Desenvolvimentos recentes na genética das encefalopatias epilépticas da infância: impacto na prática clínica

Gonsales, Marina C.; Montenegro, Maria Augusta; Soler, Camila V.; Coan, Ana Carolina; Guerreiro, Marilisa M.; Lopes-Cendes, Iscia

doi:10.1590/0004-282X20150122

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VIEWS AND REVIEWS • Arq. Neuro-Psiquiatr. 73 (11) • Nov 2015 • https://doi.org/10.1590/0004-282X20150122 copiar

Desenvolvimentos recentes na genética das encefalopatias epilépticas da infância: impacto na prática clínica

Autoria SCIMAGO INSTITUTIONS RANKINGS

Os avanços recentes em genética molecular permitiram a descoberta de vários genes para encefalopatias epilépticas da infância (EEIs). À medida que o conhecimento sobre os genes associados a este grupo de doenças se desenvolve, torna-se evidente que as EEIs apresentam uma série de características genéticas específicas, o que influencia o uso do teste molecular para fins clínicos. Entre as EEIs, há a presença de acentuada heterogeneidade genética e alta frequência de mutações de novo. Assim, os principais objetivos deste trabalho de revisão são apresentar e discutir o conhecimento atual a respeito de i) novas descobertas em genética molecular das EEIs, ii) correlações fenótipo-genótipo nas diferentes formas de EEIs; e, mais importante, iii) o impacto desses novos achados genéticos na prática clínica. Acompanhando o texto, incluímos uma tabela contendo a lista de genes conhecidos atualmente como envolvidos na etiologia da EEIs.

síndrome de Dravet; síndrome de Ohtahara; síndrome de West; síndrome de Lennox-Gastaut; síndrome de Doose; síndrome de Landau-Kleffner

