Discovering rare diseases: Beauce Ataxia

JAMA Neurol. 2013 Aug 19. doi: 10.1001/jamaneurol.2013.3268. [Epub ahead of print]

SYNE1 Mutations in Autosomal Recessive Cerebellar Ataxia.

Noreau A, Bourassa CV, Szuto A, Levert A, Dobrzeniecka S, Gauthier J, Forlani S, Durr A, Anheim M, Stevanin G, Brice A, Bouchard JP,Dion PA, Dupré N, Rouleau GA.

Source

Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada2Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.

Abstract

IMPORTANCE Autosomal recessive cerebellar ataxia type I, also known as recessive ataxia of Beauce, is a slowly progressive ataxia that leads to moderate disability with gait ataxia, dysarthria, dysmetria, mild oculomotor abnormalities, and diffuse cerebellar atrophy on brain imaging. Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene, located on chromosome 6p25, were first reported in patients who originated from a region known as "Beauce" in the province of Quebec, Canada. OBJECTIVE To better evaluate the prevalence of SYNE1 mutations in individuals with mild pure cerebellar ataxia and cerebellar atrophy, we screened the gene in additional French-Canadian (FC) families and individuals from other populations. DESIGN, SETTING, AND PARTICIPANTS Study participants were referred by their treating physician on the basis of core features of autosomal recessive cerebellar ataxia type I. After excluding individuals with known SYNE1 mutations, our cohort was composed mainly of 19 FCs and 21 individuals from other ethnic backgrounds. INTERVENTIONS Extraction of DNA from blood samples and complete resequencing of the SYNE1 gene. MAIN OUTCOMES AND MEASURES The involvement of SYNE1 mutations in individuals with ataxia worldwide by resequencing the SYNE1 gene. RESULTS Two novel truncating mutations were found among the FC participants, and 2 other novel mutations were found in a patient from France and a patient from Brazil (1 mutation each). CONCLUSIONS AND RELEVANCE This is the second report, to our knowledge, of SYNE1 gene mutations in a population other than FCs. These data suggest that mutations in SYNE1 should be investigated in families with cerebellar ataxia who live outside the FC region.

Nat Rev Neurol. 2013 Aug;9(8):474-81. doi: 10.1038/nrneurol.2013.129. Epub 2013 Jul 2.

New treatments for mitochondrial disease-no time to drop our standards.

Pfeffer G, Horvath R, Klopstock T, Mootha VK, Suomalainen A, Koene S, Hirano M, Zeviani M, Bindoff LA, Yu-Wai-Man P, Hanna M,Carelli V, McFarland R, Majamaa K, Turnbull DM, Smeitink J, Chinnery PF.

Source

Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Ageing and Health, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.

Abstract

Mitochondrial dysfunction is a common cause of inherited multisystem disease that often involves the nervous system. Despite major advances in our understanding of the pathophysiology of mitochondrial diseases, clinical management of these conditions remains largely supportive. Using a systematic approach, we identified 1,039 publications on treatments for mitochondrial diseases, only 35 of which included observations on more than five patients. Reports of a positive outcome on the basis of a biomarker of unproven clinical significance were more common in nonrandomized and nonblinded studies, suggesting a publication bias toward positive but poorly executed studies. Although trial design is improving, there is a critical need to develop new biomarkers of mitochondrial disease. In this Perspectives article, we make recommendations for the design of future treatment trials in mitochondrial diseases. Patients and physicians should no longer rely on potentially biased data, with the associated costs and risks.

Lancet Neurol. 2013 Aug;12(8):822-38. doi: 10.1016/S1474-4422(13)70124-8.

Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration.

Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, Lindley RI, O'Brien JT, Barkhof F, Benavente OR, Black SE,Brayne C, Breteler M, Chabriat H, Decarli C, de Leeuw FE, Doubal F, Duering M, Fox NC, Greenberg S, Hachinski V, Kilimann I, Mok V,Oostenbrugge Rv, Pantoni L, Speck O, Stephan BC, Teipel S, Viswanathan A, Werring D, Chen C, Smith C, van Buchem M, Norrving B,Gorelick PB, Dichgans M; STandards for ReportIng Vascular changes on nEuroimaging (STRIVE v1).

