A genetic basis is identified in 74% cases of paediatric hyperCKaemia without weakness presenting to a tertiary paediatric neuromuscular centre |
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| Affiliation: | 1. Kids Neuroscience Centre, The Children''s Hospital at Westmead, Sydney, New South Wales, Australia;2. Discipline of Child and Adolescent Health, University of Sydney, Sydney, New South Wales, Australia;3. Department of Paediatric Neurology, Children''s Hospital at Westmead, Sydney, New South Wales, Australia;4. Department of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Perth, Western Australia, Australia;5. Department of Neurology, Royal North Shore Hospital, Sydney, New South Wales, Australia;6. Children''s Medical Research Institute, 214 Hawkesbury Road, Westmead, NSW2145, Australia;7. Department of Clinical Genetics, Children''s Hospital at Westmead, Sydney, New South Wales, Australia;1. Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8551, Japan;2. Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8551, Japan;3. Department of Clinical Genome Analysis, Medical Genome Center, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8551, Japan;4. National Center of Neurology and Psychiatry, N, National Center Hospital, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8551, Japan;1. 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece;2. Laboratory of Molecular Neurobiology and Immunology, Hellenic Pasteur Institute, Athens, Greece;3. Department of Biology, National and Kapodistrian University of Athens, Athens, Greece;4. Diagnostic Department, Hellenic Pasteur Institute, Athens, Greece;1. Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan;2. Medical Genome Center, NCNP, Kodaira, Tokyo, Japan;3. Department of Pediatrics, Showa General Hospital, Kodaira, Tokyo, Japan;4. Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan;1. APHP, Service de Radiologie GH Université Paris-Saclay DMU Smart Imaging, Hôpital Raymond Poincaré, 104 boulevard Raymond Poincaré, Garches 94400, France;2. AP-HP, Service de Neurologie, GH Université Paris-Saclay, DMU Neuro-Handicap, Hôpital Raymond-Poincaré, Garches, France;3. Centre de référence des maladies neuromusculaires Nord/Est/Ile de France, France;4. AP-HP, Hôpital Pitié-Salpêtrière, Paris 75013, France;5. APHP, Laboratoire de Génétique Moléculaire, Université Paris Saclay, Hôpital Antoine Béclère, Clamart 92140, France;6. Neurosciences Department (DNS), University of Padova, Padova, Italy;7. AIM & CEA NMR Laboratory, Institute of Myology, Pitié-Salpêtrière University Hospital, Paris, France;8. UMR 1179, Université Versailles Saint Quentin en Yvelines, Paris Saclay, France;1. University Clinical Center of Serbia, Neurology Clinic, Dr Subotic Street 6, 11000 Belgrade, Serbia;2. University of Belgrade, Faculty of Medicine, Dr Subotic Street 8, 11000 Belgrade, Serbia;3. University of Belgrade, Faculty of Biology, Studentski trg 16, Belgrade, Serbia;4. University Clinical Center of Serbia, Cardiology Clinic, Pasterova 2, 11000 Belgrade, Serbia;5. Department of Neurorehabilitation Sciences, Casa Di Cura del Policlinico, Department of Biomedical Sciences for Health, University of Milan, Via Dezza 48, 20144 Milan, Italy |
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| Abstract: | Paediatric hyperCKaemia without weakness presents a clinical conundrum. Invasive investigations with low diagnostic yields, including muscle biopsy, may be considered unjustifiable. Improved access to genome-wide genetic testing has shifted first-line investigations towards genetic studies in neuromuscular disease. This research aims to provide an evidence-based diagnostic approach to paediatric hyperCKaemia without weakness, a current gap in the literature. We identified 47 individuals (10-months to 16-years-old; 34 males, 13 females) from 43 families presenting with hyperCKaemia on two or more occasions, without weakness, from The Children's Hospital at Westmead Neuromuscular Clinic Database. Clinical features, investigations and outcomes were analysed via retrospective chart review. Genetic testing has been performed in 34/43. Genetic variants explaining hyperCKaemia were identified in 25/34 (74%) using multiplex ligation-dependent probe amplification, massive parallel sequencing, single gene testing and exome sequencing. Pathogenic/likely pathogenic variants were identified in 19 neuromuscular disease genes and six metabolic myopathy genes. Individuals with metabolic diagnoses had higher peak creatine kinase levels that sometimes normalized. Conversely, creatine kinase levels remained persistently elevated those with neuromuscular diagnoses. In summary, a genetic cause is found in most paediatric patients with hyperCKaemia without weakness informing clinical management and counselling. Thus, we propose a diagnostic algorithm for this cohort. |
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