Lafora Hastalığı; Tanı, Ayırıcı Tanı ve Güncel Tedavi Yaklaşımları
Özet
Lafora hastalığı nadir görülen, otozomal resesif geçişli kalıtsal bir hastalık olup tedaviye dirençli epileptik nöbetler miyoklonus ve ilerleyici nörolojik bozulma ile karakterize ölümcül bir hastalıktır. Hastalık EPM2A (laforin) ve EPM2B (malin) genlerindeki mutasyona bağlı oluşur. Lafora cisimleri olarak adlandırılan anormal yapıdaki glikojenin dokularda birikimi hastalığın asıl temelini oluşturur. Hastalık genellikle geç çocukluk veya erken ergenlik döneminde epileptik nöbetler ile ortaya çıkar ve zamanla tedaviye dirençli miyoklonuslar, ve davranış değişiklikleri, nöropsikiyatrik semptomlar, dirençli status epileptikus gelişir ve zaman içinde solunum yetmezliğine bağlı ölüm görülür. Lafora hastalığının kesin bir tedavisi yoktur, hastalığın ilerlemesini yavaşlatacak bazı tedavi yöntemleri üzerinde deneysel çalışmalar devam etmektedir.
Lafora disease is a rare, autosomal recessive, hereditary and fatal disease characterized by drug rezistans epileptic seizures, myoclonus and progressive neurological deterioration. The disease occurs due to mutation in the EPM2A(Laforin) and EPM2B (malin) genes. The accumulation in the tissues of abnormal glycogen called as Lafora bodies forms the basis of this disease.The disease usually appears epileptic seizures in late childhood or early adolescence and over the time occurs treatment resistant myoclonus, behavioral changes, neuropsychiatric semptoms ,resistant status epilepticus develop, and death due to respiratory failure. There is no spesific treatment for Lafora disease and some treatment methods that will slow down the progression of the disease continue to be investigated.
Referanslar
Gomez-Garre P, Sanz Y, Rodriguez De Cordoba SR, Serratosa JM. Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora: high degree of allelic heterogeneity and prevalence of deletions. Eur J Hum Genet (2000); 8: 946-54.
Franceschetti S, Gambardella A, Canafoglia L, et al. Clinical and genetic findings in 26 Italian patients with Lafora disease. Epilepsia (2006); 47: 640-3.
Turnbull J, Tiberia E, Striano P, et al. Lafora disease Epileptic Disord (2016); 18 (Suppl. 2): S38-62.
Minassian BA. Lafora’s disease: towards a clinical, pathologic, and molecular synthesis. Pediatr Neurol (2001); 25: 21-9.
Striano P, Zara F, Turnbull J, et al. Typical progression of myoclonic epilepsy of the Lafora type, a case report. Nat Clin Pract Neurol (2008); 4:106-11.
Nitschke F, Ahonen SJ, Nitschke S, Mitra S, Minassian BA. Lafora disease from pathogenesis to treatment strategies, Nat Rev Neurol (2018) Oct; 14(10):606-617.
Garcia-Gimeno MA, Knecht E, Sanz P. Lafora Disease:Aubiquitination-Realated Pathology cells (2018) Jul 26;7(8):87 .
Turnbull J, Girard JM, Lohi H, et al. Early-onset Lafora body disease. Brain (2012) sep.135(Pt9): 2684–2698.
Gómez-Abad C. Gómez-Garre P, Gutiérrez-Delicado E et al. Lafora disease due to EPM2B mutations: a clinical and genetic study. Neurology (2005). 64: 982–986.
Lohi H, Chan EM, Scherer SW, Minassian BA. On the road to tractability: the current biochemical understanding of progressive myoclonus epilepsies. Adv. Neurol (2006) 97:399–415.
Singh S, Sethi I, Francheschetti S.et al. Novel NHLRC mutations and genotype-phenotype correlations in patients with Lafora’s progressive myoclonic epilepsy. J.Med. Genet (2006)sep.43(9): e48.
Baykan B, Striano P, Gianotti S, et al. Late-onset and slow-progressing Lafora disease in four siblings with EPM2B mutation. Epilepsia (2005).46:1695–1697 2005 Oct;46(10):1695-1697.
Ferlazzo E, Canafoglia L, Michelucci R, et al. Mild Lafora disease: clinical, neurophysiologic, and genetic findings. Epilepsia (2014) Dec;55(12): e129–133.
Poyrazoğlu HG, Karaca E , Per H. Three patients with lafora disease: different clinical presentations and a novel mutation. J Child Neurol. (2015) May; 30 (6) : 777-781.