Source

Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK. Electronic address: joanna.wardlaw@ed.ac.uk.

Abstract

Cerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).

Discovering rare diseses: King Denborough Syndrome

Neuromuscul Disord. 2011 Jun;21(6):420-7. doi: 10.1016/j.nmd.2011.03.006. Epub 2011 Apr 22.

King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene.

Dowling JJ, Lillis S, Amburgey K, Zhou H, Al-Sarraj S, Buk SJ, Wraige E, Chow G, Abbs S, Leber S, Lachlan K, Baralle D, Taylor A,Sewry C, Muntoni F, Jungbluth H.

Source

Division of Pediatric Neurology, Pediatric Neuromuscular Clinic, 5328 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI, USA.

Abstract

King-Denborough syndrome (KDS), first described in 1973, is a rare condition characterised by the triad of dysmorphic features, myopathy, and malignant hyperthermia susceptibility (MHS). Autosomal dominant inheritance with variable expressivity has been reported in several cases. Mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been implicated in a wide range of myopathies such as central core disease (CCD), the malignant hyperthermia (MH) susceptibility trait and one isolated patient with KDS. Here we report clinical, pathologic and genetic features of four unrelated patients with KDS. Patients had a relatively uniform clinical presentation but muscle biopsy findings were highly variable. Heterozygous missense mutations in RYR1 were uncovered in three out of four families, of which one mutation was novel and two have previously been reported in MH. Further RyR1 protein expression studies performed in two families showed marked reduction of the RyR1 protein, indicating the presence of allelic RYR1 mutations not detectable on routine sequencing and potentially explaining marked intrafamilial variability. Our findings support the hypothesis that RYR1 mutations are associated with King-Denborough syndrome but that further genetic heterogeneity is likely.

Discovering rare diseases: Schwartz Jampell disease

Spec Care Dentist. 2012 Jun;32(3):105-11. doi: 10.1111/j.1754-4505.2012.00249.x. Epub 2012 Apr 26.

Schwartz-Jampel syndrome: a review of the literature and case report.

Mallineni SK, Yiu CK, King NM.

Source

Faculty of Dentistry, University of Hong Kong, Hong Kong SAR, China.

Abstract

Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive skeletal dysplasia associated with myotonia. The manifestations of SJS include short stature, blepharophimosis, and skeletal anomalies. The combination of skeletal and muscular abnormalities may result in oro-dental manifestations such as atypical facies, with micrognathia, microstomia, pursed lips, crossbite, cleft palate, as well as mandibular hypoplasia, the risk of dentigerous cysts, and impacted teeth. The use of general anesthesia in patients with SJS is dangerous, as there is a risk of malignant hyperthermia. The purpose of this paper is to describe a 3-year-old Chinese boy diagnosed with SJS at birth. His intra-oral examination revealed significant dental findings such as dentin defects with generalized attrition and hypodontia of the permanent dentition. Comprehensive dental treatment was provided at the same time as lower right limb surgery to reduce the potential complications with general anesthesia.

Autoimmune disease preceding amyotrophic lateral sclerosis

Objective: To study whether the risk of amyotrophic lateral sclerosis (ALS) is increased in people with prior autoimmune disease.

Methods: An all-England hospital record-linkage dataset spanning 1999–2011 was used. Cohorts were constructed of people with each of a range of autoimmune diseases; the incidence of ALS in each disease cohort was compared with the incidence of ALS in a cohort of individuals without prior admission for the autoimmune disease.

Results: There were significantly more cases than expected of ALS associated with a prior diagnosis of asthma, celiac disease, younger-onset diabetes (younger than 30 years), multiple sclerosis, myasthenia gravis, myxedema, polymyositis, Sjögren syndrome, systemic lupus erythematosus, and ulcerative colitis.

Conclusions: Autoimmune disease associations with ALS raise the possibility of shared genetic or environmental risk factors.

Neurology 10.1212/WNL.0b013e3182a6cc13

Late-onset anti–NMDA receptor encephalitis

Objective: To describe the clinical features and outcome of anti–NMDA receptor (NMDAR) encephalitis in patients ≥45 years old.

Method: Observational cohort study.

