28 mars 2013 / Nathalie

Articles scientifiques sur le syndrome de Dravet parus en novembre et décembre 2011

PubMed 17 articles scientifiques sur le syndrome de Dravet parus en novembre et décembre 2011. Ci-après leur résumé.

Bonne lecture !

 

Epileptic Disord. 2011 Dec;13(4):382-8. doi: 10.1684/epd.2011.0479.

Vagus nerve stimulation: effectiveness and tolerability in 64 paediatric patients with refractory epilepsies.
Cersósimo RO, Bartuluchi M, Fortini S, Soraru A, Pomata H, Caraballo RH.

Neurology Department, Hospital de Ninos, Buenos Aires, Argentina.

AIM: We discuss the effectiveness, tolerability, and safety of vagus nerve stimulation (VNS) as adjunctive therapy in 64 paediatric patients with refractory epilepsies.

MATERIALS AND METHODS: Sixty-four patients (34 male and 30 female) implanted with VNS for refractory epilepsy were analysed. Electroclinical features were compatible with Lennox-Gastaut syndrome in 46 patients, focal epilepsies in 10 patients, Dravet syndrome in three patients, epilepsy with myoclonic-astatic seizures in three patients, and West syndrome in two. The NeuroCybernetic Prosthesis (NCP) system (Cyberonics, Webster, TX, USA) was employed and the following stimulation parameters were used: output current of 1 to 2.5mA, signal frequency of 30Hz, signal pulse width of 500μs, and signal “on” and “off” times of 30  seconds and 5  minutes, respectively.

RESULTS: Of 46 patients with LGS, 30 cases showed a significant improvement in seizure control, with a reduction in seizure frequency of at least 50%. Ten patients with focal epilepsy, three patients with myoclonic-astatic seizures, two patients with Dravet, and two patients with West showed a significant improvement in seizure control, with a reduction in seizure frequency of at least 50%. A good clinical response was evident early and efficacy progressively improved with the duration of treatment up to 36 months. In a significant number of patients, reduced seizure severity and shorter recovery time and hospital stay were also observed. VNS was well tolerated in all patients.

CONCLUSION: VNS is an effective and well-tolerated treatment for paediatric patients with refractory epilepsies, improving quality of life and neuropsychological performance.

Brain Dev. 2012 Sep;34(8):617-9. doi: 10.1016/j.braindev.2011.11.005. Epub 2011 Dec 27.

On the likelihood of SCN1A microdeletions or duplications in Dravet syndrome with missense mutation.

Shi X, Wang J, Kurahashi H, Ishii A, Higurashi N, Kaneko S, Hirose S.

Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan.

This study examines whether microdeletions and duplications of the gene encoding α1 subunit of the sodium channel (SCN1A) are underlying causes in Dravet syndrome (DS) with SCN1A missense mutation. Multiple exonic deletions were identified in 8/84 patients without mutation and 0/41 patients with missense mutations. Our findings indicate that while microdeletions are not rare in SCN1A-negative patients, they are not likely to be present simultaneously with other SCN1A mutations.

Genes Brain Behav. 2012 Mar;11(2):170-6. doi: 10.1111/j.1601-183X.2011.00756.x. Epub 2011 Dec 14.

Mosaic SCN1A mutations in familial partial epilepsy with antecedent febrile seizures.

Shi YW, Yu MJ, Long YS, Qin B, He N, Meng H, Liu XR, Deng WY, Gao MM, Yi YH,Li BM, Liao WP.

Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangdong, China.

