Next-generation sequencing approach to hyperCKemia

Abstract

ObjectiveNext-generation sequencing (NGS) was applied in molecularly undiagnosed asymptomatic or paucisymptomatic hyperCKemia to investigate whether this technique might allow detection of the genetic basis of the condition.MethodsSixty-six patients with undiagnosed asymptomatic or paucisymptomatic hyperCKemia, referred to tertiary neuromuscular centers over an approximately 2-year period, were analyzed using a customized, targeted sequencing panel able to investigate the coding exons and flanking intronic regions of 78 genes associated with limb-girdle muscular dystrophies, rhabdomyolysis, and metabolic and distal myopathies.ResultsA molecular diagnosis was reached in 33 cases, corresponding to a positive diagnostic yield of 50%. Variants of unknown significance were found in 17 patients (26%), whereas 16 cases (24%) remained molecularly undefined. The major features of the diagnosed cases were mild proximal muscle weakness (found in 27%) and myalgia (in 24%). Fourteen patients with a molecular diagnosis and mild myopathic features on muscle biopsy remained asymptomatic at a 24-month follow-up.ConclusionsThis study of patients with undiagnosed hyperCKemia, highlighting the advantages of NGS used as a first-tier diagnostic approach in genetically heterogeneous conditions, illustrates the ongoing evolution of molecular diagnosis in the field of clinical neurology. Isolated hyperCKemia can be the sole feature alerting to a progressive muscular disorder requiring careful surveillance.

Novel CAPN3 variant associated with an autosomal dominant calpainopathy

“…In addition, we describe exertional rhabdomyolysis in two siblings (3/III.1 and 3/III.2 in Figure 1). Although this clinical presentation has to be confirmed for other reported cases before considering it a definite feature of calpainopathies, such a presentation has already been described for other genes associated with LGMD, such as CAV3 , GMPPB and more recently SGCA and TCAP [34‐36]. Thus, autosomal dominant inherited calpainopathy should be considered when faced by a wide range of initial phenotypic presentations from hyperCKaemia (asymptomatic or not), myalgia with or without exertional rhabdomyolysis to mild LGMD.…”

Guidelines for genetic testing of muscle and neuromuscular junction disorders

“…[102][103][104] In addition to those with overt clinical, electrodiagnostic (EDx), or histological evidence of a myopathy, genetic testing can also be considered in certain patients with asymptomatic CK elevations. 105,106 Even in these asymptomatic patients, genetic testing can alter management, for example, by detecting dystrophinopathy carrier status or RYR1 mutations predisposing to malignant hyperthermia. 105,106 Genetic testing previously centered around serial sequencing of single genes, with the testing sequence guided by patients' phenotypes, histological findings and suspected mode of inheritance.…”

Dal fegato al muscolo: una rara malattia a esordio tardivo

“…Il percorso nel paziente pediatrico, in caso di valori moderati-alti e persistenti di CPK (>1000 U/L), prosegue in genere con l'analisi enzimatica e molecolare (esistono pannelli disponibili) e, meno frequentemente rispetto all'adulto, con l'elettromiografia e la biopsia muscolare. Lo spettro delle miopatie è tuttavia molto ampio e non ancora pienamente conosciuto, rendendo pertanto necessario nella maggior parte dei casi l'invio del bambino a un centro di riferimento per patologie neuromuscolari [1,3]. Tra le cause di miopatia metabolica, la malattia di Pompe è una patologia rara (incidenza della forma adulta di 1:60.000 nella popolazione europea), ma probabilmente sottostimata.…”