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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., Competing Interests: Declaration of Competing Interest STC is a director of Frontier Genomics Pty Ltd (Australia). STC receives no remuneration in this role. Frontier Genomics Pty Ltd (Australia) has no current financial relationships that will benefit from publication of these data. The remaining co-authors do not have any relationships, financial or otherwise, that may result in a perceived conflict of interest, (Copyright © 2022. Published by Elsevier B.V.)

Charcot-Marie-Tooth disease (CMT) causes disabling cavovarus foot deformity. Orthopaedic surgery is performed in severe cases; however few studies have investigated whether surgery improves health outcomes during childhood. This study investigated the impact of cavovarus surgery on validated physical, functional, parent/self-reported and biomechanical measures in 21 consecutive patients (mean age at surgery 12.5 years, SD 2.7) evaluated before and after surgery (mean duration 15.7 months, SD 5.9), and compared to natural history data from 206 children with CMT. Measures from the CMT Pediatric Scale evaluated foot alignment (Foot Posture Index), ankle flexibility (lunge test), strength (foot dorsiflexion/plantarflexion by hand-held dynamometry), function (balance, long jump, 6-minute walk test) and self-reported symptoms. Quality of life (Child Health Questionnaire) and gait (pressure loading) were also assessed. Foot Posture Index and lunge improved with surgery by 6.0 points (SD 3.2) and 6.1° (SD 7.3) respectively (p< 0.01), and differed to the natural course of the disease (p< 0.005). Self-reported daily trips/falls reduced from 60% to 13% (p = 0.016). Pressure improved beneath the rearfoot and midfoot (p = 0.043). Surgery had no effect on strength, function or quality of life, which generally mirrored the natural course. Cavovarus surgery improved foot alignment, ankle flexibility and self-reported trips/falls in children with CMT., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Clinical phenotypes of congenital myasthenic syndromes and primary mitochondrial disorders share significant overlap in their clinical presentations, leading to challenges in making the correct diagnosis. Next generation sequencing is transforming molecular diagnosis of inherited neuromuscular disorders by identifying novel disease genes and by identifying previously known genes in undiagnosed patients. This is evident in two patients who were initially suspected to have a mitochondrial myopathy, but in whom a clear diagnosis of congenital myasthenic syndromes was made through whole exome sequencing. In patient 1, whole exome sequencing revealed compound heterozygous mutations c.1228C > T (p.Arg410Trp) and c.679C > T (p.Arg227*) in collagen-like tail subunit (single strand of homotrimer) of asymmetric acetylcholinesterase (COLQ). In patient 2, in whom a deletion of exon 52 in Dystrophin gene was previously detected by multiplex ligation-dependent probe amplification, Sanger sequencing revealed an additional homozygous mutation c.1511&#95;1513delCTT (p.Pro504Argfs*183) in docking protein7 (DOK7). These case reports highlight the need for careful diagnosis of clinically heterogeneous syndromes like congenital myasthenic syndromes, which are treatable, and for which delayed diagnosis is likely to have implications for patient health. The report also demonstrates that whole exome sequencing is an effective diagnostic tool in providing molecular diagnosis in patients with complex phenotypes., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Charcot-Marie-Tooth disease (CMT) is genetically heterogeneous and classification based on motor nerve conduction velocity and inheritance is used to direct genetic testing. With the less common genetic forms of CMT, identifying the causative genetic mutation by Sanger sequencing of individual genes can be time-consuming and costly. Next-generation sequencing technologies show promise for clinical testing in diseases where a similar phenotype is caused by different genes. We report the unusual occurrence of CMT4J, caused by mutations in FIG4, in a apparently dominant pedigree. The affected proband and her mother exhibit different disease severities associated with different combinations of compound heterozygous FIG4 mutations, identified by whole exome sequencing. The proband was also shown to carry a de novo nonsense mutation in the dystrophin gene, which may contribute to her more severe phenotype. This study is a cautionary reminder that in families with two generations affected, explanations other than dominant inheritance are possible, such as recessive inheritance due to three mutations segregating in the family. It also emphasises the advantages of next-generation sequencing approaches that screen multiple CMT genes at once for patients in whom the common genes have been excluded., (Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.)

Charcot-Marie-Tooth disease type 4J (CMT4J), a rare form of demyelinating CMT, caused by recessive mutations in the phosphoinositide phosphatase FIG4 gene, is characterised by progressive proximal and distal weakness and evidence of chronic denervation in both proximal and distal muscles. We describe a patient with a previous diagnosis of CMT1 who presented with a two year history of rapidly progressive weakness in a single limb, resembling an acquired inflammatory neuropathy. Nerve conduction studies showed an asymmetrical demyelinating neuropathy with conduction block and temporal dispersion. FIG4 sequencing identified a compound heterozygous I41T/K278YfsX5 genotype. CMT4J secondary to FIG4 mutations should be added to the list of inherited neuropathies that need to be considered in suspected cases of inflammatory demyelinating neuropathy, especially if there is a background history of a more slowly progressive neuropathy., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)