SCN1A is the most relevant epilepsy gene. Mutations of SCN1A generate phenotypes ranging from the extremely severe form of Dravet syndrome (DS) to a mild form of generalized epilepsy with febrile seizures plus (GEFS+). Mosaic SCN1A mutations have been identified in rare familial DS. It is suspected that mosaic mutations of SCN1A may cause other types of familial epilepsies with febrile seizures (FS), which are more common clinically. Thus, we screened SCN1A mutations in 13 families with partial epilepsy with antecedent febrile seizures (PEFS+) using denaturing high-performance liquid chromatography and sequencing. The level of mosaicism was further quantified by pyrosequencing. Two missense SCN1A mutations with mosaic origin were identified in two unrelated families, accounting for 15.4% (2/13) of the PEFS+ families tested. One of the mosaic carriers with ~25.0% mutation of c.5768A>G/p.Q1923R had experienced simple FS; another with ~12.5% mutation of c.4847T>C/p.I1616T was asymptomatic. Their heterozygous children had PEFS+. Recurrent transmission occurred in both families, as noted in most of the families with germline mosaicism reported previously. The two mosaic mutations identified in this study are less destructive missense, compared with the more destructive truncating and splice-site mutations identified in the majority of previous studies. This is the first report of mosaic SCN1A mutations in families with probands that do not exhibit DS, but manifest only a milder phenotype. Therefore, such families with mild cases should be approached with caution in genetic counseling and the possibility of mosaicism origin associated with high recurrence risk should be excluded.

 

Epilepsia. 2012 Jan;53(1):87-100. doi: 10.1111/j.1528-1167.2011.03346.x. Epub 2011 Dec 9.

Pure haploinsufficiency for Dravet syndrome Na(V)1.1 (SCN1A) sodium channel truncating mutations.

Bechi G, Scalmani P, Schiavon E, Rusconi R, Franceschetti S, Mantegazza M.

Department of Neurophysiopathology, Besta Foundation Neurological Institute, Milan, Italy.

PURPOSE: Dravet syndrome (DS), a devastating epileptic encephalopathy, is mostly caused by mutations of the SCN1A gene, coding for the voltage-gated Na(+) channel Na(V)1.1 α subunit. About 50% of SCN1A DS mutations truncate Na(V)1.1, possibly causing complete loss of its function. However, it has not been investigated yet if Na(V)1.1 truncated mutants are dominant negative, if they impair expression or function of wild-type channels, as it has been shown for truncated mutants of other proteins (e.g., Ca(V) channels). We studied the effect of two DS truncated Na(V)1.1 mutants, R222* and R1234*, on coexpressed wild-type Na(+) channels.

METHODS: We engineered R222* or R1234* in the human cDNA of Na(V)1.1 (hNa(V)1.1) and studied their effect on coexpressed wild-type hNa(V)1.1, hNa(V)1.2 or hNa(V)1.3 cotransfecting tsA-201 cells, and on hNa(V)1.6 transfecting an human embryonic kidney (HEK) cell line stably expressing this channel. We also studied hippocampal neurons dissociated from Na(V)1.1 knockout (KO) mice, an animal model of DS expressing a truncated Na(V)1.1 channel.

KEY FINDINGS: We found no modifications of current amplitude coexpressing the truncated mutants with hNa(V)1.1, hNa(V)1.2, or hNa(V)1.3, but a 30% reduction coexpressing them with hNa(V)1.6. However, we showed that also coexpression of functional full-length hNa(V)1.1 caused a similar reduction. Therefore, this effect should not be involved in the pathomechanism of DS. Some gating properties of hNa(V)1.1, hNa(V)1.3, and hNa(V)1.6 were modified, but recordings of hippocampal neurons dissociated from Na(V)1.1 KO mice did not show any significant modifications of these properties. Therefore, Na(V)1.1 truncated mutants are not dominant negative, consistent with haploinsufficiency as the cause of DS.

SIGNIFICANCE: We have better clarified the pathomechanism of DS, pointed out an important difference between pathogenic truncated Ca(V)2.1 mutants and hNa(V)1.1 ones, and shown that hNa(V)1.6 expression can be reduced in physiologic conditions by coexpression of hNa(V)1.1. Moreover, our data may provide useful information for the development of therapeutic approaches.

 

Hong Kong Med J. 2011 Dec;17(6):500-2.

Genetic diagnosis of severe myoclonic epilepsy of infancy (Dravet syndrome) with SCN1A mutations in the Hong Kong Chinese patients.

