NeuroDevNet: Training the next generation of Canadian developmental neurobiologists

Enhancing Canadian capacity in the research and treatment for neurodevelopmental disorders is central to NeuroDevNet's mission. Building on the notion that it takes a network of scientists, clinicians, and educators to train the next generation researchers, NeuroDevNet brings together the diversity of expertise from across Canada to provide multifaceted, cross-disciplinary training opportunities for our trainees. Our Program provides for a diverse training experience that fosters the development of active young researchers with a collaborative focus and an eye toward the bidirectional translation of knowledge between the bench and the bedside. With funding from the NCE of Canada, as well as public and private partnerships, we offer fellowship and internship opportunities to trainees that encourage collaborative interactions, interdisciplinary exchanges and knowledge translation. This program will enhance the development and integration of NeuroDevNet as well as the Canadian community caring for the health and wellbeing of its citizens with neurodevelopmental disorders.     

Training the next generation of child neurologists: a child health-based approach

In the United States, child neurologists continue to value close, historical ties to adult neurology. However, the mandatory year of adult training for American Board of Psychiatry and Neurology certification in "Neurology with Special Qualification in Child Neurology" deprives residents of educational opportunities that would yield greater benefit for children afflicted with neurologic diseases. The need for modernization has been recognized in a Professors of Child Neurology survey in which a majority of program directors favored reducing adult neurology training and changing the certification to "Child Neurology." This article reviews the rationale for an overdue transformation of Child Neurology training.     

Dopamine agonist-induced substance addiction: The next piece of the puzzle

Traditional antiparkinson treatment strategies strive to balance the antiparkinson effects of dopaminergic drugs with the avoidance of motor response complications. Dopamine agonists have an established role in delaying the emergence of motor response complications or reducing motor “off” periods. The recent recognition of a range of “behavioural addictions” that are linked to dopamine agonist use has highlighted the role of dopamine in brain reward function and addiction disorders in general. Dopamine agonists have now even been linked occasionally to new substance addictions. The challenge now for the Parkinsonologist is to also balance the net benefits of using dopamine agonists for their motor effects with avoiding the harm from behavioural compulsions.     

The next generation of cholinesterase inhibitors

Clinical trials with tacrine (THA) have resulted in elevations of liver enzymes in Alzheimer patients that showed improvement. In an effort to minimize these side effects several THA analogues were synthesized. These analogues were compared to THA in biochemical as well as behavioural studies. The biochemical effects of these drugs on plasma cholinesterase activity and cholinergic receptors as well as the effect of these drugs on spatial learning in adult rats were examined. It is possible that some of these analogues with more potent cholinergic effect than THA might be the next generation of cholinesterase inhibitors which can be useful in the treatment of Alzheimer's disease.     

Targeted next generation sequencing in SPAST-negative hereditary spastic paraplegia

Molecular characterization is important for an accurate diagnosis in hereditary spastic paraplegia (HSP). Mutations in the gene SPAST (SPG4) are the most common cause of autosomal dominant forms. We performed targeted next generation sequencing (NGS) in a SPAST-negative HSP sample. Forty-four consecutive HSP patients were recruited from an adult neurogenetics clinic in Sydney, Australia. SPAST mutations were confirmed in 17 subjects, and therefore 27 SPAST-negative patients were entered into this study. Patients were screened according to mode of inheritance using a PCR-based library and NGS (Roche Junior 454 sequencing platform). The screening panel included ten autosomal dominant (AD) and nine autosomal recessive (AR) HSP-causing genes. A genetic cause for HSP was identified in 25.9 % (7/27) of patients, including 1/12 classified as AD and 6/15 as AR or sporadic inheritance. Several forms of HSP were identified, including one patient with SPG31, four with SPG7 (with one novel SPG7 mutation) and two with SPG5 (including two novel CYP7B1 frameshift mutations). Additional clinical features were noted, including optic atrophy and ataxia for patients with SPG5 and ataxia and a chronic progressive external ophthalmoplegia-like phenotype for SPG7. This protocol enabled the identification of a genetic cause in approximately 25 % of patients in whom one of the most common genetic forms of HSP (SPG4) was excluded. Targeted NGS may be a useful method to screen for mutations in multiple genes associated with HSP. More studies are warranted to determine the optimal approach to achieve a genetic diagnosis in this condition.     

Targeted next generation sequencing: the diagnostic value in early-onset epileptic encephalopathy

We investigated the genetic background of early-onset epileptic encephalopathy (EE) using targeted next generation sequencing analysis. Thirty sporadic or familial cases associated with early-onset EE were included. An early-onset EE gene panel including sixteen genes (ARX, CDKL5, CNTNAP2, FOLR1, FOXG1, LAMC3, MBD5, MECP2, NTNG1, PCDH19, PNKP, SCN1A, SCN1B, SCN2A, STXBP1, KCNQ2) was constituted. Nine definite and three potential causal mutations in 30 cases (40 %) were identified. All mutations presented heterozygously except one. Five mutations had been previously detected (SCN1A c.842C > T (p.P281L), SCN1A c.4907G > C (p.A1636P), PCDH19 c.1091dupC (p.Y366LfsX10), CNTNAP2 c.416A > G (p.N139S), MBD5 c.3595G > A(p.Y1199R) while other seven were novel (SCN1A c.4907G > C (p.A1636P), SCN2A c.4633A > G (p.M1545 V), CDKL5 c.197_198delCT (p.L67QfsX23), FOXG1 c.*6C > T, KCNQ2 c.560c > A (p.S187Y), KCNQ2 c.835G > A (p.G279S), STXBP1 c.1105G > T (p.E369X)). Eight of 12 mutations were de novo. While the overall mutation detection rate was found 40 %, this ratio was 55.5 % (10 out of 18) and 16.6 % (2 out of 12) in patients born to nonconsanguineous parents and consanguineous parents, respectively. In conclusion, a selected gene panel approach including mainly de novo and channel-encoding genes will result in the detection of variants in isolated patients and support the channelopathy theory underlying epilepsy, while consanguineous families will remain less diagnosed. Targeted next generation sequencing approach is an efficient diagnostic tool in the detection of the genetic basis of early-onset EE.