Ianzano L, Zhang J, Chan EM, Zhao XC, Lohi H, Scherer SW, Minassian BA, Lafora progressive myoclonus epilepsy mutation database -EPM2A and NHLRC1 (EPM2B) genes. Hum. Mutat (2005) Oct;26(4):397.
Jara-Prado A, Ochoa A , Alonso ME. et al. Late onset Lafora disease and novel EPM2A mutations: breaking paradigms. Epilepsy Res. (2014) 108: 1501–1510.
Guerrero R, Vernia S, Sanz R.et al. A PTG variant contributes to a milder phenotype in Lafora disease. PLoS ONE (2011);6(6):e21294.
Turnbull J, DePaoli-Roach AA, Zhao X.et al. PTG depletion removes Lafora bodies and rescues the fatal epilepsy of Lafora disease. PLoS Genet.(2011) Apr;7(4):e1002037.
Mitra S, Gumusgoz E, Minassian BA. Lafora dissease: current biology and therapeutic approches REv neurol (paris) 2022 April, 178(4):315-325.
Girard JM, Turnbull J, Ramachandran, Minassian BA. Progressive myoclonus epilepsy. Handb. Clin. Neurol. (2013) 113: 1731–1736.
Shahwan A, Farrell M. Delanty N Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol. (2005) 4: 239–248.
Khiari HM, Lesca G, Malafosse A. Mrabet A. A novel exon 3 mutation in a Tunisian patient with Lafora’s disease. J. Neurol. Sci. (2011) 304: 136–137.
Lesca G, Boutry-Kryza N, de Toffol B. et al. Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease. Epilepsia (2010) 51: 1691–1698.
Andrade DM, CA Ackerley, Minett TSC, Teive HAG, Bohlega S, Scherer SW, Minassian BA. Skin biopsy in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls. Neurology (2003). 61;1611–1614.
Lohi H, Turnbull J, Zhao XC. et al. Genetic diagnosis in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls. Neurology (2007); 68: 996-1001.
d’Orsi G, Lalla A, Palumbo O, et al. The presenting symptoms of Lafora Disease: An electroclinical and genetic study in five Apulian (Southern Italy) families. Seizure (2020);83:145–53.
Verhalen B, Arnold S, Minassian BA. Lafora Disease: A Review of Molecular Mechanisms and Pathology. Neuropediatrics (2018); 49(6): 357–362.
Villanueva V, Alvarez-Linera J, Gómez-Garre P, Gutiérrez J, Serratosa JM. MRI volumetry and proton MR spectroscopy of the brain in Lafora disease. Epilepsia (2006); 47: 788-92.
Pichiecchio A, Veggiotti P, Cardinali S, Longaretti F, Poloni GU, Uggetti C. Lafora disease: spectroscopy study correlated with neuropsychological findings. Eur J Paediatr Neurol(2008);12:342-7.
Berkovic SF, Andermann F, Carpenter S,Wolfe LS. Progressive myoclonus epilepsies: specific causes and diagnosis. N Engl J Med (1986); 315: 296-305.
Striano P, Zara F, Turnbull J, et al. Typical progression of myoclonic epilepsy of the Lafora type, a case report. Nat Clin Pract Neurol (2008); 4: 106-11.
Santavuori P, Lauronen L, Kirveskari E, Aberg L, Sainio K, Autti T. Neuronal ceroid lipofuscinoses in childhood. Neurol Sci (2000); 21: 35-41.
Siintola E, Topcu M, Aula N.et al. The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter. Am J Hum Genet (2007); 81: 136-46.
Nascimento FA, Andrade DM. Myoclonus epilepsy and ataxia due to potassium channel (MEAK) is caused by heterozygous KCN1 mutations. Epileptic Disord (2016) Sep 1;18(S2):135-138.
Schorlemmer K, Bauer S, Belke M. et al. Sustained seizure remission on perampanel in progressive myoclonic epilepsy (Lafora disease). Epilepsy Behav Case Rep (2013);1:118–21.
Dirani M, Nasreddine W, Abdulla F, Beydoun A. Seizure control and improvement of neurological dysfunction in Lafora disease with perampanel. Epilepsy Behav. Case Rep. (2014) 2;164– 166.
Goldsmith D, Minassian BA. Efficacy and tolerability of perampanel in ten patients with Lafora disease. Epilepsy Behav. (2016) 62; 132–135.