Mak CM, Chan KY, Yau EK, Chen SP, Siu WK, Law CY, Lam CW, Chan AY.

Kowloon West Cluster Laboratory Genetic Service, Chemical Pathology Laboratory, Department of Pathology, Princess Margaret Hospital, Laichikok, Hong Kong.makm@ha.org.hk

Comment in

Epilepsy is a clinically and genetically heterogeneous group of disorders. The advent of molecular genetics brings unprecedented advancement in diagnostic molecular pathology and reduces over-reliance on traditional clinical classification. Severe myoclonic epilepsy of infancy or Dravet syndrome is a catastrophic infantile-onset epilepsy. We report two unrelated Hong Kong Chinese patients with this condition presenting with febrile seizures, epilepsy with different semiologies, psychomotor retardation, and recurrent status epilepticus. Two different mutations were characterised, viz NM_001165963.1: c.680T>G; NP_001159435.1: p.I227S and NM_001165963.1: c.3953T>G; NP_001159435.1: p.L1318R (novel). Genetic characterisation conveys a definitive diagnosis and is important from the perspective of selecting anti-epileptic drug therapy and genetic counselling.

 

J Child Neurol. 2012 Jul;27(7):914-6. doi: 10.1177/0883073811426933. Epub 2011 Dec 2.

Thoracic myelopathy secondary to seizure following scoliosis surgery.

Myers KA, Payne ET, Esser MJ, Kirton A, Howard JJ.

Department of Pediatrics, Division of Neurology, Alberta Children’s Hospital, Calgary, Alberta, Canada. kmyers@ucalgary.ca

The incidence of spinal injuries is increased in people with epilepsy although compressive thoracic myelopathy has not been reported. We describe a 15-year-old girl with SCN1A mutation (Dravet syndrome), refractory generalized tonic-clonic seizures, and prior posterior instrumentation and fusion for scoliosis, who presented with progressive lower extremity weakness. Junctional kyphosis with disc herniation and spinal cord compression directly rostral to the instrumentation was apparent on imaging. On history, the patient had suffered a particularly severe convulsive seizure just before developing symptoms. Surgical decompression and stabilization led to a complete neurologic recovery. This unusual presentation of myelopathy illustrates the need to consider this complication in patients with epilepsy and spinal instrumentation.

 

Pediatr Neurol. 2011 Dec;45(6):392-4. doi: 10.1016/j.pediatrneurol.2011.09.008.

Does Dravet syndrome have a recognizable face?

Nolan KJ, Kay E, Camfield CS, Camfield PR.

Department of Pediatrics, IWK Health Centre, Halifax, Nova Scotia, Canada.

We hypothesized that children with Dravet syndrome manifest specific facial features that can be identified by pediatric neurologists and rendered objective by standard photographic measurements. This study comprised two parts. In Part 1, photographs of children with Dravet syndrome were compiled into a booklet with patients and their siblings randomly mixed. The booklet was sent to pediatric neurologists who anonymously identified which children they thought were affected by the syndrome and which were siblings. Although pediatric neurologists generally agreed on whether children were affected or not (20/24 cases; 83%), they were frequently incorrect (12/20; 60%). In Part 2, standard photogrammetric techniques were used to provide 16 facial ratios from digital images. No significant difference in any measurement was evident between children with Dravet syndrome and unaffected siblings (P > 0.05, two-tailed t test). This study did not demonstrate a specific facial phenotype in Dravet syndrome.

 

An Pediatr (Barc). 2012 Apr;76(4):218-23. doi: 10.1016/j.anpedi.2011.10.001. Epub 2011 Nov 21.

[Febrile seizures in the first year of life: Dravet spectrum epilepsy?].
[Article in Spanish]

Sánchez-Carpintero R, Núñez MT, Aznárez N, Narbona García J.

