Conclusions
The evidences and examples discussed in previous sections clearly
indicates that identifying the pathogenic variant in individual patients
with genetic epilepsies is relevant not only for diagnosis and
prognosis, but also for patient’s management including selection of the
best medication and/or the indication of which drugs might worsen
seizure frequency or cause severe side effects thus should be avoided.
Research is now very sensitive to the urgent need to identify a cure for
the disorder/diseases improving seizures and accompanying comorbidities.
Furthermore, our increased understanding of the aetiologies of
epilepsies, in some patients, allowed to identify specific targets for
therapies that go beyond ASM and that enable treatment of the cause of
epilepsy. We are already witnessing a major shift in our paradigm of
epilepsy treatment and have moved towards the era of therapies that
target the underlying cause and mechanisms of epilepsy. Available,
commercialised and approved by the authorities, aetiology-based
treatments are only partially satisfying, several drugs have proven
effective in some patients and not in others carrying similar genotypes.
Results are discordant and not univocal for most of the newly proposed,
precision medicines. Moreover such treatments are still focused on
stopping seizures.
There is no doubt that gene therapy will change our therapeutic approach
to monogenic epilepsies. To reverse the pathophysiological impact of
pathogenic variants, gene editing seems to be a very promising tool and
is likely to be most effective when administered during the early stages
of disease or even preventively. In this scenario, the challenge for
epileptologists is to identify the causes of epilepsy early in order to
promote preventive therapies and to avoid the occurrence of epilepsy,
including seizures and comorbidities.
In conclusion the whole scientific community is rapidly evolving towards
a more curative, pathophysiology-based and preventive therapeutic
approach of disorders featuring seizures and comorbidities. Meanwhile,
there are three main requirements for a systematic approach to precision
medicine in epilepsy: first of all is patient’s registry, a key
requirement to enrol large cohorts of individuals with epilepsy who have
been phenotypically and genomically characterized; second a standardized
functional characterization of mutations in each of the epilepsy genes
and third, since we are dealing with rare disorders, multi-center,
randomized, controlled trials are needed and feasible when functional
studies identifies new targets that might be translated into
personalized and tailored drugs. Reaching these goals depends on the
development of collaborative and integrated research groups that bring
together researchers with clinical, genetic, and biological expertise.
Physicians and families are ready and looking forward to this new era of
precision medicine.
References
- Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of
the epilepsies: Position paper of the ILAE Commission for
Classification and Terminology. Epilepsia. 2017;58(4):512-521.
- Ragona F, Granata T, Dalla Bernardina B, et al.Cognitive development
in Dravet syndrome: a retrospective, multicenter study of 26 patients.
Epilepsia. 2011;52(2):386-92
- Caraballo RH, Cejas N, Chamorro N, Kaltenmeier MC, Fortini S, Soprano
AM. Landau-Kleffner syndrome: a study of 29 patients. Seizure.
2014;23(2):98-104.
- Meldrum BS, Horton RW. Physiology of status epilepticus in primates.
Arch Neurol 1973;28:1-9.
- Trinka E, Cock H, Hesdorffer D et al. A definition and classification
of status epilepticus–Report of the ILAE Task Force on
Classification of Status Epilepticus. Epilepsia. 2015;56(10):1515-23.
- Mei D, Parrini E, Marini C, Guerrini R. The Impact of Next-Generation
Sequencing on the Diagnosis and Treatment of Epilepsy in Paediatric
Patients. Mol Diagn Ther. 2017;21(4):357-373.
- Dunn P, Albury CL, Maksemous N, et al Next Generation Sequencing
Methods for Diagnosis of Epilepsy Syndromes. Front Genet. 2018; 9: 20.
- Nabbout R, Kuchenbuch M. Impact of predictive, preventive and
precision medicine strategies in epilepsy. Nat Rev Neurol.
2020;16(12):674-688.
- Parrini E, Marini C, Mei D et al. Diagnostic Targeted Resequencing in
349 Patients with Drug-Resistant Pediatric Epilepsies Identifies
Causative Mutations in 30 Different Genes. Hum Mutat.