Gene	Associated phenotype	References
ADORA2A	Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD)	61
ALG13	Lennox-Gastaut Syndrome and/or Infantile Spasms	62
ARFGEF2	West Syndrome	63
ARHGEF15	Severe Early-onset Epilepsy	64
ARHGEF9	Severe mental retardation and epilepsy	65
ARX	Lennox-Gastaut syndrome Ohtahara Syndrome West Syndrome	16; 29; 30
ASAH1	Childhood-onset Epilepsy or Early-onset encephalopathy	66
C10orf2	Early Onset Encephalopathy Infantile onset Spinocerebellar Ataxia Syndrome	67; 68
CACNA1A	Lennox-Gastaut Syndrome and/or Infantile Spasms	62
CACNA2D2	Early infantile epileptic encephalopathies	69; 70
CASK	Ohtahara Syndrome	17
CDKL5/STK9	Early onset encephalopathy Infantile Spasms and Mental Retardation Lennox-Gastaut syndrome West Syndrome	31; 71;72; 73
CHD2	Dravet Syndrome Infantile Spasms Lennox-Gastaut syndrome	45; 62; 74; 75
CHRNA7	Congenital retinal dysfunction, Refractory epilepsy, Encephalopathy, Mental retardation, Repetitive hand movements, Severe muscular hypotonia and Macrocytosis. Severe encephalopathy with seizures and hypotonia	76; 77; 78
CLCN4	Severe Early-onset Epilepsy	64
CNTNAP2	Focal Epilepsy with Regression	79
DCX	Lennox-Gastaut Syndrome and/or Infantile Spasms	62
DOCK7	Epileptic Encephalopathy and Cortical Blindness	80
EEF1A2	Severe Early-onset Epilepsy	64
ENG	Early Infantile Epileptic Encephalopathy with suppression-burst	81
ErbB4	Early Mioclonic Encephalopathy	13
FLNA	Lennox-Gastaut Syndrome and/or Infantile Spasms	62
FOLR1	Childhood-onset Epilepsy or Early-onset encephalopathy	66
FOXG1	Rett syndrome with early-onset seizures	82; 83
GABRA1	Lennox-Gastaut Syndrome and/or Infantile Spasms	62
GABRB3	Lennox-Gastaut Syndrome and/or Infantile Spasms	62
GABRG2	Doose syndrome Dravet Syndrome Generalized epilepsy with febrile seizures plus (GEFS+)	45; 50; 84
GNAO1	Epileptic Encephalopathy with involuntary movements	85
GRIN1	Lennox-Gastaut Syndrome and/or Infantile Spasms	62
GRIN2A	Epileptic encephalopathy with continuous spike-and-wave during sleep Atypical rolandic epilepsy and speech impairment Landau-Kleffner syndrome	56;58; 86; 87;88
GRIN2B	Lennox-Gastaut Syndrome and/or Infantile Spasms Mental retardation and/or epilepsy	88; 62
HCN1	Early Infantile Epileptic Encephalopathy	89
HDAC4	Lennox-Gastaut Syndrome and/or Infantile Spasms	62
HNRNPU	Lennox-Gastaut Syndrome and/or Infantile Spasms	62; 90
HOXD	Early Infantile Epileptic Encephalopathy without Mesomelic Dysplasia	91
IQSEC2	Lennox-Gastaut Syndrome and/or Infantile Spasms	62
JNK3	Severe Developmental Epileptic Encephalopathy (Lennox-Gastaut syndrome)	42
KCNH5	Severe Early-onset Epilepsy	64
KCNQ2	Early onset epileptic encephalopathy (EOEE) Ohtahara Syndrome	18; 92; 93; 94
KCNQ3	Benign Familial Neonatal Seizures (BFNS) Early onset epileptic encephalopathy (EOEE)	65; 95; 96
KCNT1	Malignant migrating partial seizures of infancy (MMPSI) Ohtahara Syndrome	18; 22;97
KCTD7	Progressive Myoclonus Epilepsy	65; 98
KLF13	Congenital retinal dysfunction, Refractory epilepsy, Encephalopathy, Mental retardation, Repetitive hand movements, Severe muscular hypotonia and Macrocytosis.	78
MAGI2	Early-onset Epileptic Encephalopathy Infantile spasms	99; 100; 101
MBD5	West Syndrome	90
MECP2	Early-onset Encephalopathy and Cortical Myoclonus Lennox-Gastaut syndrome and Rett syndrome	41; 102
MEF2C	Severe Intellectual Disability and Early-onset Epileptic Encephalopathy	103
MTOR	Lennox-Gastaut Syndrome and/or Infantile Spasms	62
NECAP1	Severe infantile epileptic encephalopathy	104
NEDD4L	Lennox-Gastaut Syndrome and/or Infantile Spasms	62
NRG2	Hypotonia, Feeding difficulty in infancy, Severe developmental delay, and Epileptic/nonepileptic Encephalopathy associated with Delayed Myelination	105
PCDH19	Dravet Syndrome Infantile or early childhood onset epilepsy in female patients Lennox-Gastaut syndrome	45; 53; 106
PCDHG	Hypotonia, Feeding difficulty in infancy, Severe developmental delay, and Epileptic/nonepileptic Encephalopathy associated with Delayed Myelination	105
PIGA	Early-onset Epileptic Encephalopathy	15
PIGQ	Ohtahara Syndrome	18
PLCB1	Early-onset epileptic encephalopathy Malignant migrating partial seizures in infancy	26; 62; 101
PNKP	Early-onset Epileptic Encephalopathy Intractable Seizures and Developmental delay West Syndrome	100; 101; 107
PNPO	Neonatal epileptic encephalopathy	108
POLG1	Alpers syndrome Childhood progressive encephalopathy Severe Encephalopathy with Intractable Epilepsy	109; 110
PRRT2	Benign familial Infantile Epilepsy (BFIE) Infantile convulsions with choreoathetosis (ICCA) Paroxysmal kinesigenic dyskinesia (PKD)	111; 112
RB1	Infantile Spasms and Retinoblastoma	113
SCN1A	Acute Encephalopathy Doose Syndrome Dravet Syndrome Early Onset Epilepsy (EOE) Generalized Epilepsy With Febrile Seizures Plus (GEFS+) Lennox-Gastaut syndrome Malformations of Cortical Development (MCDs) Malignant Migrating Partial Seizures of Infancy West Syndrome	11; 20; 43; 47; 64; 114; 115; 116; 117;118; 119; 120
SCN1B	Dravet Syndrome Generalized epilepsy with febrile seizures plus (GEFS+)	44; 52; 121
SCN2A	Dravet Syndrome Generalized epilepsy with febrile seizures plus (GEFS+) Intractable epilepsy Lennox-Gastaut syndrome Migrating focal seizures of infancy Ohtahara Syndrome West Syndrome	18; 19; 51; 65; 60; 122; 123
SCN8A	Epilepsy of infancy with migrating focal seizures Infantile epileptic encephalopathy and SUDEP Lennox-Gastaut syndrome	21;62; 124
SERPINI1	Continuous Spike and Waves during slow-wave Sleep	55
SLC19A3	Epileptic spasms in early infancy Severe psychomotor retardation	125
SLC25A22	Early myoclonic encephalopathy Epilepsy of infancy with migrating focal seizures Neonatal Epileptic Encephalopathy with Suppression Burst	12; 24; 126
SLC2A1	Doose Syndrome GLUT1 deficiency with neurodevelopmental delay and severe ataxia	46; 127
SLC35A2	Early-onset Epileptic Encephalopathy	128
SLC9A6	Continuous Spike and Waves during slow-wave Sleep and Christianson syndrome	57
SNAP25	Severe Static Encephalopathy, Intellectual disability, and Generalized Epilepsy	129
SPTAN1	West Syndrome	39; 130
SRGAP2	Early infantile epileptic encephalopathy	131
SRPX2	Rolandic epilepsy associated with oral and speech dyspraxia and mental retardation	132
STXBP1	Borderline Early myoclonic encephalopathy and Ohtahara Syndrome Early infantile epileptic encephalopathy Lennox-Gastaut syndrome Ohtahara Syndrome West Syndrome	14; 38; 62; 101; 133; 134
SYNGAP1	Early-onset epileptic Encephalopathy	45; 66
SYNJ1	Childhood-onset Epilepsy or Early-onset encephalopathy	66
SZT2	Early-onset Epileptic Encephalopathy characterized by Refractory Epilepsy and Absent Developmental Milestones	135
TBC1D24	Familial Infantile Myoclonic Epilepsy Focal epilepsy and Intellectual disability syndrome Malignant Migrating Partial Seizures of Infancy (MMPSI) Ohtahara Syndrome	23; 136
TCF4	Pitt-Hopkins syndrome (PHS)	137
TNK2	Infantile onset Epilepsy and Intellectual Disability	138
TOR1A	Early Infantile Epileptic Encephalopathy	81
TRPM1	Congenital retinal dysfunction, Refractory epilepsy, Encephalopathy, Mental retardation, Repetitive hand movements, Severe muscular hypotonia and Macrocytosis.	78

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[1] Correspondence
: Iscia Lopes-Cendes; Rua Tessalia Vieira de Camargo, 126; Cidade Universitária Zeferino Vaz / UNICAMP; 13083-887 Campinas SP, Brasil; E-mail: icendes@unicamp.br