Lafora disease offers a unique window into neuronal glycogen metabolism

Lafora disease (LD) is a fatal, autosomal recessive, glycogen-storage disorder that manifests as severe epilepsy. LD results from mutations in the gene encoding either the glycogen phosphatase laforin or the E3 ubiquitin ligase malin. Individuals with LD develop cytoplasmic, aberrant glycogen inclusions in nearly all tissues that more closely resemble plant starch than human glycogen. This Minireview discusses the unique window into glycogen metabolism that LD research offers. It also highlights recent discoveries, including that glycogen contains covalently bound phosphate and that neurons synthesize glycogen and express both glycogen synthase and glycogen phosphorylase

Lafora Disease Is an Inherited Metabolic Cardiomyopathy

This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2015-65722-R to Dr. Lara-Pezzi and SAF2014-59594-R to Dr. Serratosa), Autonomous Community of Madrid (2010-BMD2321, FIBROTEAM Consortium), European Union's FP7 (CardioNeT-ITN-289600, CardioNext-ITN-608027), the Spanish Carlos III Institute of Health (CPII14/00027 to Dr. Lara-Pezzi, PI13/00865 to Dr. Sanchez and RD12/0042/066 to Drs. Garcia-Pavia and Lara-Pezzi), and the National Institute of Neurological Disorders And Stroke of the National Institutes of Health (P01NS097197 to Dr. Sanchez). This work was also supported by the Plan Estatal de I+D+I 2013-2016-European Regional Development Fund (FEDER) "A way of making Europe," Spain. The Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505).S

Childhood Absence Epilepsy with Tonic-Clonic Seizures and Electroencephalogram 3–4-Hz Spike and Multispike–Slow Wave Complexes: Linkage to Chromosome 8q24

SummaryChildhood absence epilepsy (CAE), a common form of idiopathic generalized epilepsy, accounts for 5%–15% of childhood epilepsies. To map the chromosomal locus of persisting CAE, we studied the clinical and electroencephalographic traits of 78 members of a five-generation family from Bombay, India. The model-free affected–pedigree member method was used during initial screening with chromosome 6p, 8q, and 1p microsatellites, and only individuals with absence seizures and/or electroencephalogram 3–4-Hz spike– and multispike–slow wave complexes were considered to be affected. Significant P values of .00000–.02 for several markers on 8q were obtained. Two-point linkage analysis, assuming autosomal dominant inheritance with 50% penetrance, yielded a maximum LOD score (Zmax) of 3.6 for D8S502. No other locus in the genome achieved a significant Zmax. For five smaller multiplex families, summed Zmax was 2.4 for D8S537 and 1.7 for D8S1761. Haplotypes composed of the same 8q24 microsatellites segregated with affected members of the large family from India and with all five smaller families. Recombinations positioned the CAE gene in a 3.2-cM interval

The 5th International Lafora Epilepsy Workshop: Basic science elucidating therapeutic options and preparing for therapies in the clinic

Lafora disease (LD) is both a fatal childhood epilepsy and a glycogen storage disease caused by recessive mutations in either the Epilepsy progressive myoclonus 2A (EPM2A) or EPM2B genes. Hallmarks of LD are aberrant, cytoplasmic carbohydrate aggregates called Lafora bodies (LBs) that are a disease driver. The 5th International Lafora Epilepsy Workshop was recently held in Alcala de Henares, Spain. The workshop brought together nearly 100 clinicians, academic and industry scientists, trainees, National Institutes of Health (NIH) representation, and friends and family members of patients with LD. The workshop covered aspects of LD ranging from defining basic scientific mechanisms to elucidating a LD therapy or cure and a recently launched LD natural history study

De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies

Correction to The American Journal of Human Genetics, Volume 95, Issue 4, 2 October 2014, Pages 360-370. Volume 100, Issue 1, 5 January 2017, Page 179.Peer reviewe

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, Pmeta = 2.5 × 10−9, OR[T] = 0.81) and 17q21.32 (rs72823592, Pmeta = 9.3 × 10−9, OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, Pmeta = 9.1 × 10−9, OR[T] = 0.68) and at 1q43 for JME (rs12059546, Pmeta = 4.1 × 10−8, OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, Pmeta = 4.0 × 10−6) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndrome

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Tracking data highlight the importance of human-induced mortality for large migratory birds at a flyway scale

Human-induced direct mortality affects huge numbers of birds each year, threatening hundreds of species worldwide. Tracking technologies can be an important tool to investigate temporal and spatial patterns of bird mortality as well as their drivers. We compiled 1704 mortality records from tracking studies across the African-Eurasian flyway for 45 species, including raptors, storks, and cranes, covering the period from 2003 to 2021. Our results show a higher frequency of human-induced causes of mortality than natural causes across taxonomic groups, geographical areas, and age classes. Moreover, we found that the frequency of human-induced mortality remained stable over the study period. From the human-induced mortality events with a known cause (n = 637), three main causes were identified: electrocution (40.5 %), illegal killing (21.7 %), and poisoning (16.3 %). Additionally, combined energy infrastructure-related mortality (i.e., electrocution, power line collision, and wind-farm collision) represented 49 % of all human-induced mortality events. Using a random forest model, the main predictors of human-induced mortality were found to be taxonomic group, geographic location (latitude and longitude), and human footprint index value at the location of mortality. Despite conservation efforts, human drivers of bird mortality in the African-Eurasian flyway do not appear to have declined over the last 15 years for the studied group of species. Results suggest that stronger conservation actions to address these threats across the flyway can reduce their impacts on species. In particular, projected future development of energy infrastructure is a representative example where application of planning, operation, and mitigation measures can enhance bird conservation

Pitfalls in genetic testing: the story of missed SCN1A mutations

Peer reviewe

Genetica clinica y molecular de la epilepsia con ausencias en la infancia

Centro de Informacion y Documentacion Cientifica (CINDOC). C/Joaquin Costa, 22. 28002 Madrid. SPAIN / CINDOC - Centro de Informaciòn y Documentaciòn CientìficaSIGLEESSpai