2017;38(2):216-225
- Hebbar M, Mefford HC. Recent advances in epilepsy genomics and genetic
testing. F1000Resaerch 2020, 12;9:F1000 Faculty Rev-185.
- Stödberg T, Tomson T, Barbaro M, et al. Epilepsy syndromes,
etiologies, and the use of next-generation sequencing in epilepsy
presenting in the first 2 years of life: A population-based study.
Epilepsia. 2020;61(11):2486-2499.
- Symonds JD, McTague. Epilepsy and developmental disorders: Next
generation sequencing in the clinic. A. Eur J Paediatr Neurol.
2020;24:15-23
- Guerrini R, Noebels J. How can advances in epilepsy genetics lead to
better treatments and cures? Adv Exp Med Biol. 2014;813:309–17.
- Szepetowski P. Genetics of human epilepsies: Continuing progress.
Presse Med. 2018;47(3):218-226
- Josephson CB, Wiebe S. Precision Medicine: Academic dreaming or
clinical reality? Epilepsia. 2021;62 Suppl 2:S78-S89.
- Thakran S, Guin D, Singh P, et al. Genetic Landscape of Common
Epilepsies: Advancing towards Precision in Treatment. Int J Mol Sci.
2020;21(20):7784
- FDA. Workshop on natural history studies of rare diseases. 2012.
Bethesda, MD: FDA. Rare diseases: natural history studies for drug
development guidance for industry. In: Administration FD, ed. 2019.
https://www.fda.gov/media/122425/download
- US Food and Drug Administration. Human gene therapy for rare diseases,
guidance for industry (FDA, 2020).
- FDA (Food and Drug Administration). Application of current statutory
authorities to human somatic cell therapy products and gene therapy
products. Fed. Regist. 58, 53248–53251 (1993).
- Mei D, Cetica V, Marini C, Guerrini R. Dravet syndrome as part of the
clinical and genetic spectrum of sodium channel epilepsies and
encephalopathies. Epilepsia. 2019;60 Suppl 3:S2-S7.
- Guerrini R, Dravet C, Genton P, Belmonte A, Kaminska A, Dulac O.
Lamotrigine and seizure aggravation in severe myoclonic epilepsy.
Epilepsia. 1998;39:508–12.
- de Lange IM, Gunning B, Sonsma ACM et al. Influence of contraindicated
medication use on cognitive outcome in Dravet syndrome and age at
first afebrile seizure as a clinical predictor in SCN1A-related
seizure phenotypes. Epilepsia. 2018;59(6):1154-1165
- Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De
Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause
severe myoclonic epilepsy of infancy. Am J Hum Genet.
2001;68(6):1327-32.
- Marini C, Mantegazza M. Na+ channelopathies and epilepsy: recent
advances and new perspectives. Expert Rev Clin Pharmacol.
2010;3(3):371-84.
- Ceulemans B, Boel M, Claes L, Dom L, Willekens H, Thiry P, Lagae L.
Severe myoclonic epilepsy in infancy: toward an optimal treatment. J
Child Neurol. 2004 Jul;19(7):516-21
- Wirrell EC, Laux L, Donner E, et al. Optimizing the Diagnosis and
Management of Dravet Syndrome: Recommendations From a North American
Consensus Panel. Pediatr Neurol. 2017;68:18-34.e3.
- Wirrell EC, Nabbout R
Recent Advances in
the Drug Treatment of Dravet Syndrome. CNS Drugs. 2019;33(9):867-881.
- Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe myoclonic
epilepsy in infancy: a randomised placebo-controlled
syndrome-dedicated trial. STICLO study group. Lancet.
2000;356:1638–42.
- Fisher JL. The effects of stiripentol on GABAA receptors. Epilepsia
2011;52:76-78
- Marini C, Porro A, Rastetter A et al. HCN1 mutation spectrum: from
neonatal epileptic encephalopathy to benign generalized epilepsy and
beyond. Brain. 2018;141(11):3160-3178.