Hajnsek S, Gadze ZP, Borovecki F.et al. Vagus nerve stimulation in Lafora body disease. Epilepsy Behav. Case Rep. (2013) 1; 150–152.
Mikati MA, Tabbara F. Managing Lafora body disease with vagal nerve stimulation. Epilept. Disord (2017) 19; 82–86.
Israelian L, Wang P, Gabrielian S, Zhao X, Minassian BA. Ketogenic diet reduces Lafora bodies in murine Lafora disease. Neurol Genet (2020);6(6):e533.
Cardinali S, Canafoglia L, Bertoli S, Franceschetti S, Lanzi G,Tagliabue A,Pierangelo Veggiotti P. A pilot study of a ketogenic diet in patients with Lafora body disease. Epilepsy Res. (2006) 69: 129–134.
Berthier A, Payá M, García-Cabrero AM et al.Pharmacological interventions to ameliorate neuropathological symptoms in a mouse model of Lafora disease. Mol. Neurobiol.(2016)53:1296–1309.
Sanchez-Elexpuru G, Serratosa JM, Sanz P, Sanchez MP. 4-Phenylbutyric acid and metformin decrease sensitivity to pentylenetetrazol-induced seizures in a malin knockout model of Lafora disease. Neuroreport (2017) 28: 268–271.
Zhou Z, Austin GL, Shaffer R,Armstrong DD, Gentry MS. Antibody-Mediated Enzyme Therapeutics and Applications in Glycogen Storage Diseases. Trends Mol Me (2019); 25(12):1094–109.
Varea O, Duran J, Aguilera M, Prats N, Guinovart JJ. Suppression of glycogen synthesis as a treatment for Lafora disease: Establishing the window of opportunity. Neurobiol Dis (2021);147:105173.
Nitschke S, Chown EE, Zhao X. et al. An inducible glycogen synthase-1 knockout halts but does not reverse Lafora disease progression in mice. J Biol Chem (2021) Jan-jun:296:100150.
Kimura S, Harashima H. Current Status and Challenges Associated with CNS-Targeted Gene Delivery across the BBB. Pharmaceutics (2020) Dec 15;12(12) 1216.
Saraiva J, Nobre RJ, de Almeida LP. Gene therapy for the CNS using AAVs: the impact of systemic delivery by AAV9. J. Control. Release (2016).241, 94–109
Choudhury SR, Hudry E, Maguire CA , Esteves MS, Breakefield XO, Grandi P. Viral vectors for therapy of neurologic diseases. Neuropharmacology (2017) 120, 63–80.
Lykken EA, Shyng C, Edwards RJ, Rozenberg A, Gray SJ. Recent progress and considerations for AAV gene therapies targeting the central nervous system. J Neurodev Disord (2018);10(1):16.
Deverman BE, Ravina BM, Bankiewicz KS, Paul SM, Sah DWY. Gene therapy for neurological disorders: progress and prospects. Nat Rev Drug Discov (2018);17(9):641–59.
Waldrop MA, Karingada C, Storey MA, Powers B, Iammarino MA, Miller NF, et al. Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes. Pediatrics (2020);146(3).
Martier R, Konstantinova P. Gene Therapy for Neurodegenerative Diseases: Slowing Down the Ticking Clock. Front Neurosci (2020);14:580179.
Referanslar
Gomez-Garre P, Sanz Y, Rodriguez De Cordoba SR, Serratosa JM. Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora: high degree of allelic heterogeneity and prevalence of deletions. Eur J Hum Genet (2000); 8: 946-54.
Franceschetti S, Gambardella A, Canafoglia L, et al. Clinical and genetic findings in 26 Italian patients with Lafora disease. Epilepsia (2006); 47: 640-3.
Turnbull J, Tiberia E, Striano P, et al. Lafora disease Epileptic Disord (2016); 18 (Suppl. 2): S38-62.
Minassian BA. Lafora’s disease: towards a clinical, pathologic, and molecular synthesis. Pediatr Neurol (2001); 25: 21-9.
Striano P, Zara F, Turnbull J, et al. Typical progression of myoclonic epilepsy of the Lafora type, a case report. Nat Clin Pract Neurol (2008); 4:106-11.
Nitschke F, Ahonen SJ, Nitschke S, Mitra S, Minassian BA. Lafora disease from pathogenesis to treatment strategies, Nat Rev Neurol (2018) Oct; 14(10):606-617.
Garcia-Gimeno MA, Knecht E, Sanz P. Lafora Disease:Aubiquitination-Realated Pathology cells (2018) Jul 26;7(8):87 .