Results: In a cohort of 661 patients with anti-NMDAR encephalitis, we identified 31 patients ≥45 years old. Compared with younger adults (18–44 years), older patients were more often male (45% vs 12%, p < 0.0001), had lower frequency of tumors (23% vs 51%, p = 0.002; rarely teratomas), had longer median time to diagnosis (8 vs 4 weeks, p= 0.009) and treatment (7 vs 4 weeks, p = 0.039), and had less favorable outcome (modified Rankin Scale score 0–2 at 2 years, 60% vs 80%, p < 0.026). In multivariable analysis, younger age (odds ratio [OR] 0.15, confidence interval [CI] 0.05–0.39, p = 0.0001), early treatment (OR 0.60, CI 0.47–0.78, p < 0.0001), no need for intensive care (OR 0.09, CI 0.04–0.22, p < 0.0001), and longer follow-up (p < 0.0001) were associated with good outcome. Rituximab and cyclophosphamide were effective when first-line immunotherapies failed (OR 2.93, CI 1.10–7.76, p = 0.031). Overall, 60% of patients older than 45 years had full or substantial recovery at 24 months follow-up.

Conclusions: Anti-NMDAR encephalitis is less severe in patients ≥45 years old than in young adults, but the outcome is poorer in older patients. In this age group, delays in diagnosis and treatment are more frequent than in younger patients. The frequency of underlying tumors is low, but if present they are usually carcinomas instead of teratomas in younger patients. Early and aggressive immunotherapy will likely improve the clinical outcome.

Neurology 10.1212/WNL.0b013e3182a4a49c

An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke

Objective: We aimed to create an index to stratify cryptogenic stroke (CS) patients with patent foramen ovale (PFO) by their likelihood that the stroke was related to their PFO.

Methods: Using data from 12 component studies, we used generalized linear mixed models to predict the presence of PFO among patients with CS, and derive a simple index to stratify patients with CS. We estimated the stratum-specific PFO-attributable fraction and stratum-specific stroke/TIA recurrence rates.

Results: Variables associated with a PFO in CS patients included younger age, the presence of a cortical stroke on neuroimaging, and the absence of these factors: diabetes, hypertension, smoking, and prior stroke or TIA. The 10-point Risk of Paradoxical Embolism score is calculated from these variables so that the youngest patients with superficial strokes and without vascular risk factors have the highest score. PFO prevalence increased from 23% (95% confidence interval [CI]: 19%–26%) in those with 0 to 3 points to 73% (95% CI: 66%–79%) in those with 9 or 10 points, corresponding to attributable fraction estimates of approximately 0% to 90%. Kaplan-Meier estimated stroke/TIA 2-year recurrence rates decreased from 20% (95% CI: 12%–28%) in the lowest Risk of Paradoxical Embolism score stratum to 2% (95% CI: 0%–4%) in the highest.

Conclusion: Clinical characteristics identify CS patients who vary markedly in PFO prevalence, reflecting clinically important variation in the probability that a discovered PFO is likely to be stroke-related vs incidental. Patients in strata more likely to have stroke-related PFOs have lower recurrence risk.

Neurology 2013

FDA Drug Safety Communication: FDA requires label changes to warn of risk for possibly permanent nerve damage from antibacterial fluoroquinolone drugs taken by mouth or by injection

http://www.fda.gov/downloads/Drugs/DrugSafety/UCM365078.pdf

Safety Announcement

[8-15-2013] The U.S. Food and Drug Administration (FDA) has required the drug labels and Medication. Guides for all fluoroquinolone antibacterial drugs be updated to better describe the serious side effect  of peripheral neuropathy. This serious nerve damage potentially caused by fluoroquinolones may occur soon after these drugs are taken and may be permanent. The risk of peripheral neuropathy occurs only with fluoroquinolones that are taken by mouth or by  injection. Approved fluoroquinolone drugs include levofloxacin (Levaquin), ciprofloxacin (Cipro),  moxifloxacin (Avelox), norfloxacin (Noroxin), ofloxacin (Floxin), and gemifloxacin (Factive). The topical  formulations of fluoroquinolones, applied to the ears or eyes, are not known to cause this risk.  If a patient develops symptoms of peripheral neuropathy, the fluoroquinolone should be stopped, and  the patient should be switched to another, non-fluoroquinolone antibacterial drug, unless the benefit of continued treatment with a fluoroquinolone outweighs the risk. Peripheral neuropathy is a nerve  disorder occurring in the arms or legs. Symptoms include pain, burning, tingling, numbness, weakness, 

 r a change in sensation to light touch, pain or temperature, or the sense of body position. It can occur  at any time during treatment with fluoroquinolones and can last for months to years after the drug is stopped or be permanent. Patients using fluoroquinolones who develop any symptoms of peripheral  neuropathy should tell their health care professionals right away.  FDA will continue to evaluate the safety of drugs in the fluoroquinolone class and will communicate with  the public again if additional information becomes available