- Bleakley LE, McKenzie CE, Soh et al. Cation leak underlies neuronal
excitability in an HCN1 developmental and epileptic encephalopathy.
Brain. 2021. Online ahead of print.
- Numis AL, Angriman M, Sullivan JE, et al. KCNQ2 encephalopathy:
delineation of theelectroclinical phenotype and treatment response.
Neurology. 2014;82:368–70.
- Pisano T, Numis AL, Heavin SB et al. Early and effective treatment of
KCNQ2 encephalopathy. Epilepsia. 2015;56:685–91.
- Ohba C, Kato M, Takahashi S et al. Early onset epileptic
encephalopathy caused by de novo SCN8A mutations. Epilepsia 2014:55,
994–1000
- Larsen J, Carvill GL, Gardella E et al. The phenotypic spectrum of
SCN8A encephalopathy. Neurology. 2015;84(5):480-9.
- Wolff M, Johannesen KM, Hedrich UB et al. Genetic and phenotypic
heterogeneity suggest therapeutic implications in SCN2A-related
disorders. Brain 2017;140, 1316–1336
- Gardella E, Møller RS. Phenotypic and genetic spectrum of
SCN8A-related disorders, treatment options, and outcomes. Epilepsia.
2019;60 Suppl 3:S77-S85.
- Dilena, R. Striano P, Gennaro E, et al. Efficacy of sodium channel
blockers in SCN2A early infantile epileptic encephalopathy. Brain Dev.
2017;39, 345–348
- Chen WJ, Lin Y, Xiong ZQ, et al. Exome sequencing identifies
truncating mutations in PRRT2 that cause paroxysmal kinesigenic
dyskinesia. Nat Genet 2011;43:1252–1255.
- Marini C, Conti V, Mei D, et al. PRRT2 mutations in familial infantile
seizures, paroxysmal dyskinesia, and hemiplegic migraine. Neurology.
2012;79(21):2109-14.
- De Gusmao CM, Silveira-Moriyama L. Paroxysmal movement disorders -
practical update on diagnosis and management. Expert Rev Neurother.
2019;19(9):807-822.
- Curatolo P, Nabbout R, Lagae L et al. Management of epilepsy
associated with tuberous sclerosis complex: updated clinical
recommendations. Eur J Paediatr Neurol. 2018;22(5):738–48.
- Hynynen J, Komulainen T, Tukiainen E, et al. Acute liver failure after
valproate exposure in patients with POLG1 mutations and the prognosis
after liver transplantation. Liver Transpl. 2014; 20:1402–12.
- Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for
Stevens-Johnson syndrome. Nature. 2004; 428:486.
- EpiPM consortium. A road Map for precision medicine in the epilepsies.
Lancet Neurol. 2015 December ; 14(12): 1219–122
- Perucca P, Perucca E. Identifying mutations in epilepsy genes: Impact
on treatment selection. Epilepsy Res. 2019 May;152:18-30
- De Vivo DC, Trifiletti RR, Jacobson RI, et al. Defective glucose
transport across the blood-brain barrier as a cause of persistent
hypoglycorrhachia, seizures, and developmental delay. N Engl J Med.
1991;325(10):703-709.
- Klepper J, Akman C, Armeno M et al. Glut1 Deficiency Syndrome
(Glut1DS): State of the art in 2020 and recommendations of the
international Glut1DS study group. Epilepsia Open. 2020;5(3):354-365.
- Weber YG, Storch A, Wuttke TV, et al. GLUT1 mutations are a cause of
paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by
a cation leak. J Clin Invest. Jun 2008;118(6):2157-2168.
- Suls A, Mullen SA, Weber YG, et al. Early-onset absence epilepsy
caused by mutations in the glucose transporter GLUT1. Ann Neurol.
2009;66(3):415-419.
