Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Determinants of persistence and tolerance of carnivores on Namibian ranches: implications for conservation on Southern African private lands.

Changing land use patterns in southern Africa have potential to dramatically alter the prospects for carnivore conservation. Understanding these influences is essential for conservation planning. We interviewed 250 ranchers in Namibia to assess human tolerance towards and the distribution of large carnivores. Cheetahs (Acinonyx jubatus), leopards (Panthera pardus) and brown hyaenas (Hyaena brunnea) were widely distributed on Namibian farmlands, spotted hyaenas (Crocuta crocuta) had a narrower distribution, and wild dogs (Lycaon pictus) and lions (Panthera leo) are largely limited to areas near source populations. Farmers were most tolerant of leopards and least tolerant of lions, wild dogs and spotted hyaenas. Several factors relating to land use correlated consistently with carnivore-presence and landowner tolerance. Carnivores were more commonly present and/or tolerated where; wildlife diversity and biomass were higher; income from wildlife was higher; income from livestock was lower; livestock biomass was lower; in conservancies; game fencing was absent; and financial losses from livestock depredation were lower. Efforts to create conditions whereby the costs associated with carnivores are lowest, and which confer financial value to them are likely to be the most effective means of promoting carnivore conservation. Such conditions are achieved where land owners pool land to create conservancies where livestock are replaced with wildlife (or where livestock husbandry is improved) and where wildlife generates a significant proportion of ranch income. Additional measures, such as promoting improved livestock husbandry and educational outreach efforts may also help achieve coexistence with carnivores. Our findings provide insights into conditions more conducive to the persistence of and tolerance towards large carnivores might be increased on private (and even communal) lands in Namibia, elsewhere in southern and East Africa and other parts of the world where carnivore conservation is being attempted on private lands

Distribution of brown hyaenas on Namibian commercial farms.

<p>Distribution of brown hyaenas on Namibian commercial farms.</p

Correlates of whether Namibian farmers wished to have various species of carnivores on their land (means ± SD) (bold/underlined values are those that were statistically significant (p≤0.05) following a multiple logistic regression.

<p>• Based on low sample sizes (n = 10 respondents provided estimates of livestock losses to lions).</p

Distribution of spotted hyaenas on commercial farms in Namibia.

<p>Distribution of spotted hyaenas on commercial farms in Namibia.</p

Distribution of cheetahs on commercial farmlands in Namibia.

<p>Distribution of cheetahs on commercial farmlands in Namibia.</p

Correlates of the presence/absence of large carnivores on Namibian farmlands (means ± SD) (bold/underlined values are those that were statistically significant (p≤0.05) following a multiple logistic regression.

a<p>Categorized as: <200 ml/year; 200–300 ml/year; 301–400 ml/year; >400 ml/year.</p>b<p>Comprising 11 vegetation categories.</p

Distribution of leopards on commercial farms in Namibia.

<p>Distribution of leopards on commercial farms in Namibia.</p

Percentage occurrence of large carnivore species on Namibian commerical farms and the percentage of farmers who wish to have those species on their properties.

<p>Percentage occurrence of large carnivore species on Namibian commerical farms and the percentage of farmers who wish to have those species on their properties.</p

Distribution of lions on commercial farms in Namibia.

<p>Distribution of lions on commercial farms in Namibia.</p