Discovering rare diseases: Argyrophilic Grain Disease

here's a link for an article
have a good time!

http://brain.oxfordjournals.org/content/131/6/1416.long

Discovering rare diseases: BIBD and NIFID

J Neuropathol Exp Neurol. 2012 Sep;71(9):795-805. doi: 10.1097/NEN.0b013e318266efb1.

Phenotypic variability within the inclusion body spectrum of basophilic inclusion body disease and neuronal intermediate filament inclusion disease in frontotemporal lobar degenerations with FUS-positive inclusions.

Gelpi E, Lladó A, Clarimón J, Rey MJ, Rivera RM, Ezquerra M, Antonell A, Navarro-Otano J, Ribalta T, Piñol-Ripoll G, Pérez A,Valldeoriola F, Ferrer I.

Source

Neurological Tissue Bank, Biobanc-Hospital Clínic-IDIBAPS, Barcelona, Spain. ellen.gelpi@gmail.com

Abstract

Basophilic inclusion body disease and neuronal intermediate filament inclusion disease (NIFID) are rare diseases included among frontotemporal lobar degenerations with FUS-positive inclusions (FTLD-FUS). We report clinical and pathologic features of 2 new patients and reevaluate neuropathologic characteristics of 2 previously described cases, including an early-onset case of basophilic inclusion body disease (aged 38 years) with a 5-year disease course and abundant FUS-positive inclusion bodies and 3 NIFID cases. One NIFID case (aged 37 years) presented with early-onset psychiatric disturbances and rapidly progressive cognitive decline. Two NIFID cases had later onset (aged 64 years and 70 years) and complex neurologic deficits. Postmortem neuropathologic studies in late-onset NIFID cases disclosed α-internexin-positive "hyaline conglomerate"-type inclusions that were positive with 1 commercial anti-FUS antibody directed to residues 200 and 250, but these were negative to amino acids 90 and 220 of human FUS. Early-onset NIFID had similar inclusions that were positive with both commercial anti-FUS antibodies. Genetic testing performed on all cases revealed no FUS gene mutations. These findings indicate that phenotypic variability in NIFID, including clinical manifestations and particular neuropathologic findings, may be related to the age at onset and individual differences in the evolution of lesions.

Breacking news: new trial for fighting Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and finally death. ALS patients suffer from asthenia and their progressive weakness negatively impacts quality of life, limiting their daily activities. They have impaired energy balance linked to lower activity of mitochondrial electron transport chain enzymes in ALS spinal cord, suggesting that improving mitochondrial function may present a therapeutic approach for ALS. When fed a ketogenic diet, the G93A ALS mouse shows a significant increase in serum ketones as well as a significantly slower progression of weakness and lower mortality rate. In this study, we treated SOD1-G93A mice with caprylic triglyceride, a medium chain triglyceride that is metabolized into ketone bodies and can serve as an alternate energy substrate for neuronal metabolism. Treatment with caprylic triglyceride attenuated progression of weakness and protected spinal cord motor neuron loss in SOD1-G93A transgenic animals, significantly improving their performance even though there was no significant benefit regarding the survival of the ALS transgenic animals. We found that caprylic triglyceride significantly promoted the mitochondrial oxygen consumption rate in vivo. Our results demonstrated that caprylic triglyceride alleviates ALS-type motor impairment through restoration of energy metabolism in SOD1-G93A ALS mice, especially during the overt stage of the disease. These data indicate the feasibility of using caprylic acid as an easily administered treatment with a high impact on the quality of life of ALS patients

(PLOS ONE 2012)

Se tutto andrà come previsto, partirà entro la fine di ottobre la prima fase dello studio clinico per testare l'efficacia del trigliceride caprilico come approccio terapeutico per il trattamento e l'eventuale rallentamento della progressione della Sla, la Sclerosi laterale amiotrofica. Nei Comitati etici del «Mount Sinai School of Medicine» e della «Cornell University» – entrambi di New York – e in quello dell'«Istituto Auxologico» di Milano sono infatti in via di approvazione i protocolli per dare il via alla sperimentazione con la molecola derivante dall'acido caprilico, un composto naturale che in natura si trova nel latte materno, nella noce di cocco e nel suo latte. 