- Mullen SA, Suls A, De Jonghe P, Berkovic SF, Scheffer IE. Absence
epilepsies with widely variable onset are a key feature of familial
GLUT1 deficiency. Neurology. 2010;75(5):432-440.
- van Karnebeek CDM, Sayson B, Lee JJY et al. Metabolic Evaluation of
Epilepsy: A Diagnostic Algorithm With Focus on Treatable
Conditions.Front Neurol. 2018;9:1016.
- Plecko B. Pyridoxine and pyridoxlaphosphate-dependent epilepsies.
Handb Clin Neurol. 2013;113:1811-7.
- Wilson MP, Plecko B, Mills PB, Clayton PT. Disorders affecting vitamin
B6 metabolism. J Inherit Metab Dis. 2019 Jul;42(4):629-646.
- Coughlin CR, Tseng LA, Abdenur JE,et al. Consensus guidelines for the
diagnosis and management of pyridoxine-dependent epilepsy due to
alpha-aminoadipic emialdehyde dehydrogenase deficiency. J Inherit
Metab Dis. 2021;44(1):178-192.
- Pope S, Artuch R, Heales S, Rahman S. Cerebral folate deficiency:
analytical tests and differential diagnosis. J Inherit Metab Dis.
2019;42:655–72.
- Wolf B. Biotinidase deficiency: “If you have to have an inherited
metabolic disease, this is the one to have.” Genet Med. 2012;14:
565–75.
- Markham A. Cerliponase Alfa: First Global Approval. Drugs.
2017;77(11):1247-1249.
- Schulz, A, Ajayi T, Specchio N, et al. Study of intraventricular
cerliponase alfa for CLN2 disease. N. Engl. J. Med.
2018;378:1898–1907
- Specchio N, Pietrafusa N, Trivisano M. Changing Times for CLN2
Disease: The Era of Enzyme Replacement Therapy. Ther Clin Risk Manag.
2020;16:213-222.
- Schulz, A. et al. Persistent treatment effect of cerliponase alfa in
children with CLN2 disease: a 3 year update from an ongoing
multicenter extension study. Mol. Genet. Metab. 2019;126:S133
- Franz DN, Belousova E, Sparagana S et al. Efficacy and safety of
everolimus for subependymal giant cell astrocytomas associated with
tuberous sclerosis complex (EXIST-1): a multicentre, randomised,
placebo-controlled phase 3 trial. Lancet 2013; 381:125–32.
- Franz DN, Belousova E, Sparagana S et al. Long-term use of everolimus
in patients with tuberous sclerosis complex: final results from the
EXIST-1 Study. PLoS ONE;2016;11:e0158476.
- Krueger DA, Care MM, Agricola K, Tudor C, Mays M, Franz DN. Everolimus
long-term safety and efficacy in subependymal giant cell astrocytoma.
Neurology 2013;80:574–80.
- French JA, Lawson JA, Yapici Z, et al. Adjunctive everolimus therapy
for treatment-resistant focal-onset seizures associated with tuberous
sclerosis (EXIST-3): a phase 3, randomised, double-blind,
placebo-controlled study. Lancet 2016; 388, 2153–2163
- Krueger DA, Capal JK, Curatolo P, et al. Short-term safety of mTOR
inhibitors in infants and very young children with tuberous sclerosis
complex (TSC): Multicentre clinical experience. Eur J Paediatr Neurol.
2018;22(6):1066-1073.
- El Achkar CM, Olson HE, Poduri A, Pearl PL. The genetics of the
epilepsies. Curr Neurol Neurosci Rep. 2015;15(7):39.
- Stödberg T, Tomson T, Barbaro M, et al. Epilepsy syndromes,
etiologies, and the use of next-generation sequencing in epilepsy
presenting in the first 2 years of life: A population-based study.
Epilepsia. 2020;61(11):2486-2499
- Alsubaie L, Aloraini T, Amoudi M, et al. Genomic testing and
counselling: The contribution of next-generation sequencing to
epilepsy genetics. Ann Hum Genet. 2020;84(6):431-436
- Willimsky EK, Munzig A, Mayer K, et al. Next Generation Sequencing in
Pediatric Epilepsy Using Customized Panels: Size Matters.