Unidad de Neurología Infantil, Departamento de Pediatría, Clínica Universidad de Navarra, Pamplona, España. rsanchezc@unav.es

INTRODUCTION: Dravet syndrome is a drug resistant epilepsy which starts in the first year of life with febrile seizures, followed by cognitive impairment and epilepsy with multiple seizure types. Diagnosis has been typically made at the age of three to four years, but earlier diagnosis is now possible as clinical features are better recognised and molecular diagnosis is available.

PATIENTS AND METHODS: We studied a series of 14 children with Dravet syndrome or Dravet spectrum epilepsy. A screening test, developed by other authors to distinguish the febrile seizures in Dravet syndrome from febrile seizures from other origin, was applied to the clinical features of the seizures occurring during the first year of life in our patients.

RESULTS: Clinical suspicion of Dravet spectrum epilepsy was possible in 100% of children in our series. Moreover, taking into consideration only the first seizure, 79% of patients scored sufficiently to detect Dravet syndrome.

CONCLUSIONS: Dravet syndrome can be recognised during the first year of life. It is important that physicians are made aware of these clinical criteria capable to distinguish febrile seizures in Dravet syndrome from febrile seizures of other origin, and set up a protocol to collect appropriate data regarding febrile seizures occurring in the first year of life.

 

Med Hypotheses. 2012 Feb;78(2):247-9. doi: 10.1016/j.mehy.2011.10.037. Epub 2011 Nov 17.

Are SCN1A gene mutations responsible for genetic susceptibility to subacute sclerosing panencephalitis?

Garg RK.

Department of Neurology, Chhatrapati Shahuji Maharaj Medical University, Uttar Pradesh, Lucknow, India. garg50@yahoo.com

Dravet syndrome, characterized predominantly by myoclonus, has a striking clinical resemblance to subacute sclerosing panencephalitis (SSPE). Patients with Dravet syndrome develop significant mental decline with advancing age of affected child like in SSPE. It is well established that SCN1A gene mutations are associated with Dravet syndrome. Even periodic EEG complexes have been described in Dravet syndrome. In addition to Dravet syndrome, several other types of acute and subacute encephalopathic syndromes having clinical and electroencephalographic resemblance to SSPE are associated with SCN1A gene mutations. SSPE is a devastating progressive inflammatory disorder of the central nervous system. It is caused by persistent infection of the brain by an aberrant measles virus. Only a few of a vast number of measles infected pediatric population develop SSPE. There are several reports describing presence of SSPE is close relatives and it has been described previously in sibling and twin pairs. A genetic susceptibility for development of SSPE is likely. In fact, a variety of genetic abnormalities have already been described in patients with SSPE. It can also be argued that because of striking clinical resemblance between Dravet and various epileptic and encephalopathic syndromes associated with SCN1A gene mutations and SSPE, SCN1A gene abnormalities may also be responsible for susceptibility to SSPE in measles infected children.

 

Epilepsia. 2012 Jan;53(1):79-86. doi: 10.1111/j.1528-1167.2011.03311.x. Epub 2011 Nov 16.

Acute encephalopathy in children with Dravet syndrome.

Okumura A, Uematsu M, Imataka G, Tanaka M, Okanishi T, Kubota T, Sudo A,Tohyama J, Tsuji M, Ohmori I, Naiki M, Hiraiwa-Sofue A, Sato H, Saitoh S, Shimizu T.

Department of Pediatrics, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan. okumura@juntendo.ac.jp

PURPOSE: The occurrence of acute encephalopathy in children with Dravet syndrome has been reported sporadically. This study clarified the features of acute encephalopathy in children with Dravet syndrome.

METHODS: Through the mailing list of the Annual Zao Conference on Pediatric Neurology, we collected 15 patients with clinically diagnosed Dravet syndrome, who had acute encephalopathy, defined as a condition with decreased consciousness with or without other neurologic symptoms, such as seizures, lasting for >24 h in association with infectious symptoms.