La sperimentazione sull'uomo del trigliceride caprilico prende le mosse dalle evidenze precliniche emerse dagli studi e dai programmi di ricerca effettuati nel laboratorio del prof. Giulio Maria Pasinetti al «Mount Sinai School of Medicine», in collaborazione con la «Cornell University» di New York. «In particolare – spiega il prof. Pasinetti, 55 anni, nato e cresciuto in Borgo Canale, ma da quasi trent'anni negli Usa, dove oggi dirige il Dipartimento di Neuroscienze della Mount Sinai School of Medicine –, questi studi suggeriscono che una molecola nota come trigliceride caprilico, capace di raggiungere il midollo spinale, sia in grado di preservare i motoneuroni colpiti dalla Sla e attenuare il danno motorio, influenzando il metabolismo energetico. Si tratta di uno studio evidentemente molto interessante – spiega Pasinetti, tra i maggiori scienziati al mondo nel campo delle malattia neurodegenerative, come il Parkinson, l'Alzheimer e la Sla –, e proprio per questo la sperimentazione che partirà entro ottobre, volta all'identificazione di una dose efficace, sicura e ben tollerata negli esseri umani, rappresenta un passo imprescindibile verso nuove prospettive di cura». 

«Grazie a questo trattamento, le recenti evidenze cliniche che sembrano suggerire connessioni molto strette tra le alterazioni presenti nel midollo spinale dei pazienti colpiti dalla Sla e quelle nel cervello dei malatti di Alzheimer e di altre forme di demenza, potrebbero aprire nuove vie di trattamento. Importanti studi clinici sostenuti dal governo statunitense, ad esempio, stanno infatti sperimentando il trigliceride caprilico in pazienti affetti dal morbo di Alzheimer. In un futuro molto prossimo, attraverso esami del sangue e di genetica, saremo in grado di capire i meccanismi attraverso cui il trigliceride caprilico potrebbe essere utile non solo per la Sla, ma anche per altre malattie degenerative del cervello, e ancora prima che queste si manifestino con i sintomi».

Il trigliceride caprilico utilizzato negli studi newyorkesi – prosegue Pasinetti – «non è al momento disponibile in commercio, ma la società che lo produce negli Stati Uniti ha accettato di fornirlo a costo zero per testarne la tollerabilità e la sicurezza nel corso della prima fase dello studio. Sulla base di queste evidenze, la Mount Sinai School of Medicine (come centro di coordinamento) e la Cornell University - Presbyterian Medical Center di New York hanno deciso di sviluppare una collaborazione con il Centro Sla dell'Istituto Auxologico di Milano diretto dal professor Vincenzo Silani». 

«L'idea è quella di reclutare pazienti sia negli Stati Uniti sia in Italia per seguire il medesimo protocollo. Questo – sottolinea ancora Pasinetti – consentirà di accelerare le sperimentazioni nei due Paesi e permetterà ai pazienti italiani di ricevere lo stesso trattamento di quelli statunitensi, senza la necessità di spostarsi oltreoceano. Da qui l'urgenza e l'importanza di avere il via libera dei Comitati etici dei centri di ricerca coinvolti. Nel frattempo, i miei laboratori stanno sviluppando alcune nuove ricerche per identificare derivati commercialmente disponibili del trigliceride caprilico, già utilizzabili come integratori e che potrebbero rappresentare, per il momento, un primissimo approccio alternativo». 