Neuropediatrics. 2021;52(2):92-97
- Weckhuysen S, Mandelstam S, Suls A et al. KCNQ2 encephalopathy:
emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol.
2012;71(1):15-25.
- Marini C, Romoli M, Parrini E, et al. Clinical features and outcome of
6 new patients carrying de novo KCNB1 gene mutations. Neurol Genet.
2017;3(6):e206.
- Corbett MA, Bellows ST, Li M, et al. Dominant KCNA2 mutation causes
episodic ataxia and pharmacoresponsive epilepsy. Neurology.
2016;87(19):1975-1984
- McTague A, Nair U, Malhotra S, et al. Clinical and molecular
characterization of KCNT1-related severe early-onset epilepsy.
Neurology. 2018;90(1):e55-e66.
- Symonds JD, McTague A. Epilepsy and developmental disorders: Next
generation sequencing in the clinic. Eur J Paediatr Neurol.
2020;24:15-23
- Nikitin ES, Vinogradova LV. Potassium channels as prominent targets
and tools for the treatment of epilepsy. Expert Opin Ther Targets.
2021:1-13.
- Orhan G, Bock M, Schepers D, et al. Dominant-negative effects of KCNQ2
mutations are associated with epileptic encephalopathy, Ann Neurol
2014;75:382–94.
- Miceli F, Soldovieri MV, Ambrosino P, et al Pharmacological Targeting
of Neuronal Kv7.2/3 Channels: A Focus on Chemotypes
and Receptor Sites, Curr Med Chem 2018; 25:2637–60.
- Millichap JJ, Park KL, Tsuchida T et al. KCNQ2 encephalopathy:
Features, mutational hot spots, and ezogabine treatment of 11
patients. Neurol Genet. 2016 22;2(5):e96
- Soldovieri MV, Freri E, Ambrosino P et al. Gabapentin treatment in a
patient with KCNQ2 developmental epileptic encephalopathy. Pharmacol
Res. 2020;160:105200.
- Devaux J, Abidi A, Roubertie A et al. A Kv7.2 mutation associated with
early onset epileptic encephalopathy with suppression-burst enhances
Kv7/M channel activity. Epilepsia. 2016;57(5):e87-93.
- Millichap JJ, Miceli F, De Maria M, et al. Infantile spasms and
encephalopathy without preceding neonatal seizures caused by KCNQ2
R198Q, a gain-of-function variant. Epilepsia. 2017;58(1):e10-e15.
- Barcia G, Fleming MR, Deligniere A et al. De novo gain-of-function
KCNT1 channel mutations cause malignant migrating partial seizures of
infancy. Nat Genet. 2012;44(11):1255-9.
- Heron SE, Smith KR, Bahlo M, et al. Missense mutations in the
sodium-gated potassium channel gene KCNT1 cause severe autosomal
dominant nocturnal frontal lobe epilepsy. Nat Genet
2012;44:1188–1190.
- Barcia G, Chemaly N, Kuchenbuch M et al. Epilepsy with migrating focal
seizures: KCNT1 mutation hotspots and phenotype variability. Neurol
Genet. 2019;5(6):e363.
- Bearden D, Strong A, Ehnot J, DiGiovine M, Dlugos D, Goldberg EM.
Targeted treatment of migrating partial seizures of infancy with
quinidine.Ann Neuro 2014;76: 457–461. 14.
- Milligan CJ, Li M, Gazina EV, Heron SE et al. KCNT1 gain of function
in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol.
2014;75(4):581-90.
- Mikati MA, JiangYH, Carboni M, et al.Quinidine in the treatment of
KCNT-positive epilepsies. Ann Neurol 2015;78:995–999.
- Chong PF, Nakamura R, Saitsu H, Matsumoto N, Kira R. Ineffective
quinidine therapy in early onset epileptic encephalopathy with KCNT1
mutation. Ann Neurol 2016;79:502–503.