Turnbull J, Girard JM, Lohi H, et al. Early-onset Lafora body disease. Brain (2012) sep.135(Pt9): 2684–2698.
Gómez-Abad C. Gómez-Garre P, Gutiérrez-Delicado E et al. Lafora disease due to EPM2B mutations: a clinical and genetic study. Neurology (2005). 64: 982–986.
Lohi H, Chan EM, Scherer SW, Minassian BA. On the road to tractability: the current biochemical understanding of progressive myoclonus epilepsies. Adv. Neurol (2006) 97:399–415.
Singh S, Sethi I, Francheschetti S.et al. Novel NHLRC mutations and genotype-phenotype correlations in patients with Lafora’s progressive myoclonic epilepsy. J.Med. Genet (2006)sep.43(9): e48.
Baykan B, Striano P, Gianotti S, et al. Late-onset and slow-progressing Lafora disease in four siblings with EPM2B mutation. Epilepsia (2005).46:1695–1697 2005 Oct;46(10):1695-1697.
Ferlazzo E, Canafoglia L, Michelucci R, et al. Mild Lafora disease: clinical, neurophysiologic, and genetic findings. Epilepsia (2014) Dec;55(12): e129–133.
Poyrazoğlu HG, Karaca E , Per H. Three patients with lafora disease: different clinical presentations and a novel mutation. J Child Neurol. (2015) May; 30 (6) : 777-781.
Ianzano L, Zhang J, Chan EM, Zhao XC, Lohi H, Scherer SW, Minassian BA, Lafora progressive myoclonus epilepsy mutation database -EPM2A and NHLRC1 (EPM2B) genes. Hum. Mutat (2005) Oct;26(4):397.
Jara-Prado A, Ochoa A , Alonso ME. et al. Late onset Lafora disease and novel EPM2A mutations: breaking paradigms. Epilepsy Res. (2014) 108: 1501–1510.
Guerrero R, Vernia S, Sanz R.et al. A PTG variant contributes to a milder phenotype in Lafora disease. PLoS ONE (2011);6(6):e21294.
Turnbull J, DePaoli-Roach AA, Zhao X.et al. PTG depletion removes Lafora bodies and rescues the fatal epilepsy of Lafora disease. PLoS Genet.(2011) Apr;7(4):e1002037.
Mitra S, Gumusgoz E, Minassian BA. Lafora dissease: current biology and therapeutic approches REv neurol (paris) 2022 April, 178(4):315-325.
Girard JM, Turnbull J, Ramachandran, Minassian BA. Progressive myoclonus epilepsy. Handb. Clin. Neurol. (2013) 113: 1731–1736.
Shahwan A, Farrell M. Delanty N Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol. (2005) 4: 239–248.
Khiari HM, Lesca G, Malafosse A. Mrabet A. A novel exon 3 mutation in a Tunisian patient with Lafora’s disease. J. Neurol. Sci. (2011) 304: 136–137.
Lesca G, Boutry-Kryza N, de Toffol B. et al. Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease. Epilepsia (2010) 51: 1691–1698.
Andrade DM, CA Ackerley, Minett TSC, Teive HAG, Bohlega S, Scherer SW, Minassian BA. Skin biopsy in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls. Neurology (2003). 61;1611–1614.
Lohi H, Turnbull J, Zhao XC. et al. Genetic diagnosis in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls. Neurology (2007); 68: 996-1001.
d’Orsi G, Lalla A, Palumbo O, et al. The presenting symptoms of Lafora Disease: An electroclinical and genetic study in five Apulian (Southern Italy) families. Seizure (2020);83:145–53.
Verhalen B, Arnold S, Minassian BA. Lafora Disease: A Review of Molecular Mechanisms and Pathology. Neuropediatrics (2018); 49(6): 357–362.
Villanueva V, Alvarez-Linera J, Gómez-Garre P, Gutiérrez J, Serratosa JM. MRI volumetry and proton MR spectroscopy of the brain in Lafora disease. Epilepsia (2006); 47: 788-92.
Pichiecchio A, Veggiotti P, Cardinali S, Longaretti F, Poloni GU, Uggetti C. Lafora disease: spectroscopy study correlated with neuropsychological findings. Eur J Paediatr Neurol(2008);12:342-7.
Berkovic SF, Andermann F, Carpenter S,Wolfe LS. Progressive myoclonus epilepsies: specific causes and diagnosis. N Engl J Med (1986); 315: 296-305.
Striano P, Zara F, Turnbull J, et al. Typical progression of myoclonic epilepsy of the Lafora type, a case report. Nat Clin Pract Neurol (2008); 4: 106-11.