KEY FINDINGS: There were seven boys and eight girls. A mutation of the SCN1A gene was present in nine (truncation in six and missense in three). The frequency of seizures during the 3 months before the onset of acute encephalopathy was monthly in seven children and none in three. The median age at the onset of acute encephalopathy was 44 months (range 8-184 months). All children had status epilepticus followed by coma as the initial manifestation. Two different distributions of brain lesions were observed on diffusion-weighted images during the acute phase: cerebral cortex-dominant lesions with or without deep gray matter involvement and subcortical-dominant lesions. Four children died; nine survived with severe sequelae, and two had moderate sequelae.

SIGNIFICANCE: We must be aware that acute encephalopathy is an important complication in children with Dravet syndrome, and associated with fulminant clinical manifestations and a poor outcome.

 

Epilepsy Res. 2012 Mar;99(1-2):21-7. doi: 10.1016/j.eplepsyres.2011.10.010. Epub 2011 Nov 8.

Early clinical features in Dravet syndrome patients with and without SCN1A mutations.

Petrelli C, Passamonti C, Cesaroni E, Mei D, Guerrini R, Zamponi N, Provinciali L.

Neurology Clinic, Polytechnic University of Marche, Ancona, Italy.cristinapetrelli84@alice.it

BACKGROUND: SCN1A is the most clinically relevant epilepsy gene, most mutations causing Dravet syndrome (also known as severe myoclonic epilepsy of infancy or SMEI). We evaluated clinical differences, if any, between young patients with and without a SCN1A mutations and a definite clinical diagnosis of Dravet syndrome.

METHODS: Twenty-five patients with a diagnosis of Dravet Syndrome (7 males, 18 females; mean age at inclusion: 10.3; median: 9±7; range: 18 months-30 years) were retrospectively studied. A clinical and genetic study focusing on SCN1A was performed, using DHPLC, gene sequencing and MLPA to detect genomic deletions/duplications. A formal cognitive and behavioral assessment was available for all patients.

RESULTS: Analysis revealed SCN1A mutations comprising missense, truncating mutations and genomic deletions/duplications in eighteen patients and no mutation in seven. The phenotype of mutation positive patients was characterized by a higher number of seizures/month in the first year of life, an earlier seizure onset and a higher frequency of episodes of status epilepticus. The cognitive and behavioral profile was slightly worst in mutation positive patients.

CONCLUSIONS: These findings confirm that SCN1A gene mutations are strongly associated to a more severe phenotype in patients with Dravet syndrome.

Epilepsy Res. 2012 Mar;99(1-2):28-37. doi: 10.1016/j.eplepsyres.2011.10.014. Epub 2011 Nov 1.

PCDH19 mutation in Japanese females with epilepsy.

Higurashi N, Shi X, Yasumoto S, Oguni H, Sakauchi M, Itomi K, Miyamoto A,Shiraishi H, Kato T, Makita Y, Hirose S.

Department of Pediatrics, School of Medicine, Fukuoka University, 7-45-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.

PURPOSE: To determine the significance of PCDH19 mutations in Japanese females with epilepsy and to delineate their phenotypes.

METHODS: PCDH19 sequencing analysis was performed in 116 females with various epilepsies, including 97 with Dravet syndrome (83.6%). They were referred for SCN1A analysis, and 52 carried SCN1A mutations.

RESULTS: Seven heterozygous mutations in exon 1 were identified in 7 patients (6.0%): 2 frameshift, 2 nonsense, and 3 missense mutations. One patient was a monozygotic twin, and her sister with mild phenotype carried the same mutation. The main clinical features among these 8 patients included early seizure onset (≤25 months of age), seizure clusters (7/8), fever-associated seizures (7/8), single seizure type (6/8), and late deterioration of intellect (5/8). Seizure durations were generally up to a few minutes, and only one patient developed status epilepticus once. The main seizure types were generalized tonic-clonic (4/8), tonic (3/8) and focal seizures, with (2/8) or without secondary generalization (3/8). Myoclonic, atonic and absence seizures were extremely rare. Two patients had Dravet syndrome (25%), and this proportion was significantly smaller than that in the total subjects (p<0.01).

