quantitative polymerase chain reaction. A new method that detects both the perypheral myelin protein 22 duplication in Charcot-MarieTooth type 1A disease and the perypheral myelin protein 22 deletion in hereditary neuropathy with liability to pressure palsies. Hum Genet 2000;107(5):494-8. 9) Kim HS, Chung KW, Kang SH, Choi SK, Cho SY, Koo H et al. Myotonic dystrophy type I combined with X-linked dominant Charcot-Marie-Tooth neuropathy. Neurogenetics 2010;11(4):425-33. John Wiley & Sons, Inc.

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Myotonia congenita combined with CMT1A 10) Kurt S, Karner H, Kaplan Y, Akat I, Battaloglu E, Druslu D et al. Combination of Myotonic dystrophy and hereditary motor and sensory neuropathy. J Neurol Sci 2010; 288:197-199. 11) Bergman C, Senderek J, Hermanns B, Jauch A, Janssen B, Schroder JM et al. Becker muscular dystrophy combined with X-linked Charcot-Marie-Tooth neuropathy. Muscle Nerve 2000, 23:818-823. 12) Schreiber O, Schneiderat P, Kress W, Rautenstrauss B, Senderek J, Schoser B et al. Facioscapulohumeral muscular dystrophy and Charcot-Marie-Tooth neuropathy 1A – evidence for “double-trouble” overlapping syndromes. BMC Medical Genetics 2013;14(1):92. 13) Hodapp JA, Carter GT, Lipe HP, Michelson SJ, Kraft GH, Bird TD. Double trouble in hereditary neuropathy: concomitant mutations in the PMP-22 gene and another gene produce novel phenotypes. Arch Neurol. 2006; 63(1):112-7.

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Figure legend Fig. 1 a) Electrophysiologic findings in propositus recorded from left tibialis anterior muscle. Needle examination at rest shows myotonic discharges (time base was set to 100 ms/division). b) Chromatogram of the sequences flanking the c.180+3A>T mutation in intron 1 and the c.1970T>C mutation in exon 17 (red bullets), identified in the patient (upper panel) and in the control (lower panels). The W indicates a heterozygous variation from an adenine (A) to a thymine (T); the Y indicates a heterozygous variation from a thymine (T) to a cytosine (C). c) Family pedigree. Cross-hatched/black symbol: individual affected with CMT1A and Becker Myotonia; vertical lines/white symbol: carrier of Becker myotonia; horizontal lines / black symbol: carrier of Becker myotonia and CMT1A.

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190x254mm (96 x 96 DPI)

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Double-trouble in pediatric neurology: myotonia congenita combined with charcot-marie-tooth disease type 1a.

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