- Mullen SA, Carney PW, Roten A et al. Precision therapy for epilepsy
due to KCNT1 mutations: A randomized trial of oral quinidine.
Neurology. 2018;90(1):e67-e72.
- Borlot F, Abushama A, Morrison-Levy N et al. KCNT1-related epilepsy:
An international multicenter cohort of 27 pediatric cases. Epilepsia.
2020;61(4):679-692.
- Carvill GL, Regan BM, Yendle SC, et al. GRIN2A mutations cause
epilepsy-aphasia spectrum disorders. Nat Genet 2013;45:1073–6.
- Lemke JR, Lal D, Reinthaler EM, et al. Mutations in GRIN2A cause
idiopathic focal epilepsy with rolandic spikes. Nat Genet
2013;45:1067–72.
- Lesca G, Rudolf G, Bruneau N, et al. GRIN2A mutations in acquired
epileptic aphasia and related childhood focal epilepsies and
encephalopathies with speech and language dysfunction. Nat Genet
2013;45:1061–6.
- Lemke JR, Hendrickx R, Geider K, et al. GRIN2B mutations in West
syndrome and intellectual disability with focal epilepsy. Ann Neurol
2014;75:147–54.
- Ghasemi M, Schachter SC. The NMDA receptor complex as a therapeutic
target in epilepsy: a review. Epilepsy Behav. 2011;22(4):617-40.
- Pierson TM, Yuan H, Marsh ED, et al. GRIN2A mutation and early-onset
epileptic encephalopathy: personalized therapy with memantine. Ann
Clin Transl Neurol 2014;1:190–8.
- Li D, Yuan H, Ortiz-Gonzalez XR et al. GRIN2D recurrent de novo
dominant mutation causes a severe epileptic encephalopathy treatable
with NMDA receptor channel blockers. Am J Hum Genet 2016;99:802–16.
- Platzer K, Yuan H, Schütz H, et al. GRIN2B encephalopathy:
novel findings on phenotype, variant clustering, functional
consequences and treatment aspects. J Med Genet. 2017;54(7):460-470
- May P, Girard S, Harrer M et al. Rare coding variants in genes
encoding GABAA receptors in genetic generalised epilepsies: an
exome-based case-control study. Lancet Neurol. 2018;17(8):699-708.
- Dibbens LM, Feng HJ., Richards M et al. GABRD encoding a protein for
extra- or peri-synaptic GABA-A receptors is a susceptibility locus for
generalized epilepsies. Hum. Molec. Genet. 2004:13: 1315-1319
- Kiss B, Karpati E. Mechanism of action of vinpocetine. Acta Pharm
Hung. 1996;66(5):213–24.
- Billakota S, Andresen JM, Gay BC, et al. Personalized medicine:
Vinpocetine to reverse effects of GABRB3 mutation. Epilepsia.
2019;60:2459– 2465.
- Bönöczk P, Gulyás B, Adam-Vizi V, et al. Role of sodium channel
inhibition in neuroprotection: effect of vinpocetine. Brain Res Bull.
2000;53(3):245–54.
- Minassian BA, Lee JR, Herbrick JA, et al. Mutations in a gene encoding
a novel protein tyrosine phosphatase cause progressive myoclonus
epilepsy. Nat. Genet. 1998, 20, 171–174
- Chan EM, Young EJ, Ianzano L, Munteanu I et al. Mutations in NHLRC1
cause progressive myoclonus epilepsy. Nat. Genet. 2003:35,125–127
- Nitschke F, Ahonen SJ, Nitschke S, Mitra S, Minassian BA. Lafora
disease - from pathogenesis to treatment strategies. Nat Rev Neurol.
2018;14(10):606-617
- Dulovic M, Jovanovic M, Xilouri M, et al. The protective role of AMP-
activated protein kinase in alpha- synuclein neurotoxicity in vitro.