CONCLUSION: PCDH19 mutation is a relatively frequent cause of epilepsy in Japanese females. Dravet syndrome was rare in our cohort.

 

Acta Neurol Scand. 2012 May;125(5):359-62. doi: 10.1111/j.1600-0404.2011.01609.x. Epub 2011 Nov 2.

Dravet syndrome–considerable delay in making the diagnosis.

Bremer A, Lossius MI, Nakken KO.

Division of Surgery and Neuroscience, National Centre for Epilepsy, Oslo University Hospital, Norway. anna.bremer@vestreviken.no

OBJECTIVES: To assess delay in diagnosis and clinical characteristics of Dravet syndrome based on the Dravet register at The National Centre for Epilepsy in Norway.

MATERIAL AND METHODS: Medical records of patients diagnosed with Dravet syndrome since 2007 were analysed.

RESULTS: Twenty-two patients were identified. In 15, genetic screening disclosed mutations/deletions in the SCN1A gene. Average time from seizure onset to diagnosis was 7.4 years. Mean age at seizure onset was 6.7 months, nine had hemiconvulsions and 13 had generalized tonic-clonic seizures. The seizures were precipitated by fever in 17, by external heating in three. During second year of life, multiple seizure types and cognitive and motoric stagnation occurred. No patients became seizure-free with antiepileptic drugs. The effect of vagal nerve stimulation was disappointing.

CONCLUSIONS: By making an early diagnosis, an extensive presurgical evaluation may be avoided, and the patient and their parents may be offered genetic guidance.

 

Pediatr Neurol. 2011 Nov;45(5):319-23. doi: 10.1016/j.pediatrneurol.2011.08.001.

When should clinicians order genetic testing for Dravet syndrome?

Fountain-Capal JK, Holland KD, Gilbert DL, Hallinan BE.

Division of Pediatric Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA. jamiekcapal@gmail.com

The role of neuronal voltage-gated sodium channel, α-1 subunit (SCN1A) gene mutations in Dravet syndrome is well-established. With a broader phenotype than initially described, some patients lack features of Dravet syndrome as defined by the International League Against Epilepsy. We evaluated the predictive value of International League Against Epilepsy criteria for a positive mutation in a cohort of consecutively tested children. Mutations of SCN1A were evident in 16 of 69 children. Exhibiting ≥4 International League Against Epilepsy criteria demonstrated 100% sensitivity. Seven criteria (resistance to multiple antiepileptic drugs, multiple seizure types, abnormal electroencephalogram features, exacerbation with hyperthermia, normal development before seizure onset, seizures beginning before age 1 year, and psychomotor retardation) were present in ≥85% of mutation-positive cases. The three criteria that best predicted a mutation in SCN1A included exacerbation with hyperthermia, normal development before seizure onset, and the appearance of ataxia, pyramidal signs, or interictal myoclonus. We have demonstrated a high-sensitivity testing strategy for detecting mutations of SCN1A in children with suspected Dravet syndrome.

 

Seizure. 2011 Dec;20(10):813-6. doi: 10.1016/j.seizure.2011.07.008. Epub 2011 Sep 3.

Infantile epilepsy associated with mosaic 2q24 duplication including SCN2A and SCN3A.

Vecchi M, Cassina M, Casarin A, Rigon C, Drigo P, De Palma L, Clementi M.

Pediatric Neurology and Clinical Neurophysiology Unit, Department of Pediatrics, University of Padova, Italy.