I pazienti che prenderanno parte alla fase iniziale delle studio clinico saranno selezionati a settembre, 10 a New York (dove sono già stati individuati) e altrettanti in Italia. «La prima fase – spiega Pasinetti – durerà tre mesi, durante i quali esploreremo la dose massima tollerabile dall'organismo umano e la sua eventuale tossicità. Dopo di che prenderà il via lo studio clinico vero e proprio durante il quale studieremo gli effetti del trigliceride caprilico e le sue potenzialità come approccio terapeutico per la Sla e l'eventuale rallentamento della progressione della Sla stessa». 

«Credo comunque – conclude Pasinetti – che questi risultati possano aprire nuove vie di prevenzione terapeutica non solo per Sla, ma anche per altre malattie neurodegenerative, dove l'alterazione e la perdita di funzioni sembrerebbero iniziare il loro corso anche decenni prima dell'insorgenza della malattia. Siamo convinti che un approccio terapeutico caratterizzato da farmaci con effetti collaterali virtualmente inesistenti a lungo termine, possa non solo prevenire ma anche curare, rappresentando così un valido futuro terapeutico per la cura della Sla». I pazienti che volessero ulteriori informazioni possono contattare direttamente sia il prof. Vincenzo Silani all'Istituto Auxologico, sia il prof. Giulio Maria Pasinetti a New York (in quest'ultimo caso l'indirizzo email è slaitaly1gmail.com).

NEVER STOP FIGHTING AGAINST ALS

Epilepsy: a new gene?

GRIN2A mutations cause epilepsy-aphasia spectrum disorders

Gemma L Carvill, Brigid M Regan, Simone C Yendle, Brian J O'Roak, Natalia Lozovaya, Nadine Bruneau, Nail Burnashev, Adiba Khan, Joseph Cook, Eileen Geraghty, Lynette G Sadleir, Samantha J Turner, Meng-Han Tsai, Richard Webster, Robert Ouvrier, John A Damiano, Samuel F Berkovic, Jay Shendure, Michael S Hildebrand, Pierre Szepetowski, Ingrid E Scheffer & Heather C Mefford

Published online: 11 August 2013 | doi:10.1038/ng.2727

Heather Mefford, Ingrid Scheffer and colleagues report the identification of inherited mutations in GRIN2A that cause epilepsy-aphasia syndromes, which have a characteristic EEG pattern and developmental regression affecting language.

First Paragraph

- GRIN2A mutations cause epilepsy-aphasia spectrum disorders

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- GRIN2A mutations cause epilepsy-aphasia spectrum disorders

 | PDF (548 KB)

- GRIN2A mutations cause epilepsy-aphasia spectrum disorders

 | Supplementary information

Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes

Johannes R Lemke, Dennis Lal, Eva M Reinthaler, Isabelle Steiner, Michael Nothnagel, Michael Alber, Kirsten Geider, Bodo Laube, Michael Schwake, Katrin Finsterwalder, Andre Franke, Markus Schilhabel, Johanna A Jähn, Hiltrud Muhle, Rainer Boor, Wim Van Paesschen, Roberto Caraballo, Natalio Fejerman, Sarah Weckhuysen, Peter De Jonghe, Jan Larsen, Rikke S Møller, Helle Hjalgrim, Laura Addis, Shan Tang, Elaine Hughes, Deb K Pal, Kadi Veri, Ulvi Vaher, Tiina Talvik, Petia Dimova, Rosa Guerrero López, José M Serratosa, Tarja Linnankivi, Anna-Elina Lehesjoki, Susanne Ruf, Markus Wolff, Sarah Buerki, Gabriele Wohlrab, Judith Kroell, Alexandre N Datta, Barbara Fiedler, Gerhard Kurlemann, Gerhard Kluger, Andreas Hahn, D Edda Haberlandt, Christina Kutzer, Jürgen Sperner, Felicitas Becker, Yvonne G Weber, Martha Feucht, Hannelore Steinböck, Birgit Neophythou, Gabriel M Ronen, Ursula Gruber-Sedlmayr, Julia Geldner, Robert J Harvey, Per Hoffmann, Stefan Herms, Janine Altmüller, Mohammad R Toliat, Holger Thiele, Peter Nürnberg, Christian Wilhelm, Ulrich Stephani, Ingo Helbig, Holger Lerche, Fritz Zimprich, Bernd A Neubauer, Saskia Biskup & Sarah von Spiczak

Published online: 11 August 2013 | doi:10.1038/ng.2728

Sarah von Spiczak, Holger Lerche and colleagues identify mutations in GRIN2Athat cause idiopathic focal epilepsy with rolandic spikes.

