DOCSLIB.ORG

Lafora Disease: Molecular Etiology Lafora Hastalığı: Moleküler Etiyoloji S

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Lafora Disease: Molecular Etiology Lafora Hastalığı: Moleküler Etiyoloji S Epilepsi 2018;24(1):1-7 DOI: 10.14744/epilepsi.2017.48278 REVIEW / DERLEME Lafora Disease: Molecular Etiology Lafora Hastalığı: Moleküler Etiyoloji S. Hande ÇAĞLAYAN1,2 1Department of Molecular Biology and Genetics, Boğaziçi University, İstanbul, Turkey S. Hande CAĞLAYAN, Ph.D. 2International Biomedicine and Genome Center, Dokuz Eylül University, İzmir, Turkey Summary Lafora Disease (LD) is a fatal neurodegenerative condition characterized by the accumulation of abnormal glycogen inclusions known as Lafora bodies (LBs). Patients with LD manifest myoclonus and tonic-clonic seizures, visual hallucinations, and progressive neurological deteri- oration beginning at the age of 8-18 years. Mutations in either EPM2A gene encoding protein phosphatase laforin or NHLRC1 gene encoding ubiquitin-ligase malin cause LD. Approximately, 200 distinct mutations accounting for the disease are listed in the Lafora progressive my- oclonus epilepsy mutation and polymorphism database. In this review, the genotype-phenotype correlations, the genetic diagnosis of LD, the downregulation of glycogen metabolism as the main cause of LD pathogenesis and the regulation of glycogen synthesis as a key target for the treatment of LD are discussed. Key words: EPM2A and NHLRC1 gene mutations; genotype-phenotype relationship; Lafora progressive myoclonus epilepsy; LD pathogenesis. Özet Lafora hastalığı (LD) Lafora cisimleri (LB) olarak bilinen anormal glikojen yapıların birikmesi ile karakterize olan ölümcül bir nörodejeneratif hastalıktır. Lafora hastalarında 8–18 yaş arası başlayan miyoklonik ve tonik-klonik nöbetler, halüsinasyonlar ve ilerleyen nörolojik bozulma görülür. Lafora hastalığı protein fosfataz laforini kodlayan EPM2A geni veya ubikitin ligaz malini kodlayan NHLRC1 geni mutasyonları ile orta- ya çıkar. Hastalığa sebep olan yaklaşık 200 farklı mutasyon “Lafora Progressive Myoclonus Epilepsy Mutation and Polymorphism Database” de listelenmiştir. Bu derleme makalede her iki gendeki mutasyonlar, genotip-fenotip ilişkileri, LD genetik tanısı, LD patojenezine yol açan başlıca mekanizma olarak glikojen metabolizmasının bozulması ve glikojen sentezi kontrolünün LD tedavisinde en önemli hedef olduğu tartışılmaktadır. Anahtar sözcükler: EPM2A ve NHLRC1 gen mutasyonları; genotip-fenotip ilişkisi; Lafora progresif miyoklonus epilepsi; LD patojenezi. Clinical Characteristics tions gradually worsen and become intractable. Dysarthria, ataxia, and spasticity, accompanied by progressive cog- LD is an autosomal recessive progressive myoclonus nitive decline and dementia, are found on neurological epilepsy (PME) characterized by onset of progresive neu- examination. EEG shows slow background, paroxysms of rodegeneration between the age of 8 and 18 years. The generalized irregular spike-wave discharges with occip- initial features can include headache, difficulties in school ital dominance, and focal abnormalities. About 10 years work, myoclonic jerks, generalized seizures, depressed after onset, affected individuals are in near-continuous mood, cognitive deficits, and frequent visual hallucinations. myoclonus with absence seizures, frequent generalized EEG shows normal or slow background. Photosensitivity is seizures, and profound dementia or a vegetative state.[1,5–7] common.[1] Many affected individuals experience isolated febrile or nonfebrile convulsions in infancy or early child- Diagnosis is usually based on clinical and EEG findings. The hood.[2] Intra- and interfamilial variability in age at onset presence of periodic acid-Schiff-positive (PAS+) polyglu- is frequently seen.