Neurobiol. Dis 2014;63:1–11
- Ashabi G, Khodagholi F, Khalaj L, Goudarzvand M. & Nasiri, M.
Activation of AMP- activated protein kinase by metformin protects
against global cerebral ischemia in male rats: interference of
AMPK/PGC-1α pathway. Metab. Brain Dis. 2014;29:47–58
- Yang Y. Zhu B, Zheng F, et al. Chronic metformin treatment facilitates
seizure termination. Biochem. Biophys. Res. Commun. 2017;484: 450–455
- Berthier A. Payá M, García-Cabrero AM et al. Pharmacological
interventions to ameliorate neuropathological symptoms in a mouse
model of Lafora disease. Mol. Neurobiol. 53, 1296–1309 (2016).
- Sanchez- Elexpuru G, Serratosa JM, Sanz P. & Sanchez MP. 4-PBA and
metformin decrease sensitivity to PTZ- induced seizures in a malin
knockout model of Lafora disease. Neuroreport 28, 268–271 (2017).
- Bisulli F, Muccioli L, d’Orsi G, et al. Treatment with metformin in
twelve patients with Lafora disease. Orphanet J Rare Dis. 2019
21;14(1):149.
- Dibbens LM, Tarpey PS, Hynes K, et al. X-linked protocadherin 19
mutations cause female-limited epilepsy and cognitive impairment. Nat
Genet. 2008;40:776–781
- Depienne C, Bouteiller D, Keren B et al. Sporadic infantile epileptic
encephalopathy caused by mutations in PCDH19 resembles dravet syndrome
but mainly affects females. PLoS Genet. 2009 5(2):e1000381
- Kolc KL, Sadleir LG, Depienne C et al. A standardized patient-centered
characterization of the phenotypic spectrum of PCDH19 girls clustering
epilepsy. Transl Psychiatry. 2020;10(1):127-
- Marini C, Darra F, Specchio N. Focal seizures with affective symptoms
are a major feature of PCDH19 gene-related epilepsy. Epilepsia.
2012;53(12):2111-9.
- Tan C, Shard C, Ranieri E et al. Mutations of protocadherin 19 in
female epilepsy (PCDH19-FE) lead to allopregnanolone deficiency. Hum
Mol Genet 2015;24:5250-9
- Pieribone VA, Tsai J, Soufflet C et al. Clinical evaluation of
ganaxolone in pediatric and adolescent patients with refractory
epilepsy. Epilepsia. 2007;48:1870–4. 98.
- Kerrigan JF, Shields WD, Nelson TY et al. Ganaxolone for treating
intractable infantile spasms: a multicenter, open-label, add-on trial.
Epilepsy Res. 2000;42:133–9.
- Lattanzi S, Riva A, Striano P. Ganaxolone treatment for epilepsy
patients: from pharmacology to place in therapy. Expert Rev Neurother.
2021:1-16.
- Chatron N, Becker F, Morsy H et al. Bi-allelic GAD1 variants cause a
neonatal onset syndromic developmental and epileptic encephalopathy.
Brain. 2020;143(5):1447-1461
- von Hardenberg S, Richter MF et al. Rational therapy with vigabatrin
and a ketogenic diet in a patient with GAD1 deficiency. Brain.
2020;143(11):e91.
- Neuray C, Maroofian R, Scala M, et al. Early-infantile onset epilepsy
and developmental delay caused by bi-allelic GAD1 variants. Brain
2020; 143: 2388–97.
- Chiron C, Dumas C, Jambaqué I, et al. Randomized trial comparing
vigabatrin and hydrocortisone in infantile spasms due to tuberous
sclerosis. Epilepsy Res. 1997;26:389-395.
- Elterman RD, Shields WD, Mansfield KA, Nakagawa J. US Infantile Spasms
Vigabatrin Study Group. Randomized trial of vigabatrin in patients
with infantile spasms. Neurology. 2001;57:1416-1421.