Epilepsies can be caused by specific genetic anomalies or by non-genetic factors, but in many cases the underlying cause is unknown. Mutations in the SCN1A and SCN2A genes are reported in childhood epilepsies; in particular SCN1A was found mutated in patients with Dravet syndrome and with generalized epilepsy with febrile seizures plus (GEFS+). In this paper we report a patient presenting with an atypical epileptic syndrome whose phenotype partially overlaps both Dravet syndrome and benign familial neonatal-infantile seizures (BFNIS). Array-CGH analysis suggested the presence of a mosaic duplication (about 12Mb) at the level of chromosome 2q23.3q24.3 involving SCN2A and SCN3A genes. Additional analyses (radiolabeled RFLP and quantitative PCR) confirmed the mosaicism of the duplication. We suggest that the array-CGH analysis is mandatory for children presenting with epilepsy and psycho-motor retardation even without dysmorphisms or other clinical features suggesting a specific genetic/epileptic syndrome. The analysis must nevertheless be performed taking into account the possibility of a mosaicism.

 

Seizure. 2011 Dec;20(10):789-94. doi: 10.1016/j.seizure.2011.08.002. Epub 2011 Aug 24.

SCN1A mutational analysis in Korean patients with Dravet syndrome.

Lim BC, Hwang H, Chae JH, Choi JE, Hwang YS, Kang SH, Ki CS, Kim KJ.

Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.

OBJECTIVE: The aim of this study was to characterize the SCN1A mutation spectrum in Korean patients with Dravet syndrome.

METHODS: Twenty-nine patients diagnosed with Dravet syndrome at the Seoul National University Children’s Hospital were included in the study. Direct sequencing and multiplex ligation-dependent probe amplification (MLPA) were used to identify SCN1A mutations. Mutations were classified as either truncation (nonsense and frameshift) or missense mutations.

RESULTS: Nineteen pathogenic mutations (19/29; 66%) and three unclassified variants were identified. One large deletion mutation spanning exons 1-20 was detected using MLPA. Fifteen of these 19 SCN1A mutations were novel. Eleven mutations were classified as truncations (seven frameshift and four nonsense mutations) and seven were classified as missense mutations. Truncating mutations spanned the whole span of subunits of the SCN1A protein, whereas all missense mutations were localized at either the voltage sensor (S4) or the ion pore (S5-S6) regions. Analysis according to clinical phenotype revealed that SCN1A mutations were more frequent in the classic group than in the borderline group (78% vs. 45%).

CONCLUSIONS: SCN1A mutational analysis of Korean Dravet syndrome patients resulted in the identification of 15 novel mutations, which could expand the spectrum of SCN1A mutations and confirms the current understanding of genotype-phenotype correlations.

 

Epilepsia. 2011 Nov;52(11):2050-6. doi: 10.1111/j.1528-1167.2011.03211.x. Epub 2011 Jul 29.

Protective effect of the ketogenic diet in Scn1a mutant mice.

Dutton SB, Sawyer NT, Kalume F, Jumbo-Lucioni P, Borges K, Catterall WA,Escayg A.

Department of Human Genetics, Emory University, Atlanta, Georgia 30322, USA.

PURPOSE: We evaluated the ability of the ketogenic diet (KD) to improve thresholds to flurothyl-induced seizures in two mouse lines with Scn1a mutations: one that models Dravet syndrome (DS) and another that models genetic (generalized) epilepsy with febrile seizures plus (GEFS+).

METHODS: At postnatal day 21, mouse models of DS and GEFS+ were fasted for 12-14 h and then placed on either a 6:1 (fats to proteins and carbohydrates) KD or a standard diet (SD) for 2 weeks. At the end of the 2-week period, we measured thresholds to seizures induced by the chemiconvulsant flurothyl. Body weight, β-hydroxybutyrate (BHB) levels, and glucose levels were also recorded every 2 days over a 2-week period in separate cohorts of mutant and wild-type mice that were either on the KD or the SD.

KEY FINDINGS: Mice on the KD gained less weight and exhibited significantly higher BHB levels compared to mice on the SD. It is notable that thresholds to flurothyl-induced seizures were restored to more normal levels in both mouse lines after 2 weeks on the KD.

SIGNIFICANCE: These results indicate that the KD may be an effective treatment for refractory patients with SCN1A mutations. The availability of mouse models of DS and GEFS+ also provides an opportunity to better understand the mechanism of action of the KD, which may facilitate the development of improved treatments.

 

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