[3,4] Myoclonus, seizures, and hallucina- cosan inclusion bodies called Lafora bodies (LB) is a hallmark Submitted (Geliş) : 23.11.2017 Accepted (Kabul) : 16.12.2017 © 2018 Türk Epilepsi ile Savaş Derneği Correspondence (İletişim): S. Hande ÇAĞLAYAN, Ph.D. © 2018 Turkish Epilepsy Society e-mail (e-posta): [email protected] 1 Epilepsi 2018;24(1):1-7 of the disease. Besides axons and dendrites of the central tinct proteins in alternate reading frames exist. Two novel nervous system, LBs are also found in the retina, heart, liver, isoforms, when ectopically expressed in cell lines, show dis- muscle, and skin.[8] LD occurs worldwide, but is relatively tinct subcellular localization, and interact with and serve as common in the Mediterranean Basin and in other parts of substrates of malin. Alternative splicing could possibly be the world with a high rate of consanguinity.[8] At present, no one of the mechanisms through which EPM2A regulates the preventive or curative treatment for LD is available. cellular functions of the protein it codes for.[17] Molecular Genetics To date, 102 different pathogenic variants inEPM2A have been reported in more than 100 families. Nucleotide substi- At least three loci are implicated in LD. The first one,EPM2A tutions resulting in missense, nonsense, and frameshift vari- at 6q24.3 was discovered in 1998/1999,[9,10] and the second ants and indels form 74% and 26% of the total, respectively. gene, NHLRC1 (EPM2B) at 6p22.3 was discovered in 2003.[11,12] One splice site variant has been reported for EPM2A. An In about 80% of cases defects have been found in EPM2A overview of the different pathogenic variants can be found and NHLRC. In one family with three biopsy-confirmed LD in the Lafora PME mutation and polymorphism database patients and no identifiable pathogenic variants in both (http://projects.tcag.ca/lafora; updated Sep 5, 2017). Of all genes, linkage and haplotype analysis excluded both loci the types of pathogenic variants in EPM2A described to from disease association and provided indirect evidence date, 45% represent missense variants. All the known mis- for a third locus for LD.[13] The findings were supported by sense variants target either the CBD or DSPD of laforin.[18] the lack of EPM2A mutations in the Japanese population.[14] However, no studies have been conducted to identify the Except for the larger deletions, all the pathogenic variants gene of interest. are evenly distributed across EPM2A. The only exception is the high prevalence of the nonsense c.721C<T variant Early-onset LD typically presenting at around 5 years of age (p.Arg241X), the so called Spanish pathogenic variant, in caused by pathogenic variants in PRDM8 is a newly recog- over 23 families which is the result of both a founder effect [9,10] nized condition characterized by progressive myclonus and recurrent events. The variant is also found in two epilepsy and LBs.[15] Turkish patients; one as an unpublished observation and the other as reported in Salar et al. 2012.[19] Exon 2 deletion EPM2A is the second frequently observed mutation occurring in EPM2A encodes a dual-specificity protein phosphatase, eight families. Other variants recurring 5-6 times are exon called laforin that localizes in the rough endoplasmic reticu- 1-2 deletion; c.258C<G (p.Tyr86X); c.322C>T (p.Arg108Cys); lum. EPM2A has four exons spanning 130kb and is known to and c.512G>A (p.Arg171His). encode two distinct proteins by differential splicing: phos- phatase active cytoplasmic isoform-a, and phosphatase Several polymorphisms in EPM2A have also been de- inactive nuclear isoform-b.[9,10] Both isoforms of the laforin scribed. Among these, c.136G<C (p.Ala46Pro) is specific to protein have the unique C termini. The carboxyl terminal the Japanese and Chinese populations.[20] The c.163C<A of isoform-b targets laforin to the nucleus. The pathogen- (p.Gln55Lys) polymorphism in EPM2A was found in two af- esis of LD is caused by the physiologic functions of laforin fected persons who were also heterozygous for a deletion isoform-a.