First Paragraph

- Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes

 | Full Text

- Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes

 | PDF (710 KB)

- Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes

 | Supplementary information

GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction

Gaetan Lesca, Gabrielle Rudolf, Nadine Bruneau, Natalia Lozovaya, Audrey Labalme, Nadia Boutry-Kryza, Manal Salmi, Timur Tsintsadze, Laura Addis, Jacques Motte, Sukhvir Wright, Vera Tsintsadze, Anne Michel, Diane Doummar, Karine Lascelles, Lisa Strug, Patrick Waters, Julitta de Bellescize, Pascal Vrielynck, Anne de Saint Martin, Dorothee Ville, Philippe Ryvlin, Alexis Arzimanoglou, Edouard Hirsch, Angela Vincent, Deb Pal, Nail Burnashev, Damien Sanlaville & Pierre Szepetowski

Published online: 11 August 2013 | doi:10.1038/ng.2726

Pierre Szepetowski and colleagues report the identification of mutations in GRIN2Ain individuals with acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.

First Paragraph

- GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction

 | Full Text

- GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction

 | PDF (862 KB)

- GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction

 | Supplementary information

Discovering rare diseases: Paroxysmal non kinesigenic dyskinesia

here is the link for some articles about this disease

the video is taken from Youtube only for scientifical purposes

http://archneur.jamanetwork.com/article.aspx?articleid=775082
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002546/
http://hmg.oxfordjournals.org/content/18/6/1058.full.pdf+html

another update

The clinical maze of mitochondrial neurology

Salvatore DiMauro, Eric A. Schon, Valerio Carelli & Michio Hirano

Abstract

Mitochondrial diseases involve the respiratory chain, which is under the dual control of nuclear and mitochondrial DNA (mtDNA). The complexity of mitochondrial genetics provides one explanation for the clinical heterogeneity of mitochondrial diseases, but our understanding of disease pathogenesis remains limited. Classification of Mendelian mitochondrial encephalomyopathies has been laborious, but whole-exome sequencing studies have revealed unexpected molecular aetiologies for both typical and atypical mitochondrial disease phenotypes. Mendelian mitochondrial defects can affect five components of mitochondrial biology: subunits of respiratory chain complexes (direct hits); mitochondrial assembly proteins; mtDNA translation; phospholipid composition of the inner mitochondrial membrane; or mitochondrial dynamics. A sixth category—defects of mtDNA maintenance—combines features of Mendelian and mitochondrial genetics. Genetic defects in mitochondrial dynamics are especially important in neurology as they cause optic atrophy, hereditary spastic paraplegia, and Charcot–Marie–Tooth disease. Therapy is inadequate and mostly palliative, but promising new avenues are being identified. Here, we review current knowledge on the genetics and pathogenesis of the six categories of mitochondrial disorders outlined above, focusing on their salient clinical manifestations and highlighting novel clinical entities. An outline of diagnostic clues for the various forms of mitochondrial disease, as well as potential therapeutic strategies, is also discussed.

full test at:

Nature Reviews Neurology 9, 429-444 (August 2013) 

An interesting update

Advances in the genetics of Parkinson disease

Joanne Trinh & Matt Farrer

Abstract

Parkinson disease (PD) is a multifactorial neurodegenerative disease that was long considered the result of environmental factors. In the past 15 years, however, a genetic aetiology for PD has begun to emerge. Here, we review results from linkage and next-generation sequencing studies of familial parkinsonism, as well as candidate gene and genome-wide association findings in sporadic PD. In these studies, many of the genetic findings overlap, despite different designs and study populations, highlighting novel therapeutic targets. The molecular results delineate a sequence of pathological events whereby deficits in synaptic exocytosis and endocytosis, endosomal trafficking, lysosome-mediated autophagy and mitochondrial maintenance increase susceptibility to PD. These discoveries provide the rationale, molecular insight and research tools to develop neuroprotective and disease-modifying therapies.

Nature Reviews Neurology 9, 445-454 (August 2013) | doi:10.1038/nrneurol.2013.132