Congenital myopathies are a group of inherited muscle disorders characterized by hypotonia, weakness and a non-dystrophic muscle biopsy with the presence of one or more characteristic histological features. Neuromuscular transmission defects have recently been reported in several patients with congenital myopathies (CM). Mutations in KLHL40 are among the most common causes of severe forms of nemaline myopathy. Clinical features of affected individuals include fetal akinesia or hypokinesia, respiratory failure, and swallowing difficulties at birth. Muscle weakness is usually severe and nearly half of the individuals have no spontaneous antigravity movement. The average age of death has been reported to be 5 months in a recent case series. Herein we present a case of a patient with a nemaline myopathy due to KLHL40 mutations (c.604delG, p.Ala202Argfs*56 and c.1513G>C, p.Ala505Pro) with an impressive and prolonged beneficial response to treatment with high-dose pyridostigmine. Myasthenic features or response to ACEI have not previously been reported as a characteristic of nemaline myopathy or KLHL40-related myopathy.
This is a preview of subscription content, log in to check access.
The authors would like to thank the family for taking part in this study.
The Institute of Genetic Medicine in Newcastle is part of the MRC Centre for Neuromuscular Diseases and the TREAT-NMD Alliance (http://www.treat-nmd.eu). This study was supported by the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 305444 (RD-Connect) and 305121 (Neuromics).
We are indebted to the ‘Biobanc de l’Hospital Infantil Sant Joan de Deu per a la Investigacio’, integrated in the Spanish Biobank network of ISCIII, for sample procurement.
Maggi L, Scoto M, Cirak S et al (2013) Congenital myopathies-clinical features and frequency of individual subtypes diagnosed over a 5-year period in the United Kingdom. Neuromuscul Disord 23:195–205CrossRefPubMedGoogle Scholar
Robb SA, Sewry CA, Dowling JJ et al (2011) Impaired neuromuscular transmission and response to acetylcholinesterase inhibitors in centronuclear myopathies. Neuromuscul Disord 21:379–386CrossRefPubMedGoogle Scholar
Rodríguez Cruz PM, Sewry C, Beeson D et al (2014) Congenital myopathies with secondary neuromuscular transmission defects; A case report and review of the literature. Neuromuscul Disord 24(12):1103–1110CrossRefPubMedGoogle Scholar
Claeys KG, Maisonobe T, Böhm J et al (2010) Phenotype of a patient with recessive centronuclear myopathy and a novel BIN1 mutation. Neurology 74:519–521CrossRefPubMedGoogle Scholar
Gibbs EM, Clarke NF, Rose K et al (2013) Neuromuscular junction abnormalities in DNM2-related centronuclear myopathy. J Mol Med (Berl) 91:727–737CrossRefGoogle Scholar
Munot P, Lashley D, Jungbluth H et al (2010) Congenital fibre type disproportion associated with mutations in the tropomyosin 3 (TPM3) gene mimicking congenital myasthenia. Neuromuscul Disord 20:796–800CrossRefPubMedGoogle Scholar
Illingworth M, Main M, Pitt M et al (2014) RYR1-related congenital myopathy with fatigable weakness, responding to pyridostigmine. Neuromuscul Disord 24(8):707–712CrossRefPubMedGoogle Scholar
Schara U, Barisic N, Deschauer M et al (2009) Ephedrine therapy in eight patients with congenital myasthenic syndrome due to DOK7 mutations. Neuromuscul Disord 19(12):828–832CrossRefPubMedGoogle Scholar
Klein A, Pitt MC, McHugh JC et al (2013) DOK7 congenital myasthenic syndrome in childhood: early diagnostic clues in 23 children. Neuromuscul Disord 23(11):883–891CrossRefPubMedGoogle Scholar
Ben Ammar A, Petit F, Alexandri N et al (2010) Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7. J Neurol 257:754–766CrossRefPubMedGoogle Scholar
Cossins J, Liu WW, Belaya K et al (2012) The spectrum of mutations that underlie the neuromuscular junction synaptopathy in DOK7 congenital myasthenic syndrome. Hum Mol Genet 21(17):3765–3775CrossRefPubMedGoogle Scholar
Ravenscroft G, Miyatake S, Lehtokari VL et al (2013) Mutationsin KLHL40 are a frequent cause of severe autosomal recessive nemaline myopathy. Am J Hum Genet 93:6–18CrossRefPubMedPubMedCentralGoogle Scholar
Kawase K, Nishino I, Sugimoto M et al (2015) Nemaline myopathy with KLHL40 mutation presenting as congenital totally locked-in state. Brain Dev 37(9):887–890CrossRefPubMedGoogle Scholar