[16] Laforin contains an N-terminal carbohydrate- in NHLRC1, in seven of the 500 individuals without LD, and binding domain (CBD), encoded mainly by exon 1, and a in a person with adult onset disease, also in the heterozy- dual-specificity phosphatase domain (DSPD) spanning ex- gous state. It is unclear whether this change constitutes a ons 3 and 4, common to both isoforms (Fig. 1). Three ad- rare benign SNP of no consequence, whether it may cause ditional splice variants with potential to code for five dis- LD when homozygous, or whether it could predispose to NHLRC1 deletion in certain situations.[4] CBM20 DSPD The pathogenic variants (nonsense, missense, and inser- EXON 1 EXON 2 EXON 3 EXON 4 tions and deletions) located in the DSPD and CBD of EPM2A Fig. 1. A schematic representation of EPM2A gene and its have the functional consequence of a “null effect” with the product, laforin. loss of phosphatase activity.[21] Although, all aspects of the 2 Lafora Disease: Molecular Etiology protein function have not been tested for each missense one Turkish family.[19] The second most common patho- variant, transfection experiments overexpressing missense genic variant in NHLRC1 is c.468-469delAG.[12,26] It has been mutants that resulted in ubiquitin-positive cytoplasmic ag- identified in 14 individuals belonging to the same genetic gregates, suggest that they were folding mutants destined isolate of tribal Oman. All shared a common haplotype, for degradation.[22] It is also observed that missense mutants suggesting a founder effect.[27] Both c.205C<G and c.468- affect the subcellular localization of laforin and disrupt the 469delAG pathogenic variants have been identified in interaction of laforin with protein targeting glycogen (PTG) different ethnic groups, suggesting a recurrent mutation and malin proteins that interact with laforin in vivo.[21,23] event. Thus, these two sites represent hot
Load more

Recommended publications
  • ILAE Classification and Definition of Epilepsy Syndromes with Onset in Childhood: Position Paper by the ILAE Task Force on Nosology and Definitions
    ILAE Classification and Definition of Epilepsy Syndromes with Onset in Childhood: Position Paper by the ILAE Task Force on Nosology and Definitions N Specchio1, EC Wirrell2*, IE Scheffer3, R Nabbout4, K Riney5, P Samia6, SM Zuberi7, JM Wilmshurst8, E Yozawitz9, R Pressler10, E Hirsch11, S Wiebe12, JH Cross13, P Tinuper14, S Auvin15 1. Rare and Complex Epilepsy Unit, Department of Neuroscience, Bambino Gesu’ Children’s Hospital, IRCCS, Member of European Reference Network EpiCARE, Rome, Italy 2. Divisions of Child and Adolescent Neurology and Epilepsy, Department of Neurology, Mayo Clinic, Rochester MN, USA. 3. University of Melbourne, Austin Health and Royal Children’s Hospital, Florey Institute, Murdoch Children’s Research Institute, Melbourne, Australia. 4. Reference Centre for Rare Epilepsies, Department of Pediatric Neurology, Necker–Enfants Malades Hospital, APHP, Member of European Reference Network EpiCARE, Institut Imagine, INSERM, UMR 1163, Université de Paris, Paris, France. 5. Neurosciences Unit, Queensland Children's Hospital, South Brisbane, Queensland, Australia. Faculty of Medicine, University of Queensland, Queensland, Australia. 6. Department of Paediatrics and Child Health, Aga Khan University, East Africa. 7. Paediatric Neurosciences Research Group, Royal Hospital for Children & Institute of Health & Wellbeing, University of Glasgow, Member of European Refence Network EpiCARE, Glasgow, UK. 8. Department of Paediatric Neurology, Red Cross War Memorial Children’s Hospital, Neuroscience Institute, University of Cape Town, South Africa. 9. Isabelle Rapin Division of Child Neurology of the Saul R Korey Department of Neurology, Montefiore Medical Center, Bronx, NY USA. 10. Programme of Developmental Neurosciences, UCL NIHR BRC Great Ormond Street Institute of Child Health, Department of Clinical Neurophysiology, Great Ormond Street Hospital for Children, London, UK 11.