- de Vries PJ, Whittemore VH, Leclezio L, et al. Tuberous sclerosis
associated neuropsychiatric disorders (TAND) and the TAND Checklist.
Pediatr Neurol. 2015;52:25-35.
- O’Callaghan FJK, Harris T, Joinson C, et al. The relation of infantile
spasms, tubers, and intelligence in tuberous sclerosis complex. Arch
Dis Child. 2004; 89:530-533.
- Jóźwiak S, Kotulska K, Domańiska-Pakiela D, et al. Antiepileptic
treatment before the onset of seizures reduces epilepsy severity and
risk of mental retardation in infants with tuberous sclerosis complex.
Eur J Paediatr Neurol. 2011;15:424-431.
- Kotulska K, Kwiatkowski DJ, Curatolo P, et al Prevention of Epilepsy
in Infants with Tuberous Sclerosis Complex in the EPISTOP Trial. Ann
Neurol. 2021;89(2):304-314.
- Stockler S, Plecko B, Gospe SM Jr et al. Pyridoxine dependent epilepsy
and antiquitin deficiency: clinical and molecular characteristics and
recommendations for diagnosis, treatment and follow-up. Mol Genet
Metab. 2011;104(1-2):48-60.
- Bennett CF, Krainer AR, Cleveland DW. Antisense Oligonucleotide
Therapies for Neurodegenerative Diseases. Annu Rev Neurosci.
2019;42:385-406.
- Wirrell EC, Nabbout R. Recent Advances in the Drug Treatment of Dravet
Syndrome. CNS Drugs. 2019;33(9):867-881.
- Han Z, Chen C, Christiansen A, et al. Antisense oligonucleotides
increase Scn1a expression and reduce seizures and SUDEP incidence in a
mouse model of Dravet syndrome. Sci Transl Med. 2020;12(558):eaaz6100.
- Lenk GM, Jafar-Nejad P, Hill SF et al. Scn8a Antisense Oligonucleotide
Is Protective in Mouse Models of SCN8A Encephalopathy and Dravet
Syndrome. Ann Neurol. 2020 Mar;87(3):339-346.
- Ahonen S, Nitschke S, Tamar R et al. Gys1 antisense therapy rescues
neuropathological bases of murine Lafora disease.
https://doi.org/10.1101/2021.02.11.430846
- Morkous SS. Treatment with Ataluren for Duchene Muscular Dystrophy.
Pediatr Neurol Briefs. 2020;34:12.
- Gene Therapy Clinical Trials Worldwide. Hippocampal NPY gene transfer
in subjects with Intractable Temporal Lobe Epilepsy. Abedia.com
http://www.abedia.com/ wiley/record_detail.php?ID=1758 (2004).
- Piguet F, de Saint Denis T, Audouard E et al. The Challenge of Gene
Therapy for Neurological Diseases: Strategies and Tools to Achieve
Efficient Delivery to the Central Nervous System. Hum Gene Ther. 2021;
online ahead of print.
- Servais L, Baranello G, Scoto M, Daron A, Oskoui M. Therapeutic
interventions for spinal muscular atrophy: preclinical and early
clinical development opportunities. Expert Opin Investig Drugs. 2021
Apr 13:1-9.
- Cattaneo S, Verlengia G, Marino P Simonato M, Bettegazzi B. NPY and
Gene Therapy for Epilepsy: How, When,… and Y. Front Mol Neurosci
2021;13:608001. doi: 10.3389/fnmol.2020.608001.
- Wickham, J. et al. Inhibition of epileptiform activity by neuropeptide
Y in brain tissue from drug-resistant temporal lobe epilepsy patients.
Sci. Rep. 9, 19393 (2019). 137.
- Gumusgoz E, Guisso DR, Kasiri S, et al. Targeting Gys1 with AAV-SaCas9
Decreases Pathogenic Polyglucosan Bodies and Neuroinflammation in
Adult Polyglucosan Body and Lafora Disease Mouse Models
Neurotherapeutics. 2021 Apr 8. Online ahead of print.