No abstract

Myoclonus is a hyperkinetic movement disorder characterized by brief, involuntary muscular jerks. Recognition of myoclonus and determination of the underlying aetiology remains challenging given that both acquired and genetically determined disorders have varied manifestations. The diagnostic work-up in myoclonus is often time-consuming and costly, and a definitive diagnosis is reached in only a minority of patients. On the basis of a systematic literature review up to June 2015, we propose a novel diagnostic eight-step algorithm to help clinicians accurately, efficiently and cost-effectively diagnose myoclonus. The large number of genes implicated in myoclonus and the wide clinical variation of these genetic disorders emphasize the need for novel diagnostic techniques. Therefore, and for the first time, we incorporate next-generation sequencing (NGS) in a diagnostic algorithm for myoclonus. The initial step of the algorithm is to confirm whether the movement disorder phenotype is consistent with, myoclonus, and to define its anatomical subtype. The next steps are aimed at identification of both treatable acquired causes and those genetic causes of myoclonus that require a diagnostic approach other than NGS. Finally, other genetic diseases that could cause myoclonus can be investigated simultaneously by NGS techniques. To facilitate NGS diagnostics, we provide a comprehensive list of genes associated with myoclonus.

Van Buchem disease (VBD) is a rare bone sclerosing dysplasia caused by the lack of a regulatory element of the SOST gene, which encodes for sclerostin, an osteocyte-derived negative regulator of bone formation. We studied the demographic, clinical, biochemical, and densitometric features of 15 patients with VBD (12 adults and 3 children) and 28 related carriers of the gene mutation. The most common clinical findings in patients were facial palsy (100%) and various degrees of hearing impairment (93%); raised intracranial pressure had been documented in 20%. The clinical course of the disease appeared to stabilize in adulthood, with the majority of patients reporting no progression of symptoms or development of complications with time. Carriers of the disease had none of the clinical features or complications of the disease. Sclerostin could be detected in the serum in all but 1 VBD patients (mean 8.0 pg/mL; 95% confidence interval [CI], 4.9-11.0 pg/mL), and were lower than those of carriers (mean 28.7 pg/mL; 95% CI, 24.5-32.9 pg/mL; p < 0.001) and healthy controls (mean 40.0 pg/mL; 95% CI, 34.5-41.0 pg/mL; p < 0.). Serum procollagen type 1 amino-terminal propeptide (P1NP) levels were also significantly higher in adult patients (mean 96.0; 95% CI, 54.6-137.4 ng/mL versus mean 47.8; 95% CI, 39.4-56.2 ng/mL, p ¼ 0.003 in carriers and mean 37.8; 95% CI, 34.5-41.0 ng/mL, p ¼ 0.028 in healthy controls) and declined with age. Bone mineral density (BMD) was markedly increased in all patients (mean Z-score 8.7 AE 2.1 and 9.5 AE 1.9 at the femoral neck and spine, respectively); BMD of carriers was significantly lower than that of patients but varied widely (mean Z-scores 0.9 AE 1.0 and 1.3 AE 1.5 at the femoral neck and spine, respectively). Serum sclerostin levels were inversely correlated with serum P1NP levels (r ¼ -0.39, p ¼ 0.018) and BMD values (femoral neck r ¼ -0.69, p < 0.001; lumbar spine r ¼ -0.78, p < 0.001). Our results show that there is a gene-dose effect of the VBD deletion on circulating sclerostin and provide further in vivo evidence of the role of sclerostin in bone formation in humans. The small amounts of sclerostin produced by patients with VBD may explain their milder phenotype compared to that of patients with sclerosteosis, in whom serum sclerostin is undetectable. ß