    [Show full text]
  • Mutations in the NHLRC1 Gene Are the Common Cause for Lafora Disease in the Japanese Population
    J Hum Genet (2005) 50:347–352 DOI 10.1007/s10038-005-0263-7 ORIGINAL ARTICLE Shweta Singh Æ Toshimitsu Suzuki Æ Akira Uchiyama Satoko Kumada Æ Nobuko Moriyama Æ Shinichi Hirose Yukitoshi Takahashi Æ Hideo Sugie Æ Koichi Mizoguchi Yushi Inoue Æ Kazue Kimura Æ Yukio Sawaishi Kazuhiro Yamakawa Æ Subramaniam Ganesh Mutations in the NHLRC1 gene are the common cause for Lafora disease in the Japanese population Received: 11 March 2005 / Accepted: 30 May 2005 / Published online: 15 July 2005 Ó The Japan Society of Human Genetics and Springer-Verlag 2005 Abstract Lafora disease (LD) is a rare autosomal NHLRC1 and encoding a putative E3 ubiquitin ligase, recessive genetic disorder characterized by epilepsy, was recently identified on chromosome 6p22. The LD is myoclonus, and progressive neurological deterioration. relatively common in southern Europe, the Middle East, LD is caused by mutations in the EMP2A gene encoding and Southeast Asia. A few sporadic cases with typical a protein phosphatase. A second gene for LD, termed LD phenotype have been reported from Japan; however, our earlier study failed to find EPM2A mutations in four Japanese families with LD. We recruited four new fam- S. Singh Æ S. Ganesh Department of Biological Sciences and Bioengineering, ilies from Japan and searched for mutations in EPM2A. Indian Institute of Technology, All eight families were also screened for NHLRC1 Kanpur, India mutations. We found five independent families having T. Suzuki Æ K. Yamakawa (&) novel mutations in NHLRC1. Identified mutations in- Laboratory for Neurogenetics, clude five missense mutations (p.I153M, p.C160R, RIKEN Brain Science Institute, 2-1, Hirosawa, Wako, p.W219R, p.D245N, and p.R253K) and a deletion Saitama 351-0198, Japan mutation (c.897insA; p.S299fs13).
    [Show full text]
  • Lafora Disease Masquerading As Hepatic Dysfunction
    Thomas Jefferson University Jefferson Digital Commons Abington Jefferson Health Papers Abington Jefferson Health 8-24-2018 Lafora Disease Masquerading as Hepatic Dysfunction Faisal Inayat Allama Iqbal Medical College Waqas Ullah Abington Jefferson Health Hanan T. Lodhi University of Nebraska at Omaha Zarak H. Khan St. Mary Mercy Hospital Livonia Ghulam Ilyas SUNY Downstate Medical Center Follow this and additional works at: https://jdc.jefferson.edu/abingtonfp See next page for additional authors Part of the Gastroenterology Commons, and the Medical Genetics Commons Let us know how access to this document benefits ouy Recommended Citation Inayat, Faisal; Ullah, Waqas; Lodhi, Hanan T.; Khan, Zarak H.; Ilyas, Ghulam; Ali, Nouman Safdar; and Abdullah, Hafez Mohammad A., "Lafora Disease Masquerading as Hepatic Dysfunction" (2018). Abington Jefferson Health Papers. Paper 7. https://jdc.jefferson.edu/abingtonfp/7 This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Abington Jefferson Health Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: [email protected]. Authors Faisal Inayat, Waqas Ullah, Hanan T. Lodhi, Zarak H. Khan, Ghulam Ilyas, Nouman Safdar Ali, and Hafez Mohammad A.
