Interstitial 16p13.3 microduplication: Case report and critical review of genotype–phenotype correlation

We report on a patient with a recognizable phenotype of intellectual disability, multiple congenital anomalies, musculoskeletal anomalies and craniofacial dysmorphisms, carrying a de novo 0.4 Mb duplication of chromosome region 16p13.3 detected by SNP-array analysis. In addition, myopia, microcephaly and growth retardation were observed. The causal 16p13.3 duplication is one of the smallest reported so far, and includes the CREB binding protein gene (CREBBP, MIM 600140), whose haploinsufficiency is responsible for the Rubinstein–Taybi syndrome, and the adenylate cyclase 9 gene (ADCY9, MIM 603302). By comparing the clinical manifestations of our patient with those of patients carrying similar rearrangements, we confirmed that 16p13.3 microduplications of the Rubinstein–Taybi region result in a recognizable clinical condition that likely represents a single gene disorder. In addition, our case allowed us to define with more precision the smallest region of overlap (SRO) in all patients reported so far, encompassing only the CREBBP gene, and is useful to confirm and further define the phenotypic characteristics due to duplication of the CREBBP gene, being the first case of interstitial duplication with microcephaly and growth defects reported to date.     

Kv1.1 knock-in ataxic mice exhibit spontaneous myokymic activity exacerbated by fatigue, ischemia and low temperature

Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder characterized by myokymia and attacks of ataxic gait often precipitated by stress. Several genetic mutations have been identified in the Shaker-like K(+) channel Kv1.1 (KCNA1) of EA1 individuals, including V408A, which result in remarkable channel dysfunction. By inserting the heterozygous V408A, mutation in one Kv1.1 allele, a mouse model of EA1 has been generated (Kv1.1(V408A/+)). Here, we investigated the neuromuscular transmission of Kv1.1(V408A/+) ataxic mice and their susceptibility to physiologically relevant stressors. By using in vivo preparations of lateral gastrocnemius (LG) nerve-muscle from Kv1.1(+/+) and Kv1.1(V408A/+) mice, we show that the mutant animals exhibit spontaneous myokymic discharges consisting of repeated singlets, duplets or multiplets, despite motor nerve axotomy. Two-photon laser scanning microscopy from the motor nerve, ex vivo, revealed spontaneous Ca(2+) signals that occurred abnormally only in preparations dissected from Kv1.1(V408A/+) mice. Spontaneous bursting activity, as well as that evoked by sciatic nerve stimulation, was exacerbated by muscle fatigue, ischemia and low temperatures. These stressors also increased the amplitude of compound muscle action potential. Such abnormal neuromuscular transmission did not alter fiber type composition, neuromuscular junction and vascularization of LG muscle, analyzed by light and electron microscopy. Taken together these findings provide direct evidence that identifies the motor nerve as an important generator of myokymic activity, that dysfunction of Kv1.1 channels alters Ca(2+) homeostasis in motor axons, and also strongly suggest that muscle fatigue contributes more than PNS fatigue to exacerbate the myokymia/neuromyotonia phenotype. More broadly, this study points out that juxtaparanodal K(+) channels composed of Kv1.1 subunits exert an important role in dampening the excitability of motor nerve axons during fatigue or ischemic insult.     

The Contemporary Use of Radium-223 in Metastatic Castration-resistant Prostate Cancer

Radium-223 dichloride (radium-223) was approved for the treatment of patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases in the United States and Europe in 2013. This followed a reported overall survival benefit for patients treated with radium-223 and best standard of care (BSoC) when compared with placebo and BSoC in the ALpharadin in SYMptomatic Prostate CAncer (ALSYMPCA) trial. At that time, docetaxel was the standard first-line choice for patients with metastatic CRPC (mCRPC). Since then, the treatment landscape has changed dramatically with new hormonal agents (abiraterone and enzalutamide) considered to be the first-line choice for many patients. The optimal patient profile for radium-223 in the modern setting, and its best use either in sequence or in combination with other approved agents are unclear, with few definitive guidelines available. This article reports on the views of a group of urologists and medical oncologists experienced in treating patients with mCRPC with radium-223 in routine clinical practice. The aim is to provide an overview of the current use of radium-223 in the treatment of patients with mCRPC, and to discuss best practices for patient selection and on-treatment monitoring. Where agreement was reached, guidance on the optimal use of radium-223 is provided.     

Testosterone Levels and Prostate Cancer Prognosis: Systematic Review and Meta-analysis

Androgen receptor is the major driver of and testosterone the natural growth factor of prostate cancer (PC). Studies exploring the relationship among circulating testosterone levels, PC aggressiveness, and patient prognosis showed contradictory results. We performed a comprehensive literature search for studies reporting the independent relationship between serum testosterone and prognosis of PC patients. Meta-analyses using random effects models were conducted to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs). We identified 25 articles that evaluated the prognostic value of testosterone in early-stage PC (8 studies), in advanced PC either before (4 studies) or during androgen deprivation therapy (ADT) (5 studies), and in castration-resistant PC (8 studies). In early PC, serum testosterone level was not prognostic in terms of overall survival (HR = 1.03; 95% CI, 0.99-1.08; P = .19) and biochemical recurrence (HR = 0.99; 95% CI, 0.87-1.13; P = .93). In advanced PC, higher testosterone levels before ADT were associated with a reduced risk of death (HR = 0.58; 95% CI, 0.45-0.74; P < .0001). During ADT, lower levels were associated with a reduced risk of death (HR = 0.48; 95% CI, 0.28-0.81; P = .006) and progression (HR = 0.59; 95% CI, 0.46-0.77; P < .0001). In castration-resistant PC patients, higher testosterone levels predicted a reduced risk of progression (HR = 0.33; 95% CI, 0.11-0.97; P = .04) but not of death (HR = 0.86; 95% CI, 0.69-1.07; P = .18). The heterogeneity of the included studies is a major limitation of this meta-analysis. The relationship between circulating testosterone and PC prognosis varies in different clinical settings and according to ADT administration.