Santavuori P, Lauronen L, Kirveskari E, Aberg L, Sainio K, Autti T. Neuronal ceroid lipofuscinoses in childhood. Neurol Sci (2000); 21: 35-41.
Siintola E, Topcu M, Aula N.et al. The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter. Am J Hum Genet (2007); 81: 136-46.
Nascimento FA, Andrade DM. Myoclonus epilepsy and ataxia due to potassium channel (MEAK) is caused by heterozygous KCN1 mutations. Epileptic Disord (2016) Sep 1;18(S2):135-138.
Schorlemmer K, Bauer S, Belke M. et al. Sustained seizure remission on perampanel in progressive myoclonic epilepsy (Lafora disease). Epilepsy Behav Case Rep (2013);1:118–21.
Dirani M, Nasreddine W, Abdulla F, Beydoun A. Seizure control and improvement of neurological dysfunction in Lafora disease with perampanel. Epilepsy Behav. Case Rep. (2014) 2;164– 166.
Goldsmith D, Minassian BA. Efficacy and tolerability of perampanel in ten patients with Lafora disease. Epilepsy Behav. (2016) 62; 132–135.
Hajnsek S, Gadze ZP, Borovecki F.et al. Vagus nerve stimulation in Lafora body disease. Epilepsy Behav. Case Rep. (2013) 1; 150–152.
Mikati MA, Tabbara F. Managing Lafora body disease with vagal nerve stimulation. Epilept. Disord (2017) 19; 82–86.
Israelian L, Wang P, Gabrielian S, Zhao X, Minassian BA. Ketogenic diet reduces Lafora bodies in murine Lafora disease. Neurol Genet (2020);6(6):e533.
Cardinali S, Canafoglia L, Bertoli S, Franceschetti S, Lanzi G,Tagliabue A,Pierangelo Veggiotti P. A pilot study of a ketogenic diet in patients with Lafora body disease. Epilepsy Res. (2006) 69: 129–134.
Berthier A, Payá M, García-Cabrero AM et al.Pharmacological interventions to ameliorate neuropathological symptoms in a mouse model of Lafora disease. Mol. Neurobiol.(2016)53:1296–1309.
Sanchez-Elexpuru G, Serratosa JM, Sanz P, Sanchez MP. 4-Phenylbutyric acid and metformin decrease sensitivity to pentylenetetrazol-induced seizures in a malin knockout model of Lafora disease. Neuroreport (2017) 28: 268–271.
Zhou Z, Austin GL, Shaffer R,Armstrong DD, Gentry MS. Antibody-Mediated Enzyme Therapeutics and Applications in Glycogen Storage Diseases. Trends Mol Me (2019); 25(12):1094–109.
Varea O, Duran J, Aguilera M, Prats N, Guinovart JJ. Suppression of glycogen synthesis as a treatment for Lafora disease: Establishing the window of opportunity. Neurobiol Dis (2021);147:105173.
Nitschke S, Chown EE, Zhao X. et al. An inducible glycogen synthase-1 knockout halts but does not reverse Lafora disease progression in mice. J Biol Chem (2021) Jan-jun:296:100150.
Kimura S, Harashima H. Current Status and Challenges Associated with CNS-Targeted Gene Delivery across the BBB. Pharmaceutics (2020) Dec 15;12(12) 1216.
Saraiva J, Nobre RJ, de Almeida LP. Gene therapy for the CNS using AAVs: the impact of systemic delivery by AAV9. J. Control. Release (2016).241, 94–109
Choudhury SR, Hudry E, Maguire CA , Esteves MS, Breakefield XO, Grandi P. Viral vectors for therapy of neurologic diseases. Neuropharmacology (2017) 120, 63–80.
Lykken EA, Shyng C, Edwards RJ, Rozenberg A, Gray SJ. Recent progress and considerations for AAV gene therapies targeting the central nervous system. J Neurodev Disord (2018);10(1):16.
Deverman BE, Ravina BM, Bankiewicz KS, Paul SM, Sah DWY. Gene therapy for neurological disorders: progress and prospects. Nat Rev Drug Discov (2018);17(9):641–59.
Waldrop MA, Karingada C, Storey MA, Powers B, Iammarino MA, Miller NF, et al. Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes. Pediatrics (2020);146(3).
Martier R, Konstantinova P. Gene Therapy for Neurodegenerative Diseases: Slowing Down the Ticking Clock. Front Neurosci (2020);14:580179.