    [Show full text]
  • Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities
    1 Autophagy and neurodegeneration: Pathogenic mechanisms and therapeutic opportunities Fiona M Menzies1ǂ,#, Angeleen Fleming1ǂ, Andrea Caricasole2ǂ, Carla F Bento1ǂ, Steven P Andrews2ǂ, Avraham Ashkenazi1ǂ, Jens Füllgrabe1ǂ, Anne Jackson1ǂ, Maria Jimenez Sanchez1ǂ, Cansu Karabiyik1ǂ, Floriana Licitra1ǂ, Ana Lopez Ramirez1ǂ, Mariana Pavel1ǂ, Claudia Puri1ǂ, Maurizio Renna1ǂ, Thomas Ricketts1ǂ Lars Schlotawa1ǂ, Mariella Vicinanza1ǂ, Hyeran Won1ǂ, Ye Zhu1ǂ, John Skidmore2ǂ and David C Rubinsztein1* 1 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK. 2 Alzheimer's Research UK Cambridge Drug Discovery Institute, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0AH, UK. # Current address: Eli Lilly and Company Limited, Erl Wood Manor, Sunninghill Road Windlesham, Surrey, GU20 6PH, UK. ǂDenotes equal contribution *E-mail address for correspondence: [email protected] (DCR) 2 In Brief This review discusses the importance of autophagy function for brain health, outlining connections between autophagy dysfunction and neurodegenerative disorders. The potential for autophagy as a therapeutic strategy for neurodegenerative disease is discussed, along with how this may be achieved. Summary Autophagy is a conserved pathway that delivers cytoplasmic contents to the lysosome for degradation. Here we consider its roles in neuronal health and disease. We review evidence from mouse knock-out studies demonstrating the normal functions of autophagy as a protective factor against neurodegeneration associated with intracytoplasmic aggregate-prone protein accumulation, as well as other roles including in neuronal stem cell differentiation. We then describe how autophagy may be affected in a range of neurodegenerative diseases.
    [Show full text]
  • Types of Photic-Induced Seizures and Epileptic Types Associated With
    SEIZURE DISORDERS EPILEPTIC SYNDROMES AND PHOTOSENSITIVE SEIZURES The clinical features of different types of photic-induced seizures and epileptic syndromes characterized by visual sensitivity are reviewed from the University of Pisa, Italy, and Centre St Paul, Marseille, France. Seizure types associated with clinical photosensitivity include eyelid myoclonus, generalized myoclonic jerks, tonic-versive seizures, absence, generalized tonic clonic, and focal seizures. Epileptic syndromes with photic-induced seizures include benign myoclonic epilepsy in infancy, absence epilepsy, juvenile myoclonic epilepsy, epilepsy with myoclonic-astatic seizures, primary reading epilepsy, severe myoclonic epilepsy of infancy, photosensitive occipital lobe epilepsy, and progressive myoclonus epilepsies (PME). PME with photic sensitivity are symptoms of neuronal ceroid lipofuscinosis, Lafora's disease, Unverricht-Lundborg disease, and myoclonus epilepsy and ragged red fibers (MERRF). Visually induced seizures can be generalized or focal, idiopathic or symptomatic, or represent a pure reflex photosensitive epilepsy. (Guerrini R, Genton P. Epileptic syndromes and visually induced seizures. Epilepsia January 2004;45 (Suppl 1): 14- 18). (Reprints: Dr R Guerrini, Division of Child Neurology and Psychiatry, University of Pisa & IRCCS Fondazione Stella Maris, via dei Giacinti 2, 56018 Calambrone, Pisa, Italy). COMMENT. The treatment of photosensitive epilepsies involves preventive measures and antiepileptic medications (AED). (Covanis A et al. Epilepsia Jan 2004;45(Suppl l):40-45; Bureau M et al. Epilepsia Jan 2004;45(Suppl l):24-26). Preventive measures include the following: avoid stimuli (eg TV, videogames); use small TV, 100-Hz screen, remote control, sit >2 m away from screen, wear spectacles, avoid stress and fatigue. Usually a combination of avoidance of stimuli and an AED is necessary.
