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Sarcolemmal voltage-gated sodium and calcium ion channels are essential for generating action potentials and excitation contraction coupling required for muscle contraction. Autosomal dominant sodium and calcium ion channel gene disorders cause episodic symptoms of periodic paralysis (PP) and myotonia.1 Acetazolamide treatment improves these symptoms.2 Recently, recessive congenital myopathies due to compound heterozygous or homozygous ion channel gene mutations have been described with fixed muscle weakness and disability.3 4
In case series we previously reported, two individuals with ion channel-related congenital myopathy had additional discrete episodic or fluctuant weakness causing added morbidity.3 4 Here, we delineate the long-term benefit of treatment with acetazolamide for these individuals and discuss the implications for genetic diagnosis and management of future cases.
A 16-year-old girl with compound heterozygous SCN4A gene mutations (figure 1B).3 Reduced fetal movements were noted during pregnancy with a breech presentation at birth. Features of congenital myopathy included neonatal hypotonia, weak cry, talipes, thin muscle build and weak suck requiring nasogastric tube feeding for 12 days. With maturity, significant proximal and axial weakness occurred with difficulties running, going upstairs, rising from the floor and walking long distances. Due to respiratory insufficiency, she required nocturnal BiLevel Positive Airway Pressure (BiPAP) from age 6. Progressive scoliosis required surgical fixation at age 12.
From age 12, she reported new episodic symptoms. The most severe occurred during a viral illness when she had profound leg weakness and was unable to walk without assistance for 2 days. Subsequently, she reported daily (up to 10 min) episodes of leg weakness after exercise or prolonged sitting and diurnal episodes of fatigue after school.
Genetic diagnosis was made at age 14. On the basis that one of her SCN4A mutations, R1135C, had been previously described in periodic paralysis5 and that she reported discrete episodic exacerbations in limb strength, she was started on acetazolamide 125 mg twice daily at age 15, increased incrementally to 250 mg twice daily. Subjectively, she reported a reduction in episodic weakness and fatigue. Objectively, her functional scores, timed function test and respiratory function improved between approximately 20% and 30% (figure 1A).
A 10-year-old boy with compound heterozygous CACNA1S mutations (figure 1C).4 Reduced fetal movements were noted during pregnancy. At birth, neonatal hypotonia with hip, knee and ankle contractures was observed. He had bulbar and facial weakness, ophthalmoplegia, ptosis and high arched palate. He required nocturnal BiPAP from age 7. He has never been able to walk but can sit independently. From age 5, his parents reported periodic episodes lasting up to an hour where he loses head control and develops slurred speech communicating using gestures. These were triggered by rest, hot weather, fasting and illness. They occurred at least three times a week often in the morning and he frequently missed school. They were also prominent at night, waking him from sleep feeling weak and dribbling saliva. This resulted in marked fluctuation in his swallow causing recurrent aspiration and lung collapses requiring frequent prolonged hospitalisation and escalation of pressures for non-invasive ventilation.
One of his CACNA1S gene mutations E100K was predicted to share biophysical properties with other periodic paralysis mutations. Due to this and the reported episodic symptoms, he was started on acetazolamide 125 mg twice daily, increased to 250 mg twice daily. Periodic symptoms resolved completely and he consistently attended school. Respiratory and bulbar function improved such that he no longer aspirated or required hospitalisation and ventilator pressures were weaned.
Periodic paralysis causes episodes of profound muscle weakness or paralysis due to prolonged muscle membrane depolarisation. PP gene mutations of the skeletal muscle voltage-gated sodium or calcium channels share a common pathomechanism of disrupting bonds between positively charged amino acid residues in the channel voltage sensor (S4) and negative charges in the interacting S1 to S3 segments (figure 1D) to introduce an anomalous inward ionic leak current across the sarcolemma.1
Acetazolamide is used to treat periodic paralysis. We have observed it to also have benefit in congenital myopathy for children with compound heterozygous mutations in ion channel genes where one of their mutations is identified as sharing biophysical features with a PP mutation (figure 1D).
Congenital myopathies are a heterogeneous group of disorders and ion channel-related congenital myopathy is only relatively recently recognised. Disability in congenital myopathy is usually regarded as fixed with supportive treatment being the only available intervention. Genetic testing can be prolonged due to the number of possible genetic diagnoses, and in some countries cost can be prohibitive. Our cases demonstrate, however, that there is a reversible component to some ion channel-related congenital myopathy and genotype may predict this. This has important implications for children presenting with congenital myopathy. We propose it is essential to pursue a genetic diagnosis and those with an ion channel gene mutation predicted to act in a biophysical fashion similar to PP mutations and who have episodic or fluctuant symptoms warrant a trial of acetazolamide.
The support of the MRC Neuromuscular Centre and of the Muscular Dystrophy UK to FM is gratefully acknowledged.
Contributors EM: drafting the manuscript for content, analysis or interpretation of data, study concept. LH: revising the manuscript for content, analysis or interpretation of data, study concept. RS: revising the manuscript for content, analysis or interpretation of data. MGH: revising the manuscript for content, analysis or interpretation of data. FM: revising the manuscript for content, analysis or interpretation of data, study concept. PM: revising the manuscript for content, analysis or interpretation of data, study concept.
Funding EM has received funding from an NIHR rare disease TRC postdoctoral fellowship, which is supported via the UCLH NIHR BRC. Part of this work was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme. MGH is supported by a Medical Research Council Centre grant, the UCLH NIHR BRC and receives research funding from the Muscular Dystrophy Campaign. FM is supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London.
Competing interests None declared.
Patient consent Next of kin consent obtained.
Ethics approval The London—West London and GTAC Research Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement This is a letter describing two clinical cases. All data are reported in the letter.
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