    [Show full text]
  • Relation of Photosensitivity to Epileptic Syndromes
    J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.49.12.1386 on 1 December 1986. Downloaded from Journal of Neurology, Neurosurgery, and Psychiatry 1986;49:1386-1391 Relation of photosensitivity to epileptic syndromes P WOLF,* R GOOSSES Abteilungfiir Neurologie, Klinikum Charlottenburg der Freien Universitdt, Berlin, Federal Republic ofGermany SUMMARY Photosensitivity is the most common mode of seizure precipitation. It is age-related, more frequent in females, and most often found in generalised epilepsies. Little is known about its relation to individual epileptic syndromes. This study on 1062 epileptic patients who had 4007 split screen video EEG investigations revealed that the relation to generalised epilepsy is even more close than generally believed. Versive seizures with visual hallucinations was the only focal seizure type related to photosensitivity. Of the syndromes of generalised epilepsy, only childhood absence epi- lepsy, juvenile myoclonic epilepsy, and epilepsy with grand mal on awakening were related to photosensitivity. The closest correlation was with juvenile myoclonic epilepsy. This is confirmed by a relation to the poly-spike wave pattern, and by an increase of myoclonic seizures by intermittent light stimuli. No relation was found with early childhood syndromes of generalised epilepsy, or generalised tonic-clonic seizures in the evening, or, most remarkably, with juvenile absence epilepsy. guest. Protected by copyright. In generalised epilepsies with onset around puberty, photosensitivity could thus act as a patho- plastic factor. The female preponderance in both childhood absences and photosensitivity could be due to the same unknown factor. Photosensitivity does not necessarily signify epi- of increasing and decreasing frequency from 3 to 30 Hz were lepsy.' In connection with epilepsy, photosensitivity applied.
    [Show full text]
  • A Type of Progressive Myoclonic Epilepsy, Lafora Disease: a Case Report
    Eastern Journal of Medicine 18 (2013) 34-36 Case Report A type of progressive myoclonic epilepsy, Lafora disease: A case report Ömer Bektaşa,*, Arzu Yılmaza, Aylin Heper Okcuc, Serap Teberb, Erhan Aksoya, Gülhis Dedaa aDepartment of Pediatric Neurology, School of Medicine, Ankara University,Turkey bDepartment of Pediatric Neurology, Dıskapı Hematology-Oncology Hospital, Turkey cDepartment of Pediatric Pathology, School of Medicine, Ankara University, Turkey Abstract. Lafora disease is a rare group of progressive myoclonic epilepsies characterized with progressive neurological dysfunction, myoclonus, focal and generalized seizures. Generally, a generalized tonic clonic seizure is the first symptom of the disease. An 11-year-old male patient had been followed-up at another center for epilepsy for 8 years. The patient had a history of myoclonic seizures for nearly every day for the last 2 years and cognitive detoriation for the last 8 months. He admitted to our hospital with the desire of his family. Eccrine sweat gland biopsy was performed. The biopsy of the sweat gland was positive for PAS and contained diastase resistant polyglican content (Lafora bodies), and thus, a diagnosis of Lafora disease was established. The patient presented here constitutes a rare case of pediatric epilepsy, which caused neurodegeneration in late-childhood and onset with typical epilepsy symptoms. This report also aimed to show that biopsy obtained from proper area is important for diagnosis Our patient developed cognitive dysfunction a short period of eight months. To our knowledge, this is the shortest period in literature. Key words: Lafora Disease, progressive myoclonic epilepsy, neurodegeneration 1. Introduction 2. Case report Progressive myoclonic epilepsy is a rare group An 11-year-old male patient had been followed- of diseases characterized with progressive up for epilepsy for 8 years.
    [Show full text]
  • Lafora Disease and Congenital Generalized Lipodystrophy: a Case Report
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector LAFORA DISEASE AND CONGENITAL GENERALIZED LIPODYSTROPHY: A CASE REPORT Chih-Fan Tseng,1 Che-Sheng Ho,1,2 Nan-Chang Chiu,1,2 Shuan-Pei Lin,1,2,3 Chi-Yuan Tzen,2,4 and Yu-Hung Wu2,5 Departments of 1Pediatrics, 3Medical Research, 4Pathology and 5Dermatology, Mackay Memorial Hospital; and 2Mackay Medicine, Nursing and Management College, Taipei, Taiwan. We report a patient with congenital generalized lipodystrophy who had suffered from seizures, myoclonus, ataxia and cognitive decline since late childhood. Lafora disease was diagnosed based on skin biopsy results, which revealed pathognomonic Lafora bodies. The results of genetic analysis for mutations in EPM2A and EPM2B genes were negative. This is the first case report describing an association between congenital generalized lipodystrophy and Lafora dis- ease. Further studies focusing on the relationship between these two diseases and the identifica- tion of a third locus for Lafora disease are needed. Key Words: Lafora disease, lipodystrophy, myoclonus, progressive myoclonic epilepsy (Kaohsiung J Med Sci 2009;25:663–8) Congenital generalized lipodystrophy (Berardinelli- develop during late childhood or adolescence. We Seip syndrome) was initially reported by Berardinelli report a child with congenital generalized lipodys- [1] and Seip [2] and is an extremely rare autosomal trophy and LD, a previously undescribed association, recessive disorder with genetic heterogeneity. Its and attempt to clarify the relationship between these prevalence has been estimated to be less than one in two diseases. one million. Three different loci (AGPAT2, BSCL2 and CAV1), which map to chromosomes 9q34, 11q13 and 7q31, respectively, have been identified [3–5].
    [Show full text]
  • A Novel Deletion Mutation in EPM2A Underlies Progressive Myoclonic Epilepsy (Lafora Body Disease) in a Pakistani Family
    Neurology Asia 2021; 26(2) : 427 – 433 A novel deletion mutation in EPM2A underlies progressive myoclonic epilepsy (Lafora body disease) in a Pakistani family 1Fizza Orooj MRCP, 2Umm-e-Kalsoom PhD, 3XiaoChu Zhao, 1Arsalan Ahmad MD, 4Imran Nazir Ahmed MD, 5Muhammad Faheem PhD, 5Muhammad Jawad Hassan PhD, 3,6Berge A. Minasian MD 1Division of Neurology, Shifa International Hospital, Shifa Tameer-e-Millat University, Islamabad, Pakistan; 2Department of Biochemistry, Hazara University, Mansehra, KPK, Pakistan; 3Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada; 4Department of Pathology, Shifa International Hospital, Shifa Tameer-e-Millat University, Islamabad, Pakistan; 5Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, Pakistan; 6Department of Pediatrics, University of Texas Southwestern, Dallas, Teas, USA Abstract Lafora body disease (MIM-254780), a glycogen storage disease, characterized by Lafora bodies (deformed glycogen molecules) accumulating in multiple organs, is a rare form of myoclonic epilepsy. It manifests in early adolescent years, initially with seizures and myoclonus, followed by dementia and progressive cognitive decline, ultimately culminating in death within 10 years. In Pakistan so far 5 cases have been reported. Here, we report a new case of Lafora body disease belonging to a consanguineous family from Pakistan. Histopathological analysis confirmed presence of lafora bodies in the patient`s skin. Sanger sequencing revealed novel homozygous 5bp deletion mutation (NM_005670.4; c.359_363delGTGTG) in exon 2 of the EPM2A gene, which was truly segregated in the family. These results will increase our understanding regarding the aetiology of this disorder and will further add to the mutation spectrum of EPM2A gene.
    [Show full text]
  • The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force
    The Cerebellum (2019) 18:1098–1125 https://doi.org/10.1007/s12311-019-01052-2 CONSENSUS PAPER The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force Marie Beaudin1,2 & Antoni Matilla-Dueñas3 & Bing-Weng Soong4,5 & Jose Luiz Pedroso6 & Orlando G. Barsottini6 & Hiroshi Mitoma7 & Shoji Tsuji8,9 & Jeremy D. Schmahmann10 & Mario Manto11,12 & Guy A Rouleau13 & Christopher Klein14 & Nicolas Dupre1,2 Published online:: 2 J uly 2019 # The Author(s) 2019 Abstract There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia.
    [Show full text]
  • An Unprecedented Impact a Series of Fact Sheets on Covid-19 and Biomedical Research July 2020
    AN UNPRECEDENTED IMPACT A SERIES OF FACT SHEETS ON COVID-19 AND BIOMEDICAL RESEARCH JULY 2020 We must maintain and strengthen our nation’s investment in medical research through the National Institutes of Health. This is an urgent priority for Congress, as our nation works to restart stalled research, keep up with pressing public health challenges, continue to fightCOVID-19 and prepare for the next potential pandemic. PART 3 | PROGRESS ON HOLD | Researcher Profiles While research on the disease caused by the novel coronavirus has been on a fast track the past several months, most other medical research ground to a halt in March and has yet to resume at anything near its pre-COVID pace. It is impossible to know the full implications of suspended work, lost experiments and delayed clinical trials, but for those waiting for a cure, time matters. After 17 years of work, DR. MATTHEW GENTRY is within reach of the holy grail — a potential treatment for Lafora disease, a devastating and The episodes increase quickly, and extremely rare form of epilepsy that strikes healthy regression is pretty fast. As we still teens and takes their lives within 10 years. In March, don’t know the window of opportunity his lab was preparing to conduct one final mouse test, a crucial step toward the goal of testing treatments in to treat and find a response, every patients by next year. That’s when COVID hit and the month matters to these patients. University of Kentucky was forced to shut down all non-essential activity — including his.
    [Show full text]
  • Lafora Progressive Myoclonus Epilepsy
    Lafora progressive myoclonus epilepsy Description Lafora progressive myoclonus epilepsy is a brain disorder characterized by recurrent seizures (epilepsy) and a decline in intellectual function. The signs and symptoms of the disorder usually appear in late childhood or adolescence and worsen with time. Myoclonus is a term used to describe episodes of sudden, involuntary muscle jerking or twitching that can affect part of the body or the entire body. Myoclonus can occur when an affected person is at rest, and it is made worse by motion, excitement, or flashing light (photic stimulation). In the later stages of Lafora progressive myoclonus epilepsy, myoclonus often occurs continuously and affects the entire body. Several types of seizures commonly occur in people with Lafora progressive myoclonus epilepsy. Generalized tonic-clonic seizures (also known as grand mal seizures) affect the entire body, causing muscle rigidity, convulsions, and loss of consciousness. Affected individuals may also experience occipital seizures, which can cause temporary blindness and visual hallucinations. Over time, the seizures worsen and become more difficult to treat. A life-threatening seizure condition called status epilepticus may also develop. Status epilepticus is a continuous state of seizure activity lasting longer than several minutes. About the same time seizures begin, intellectual function starts to decline. Behavioral changes, depression, confusion, and speech difficulties (dysarthria) are among the early signs and symptoms of this disorder. As the condition worsens, a continued loss of intellectual function (dementia) impairs memory, judgment, and thought. Affected people lose the ability to perform the activities of daily living by their mid-twenties, and they ultimately require comprehensive care.
    [Show full text]