SCN1A (2528delG) novel truncating mutation with benign outcome of severe myoclonic epilepsy of infancy S. Buoni, MD; A. Orrico, MD; L. Galli, PhD; R. Zannolli, MD; L. Burroni, MD; J. Hayek, MD; A. Fois, MD; and V. Sorrentino, MD The epileptic syndrome related to mutations in the SCN1A gene includes benign febrile seizures (FS), the more variable phenotype FS+, and severe myoclonic epilepsy in infancy (SMEI) or Dravet syndrome, one of the most severe types of infant epilepsy, which is resistant to drugs. 1 The clinical spectrum related to mutations of the SCN1A gene (chromosome 2q) has been divided according to the type of seizure and CNS impairment into four categories from the lightest (benign FS) to the most severe (classic type SMEI). 2 Evidence suggests that a severe disturbance of the func- tion of the SCN1A gene is a major cause of SMEI, and that FS, FS+ (even with other types of seizures), and the milder and clas- sic types of SMEI form a continuum of mutations in the  subunit of SCN1A. Severe de novo mutations, such as truncating muta- tions, have been reported in SMEI. 2,3 We report a patient with SMEI with a benign outcome, in whom the clinical picture changed from SMEI in infancy to FS+ in adolescence and was associated with a novel, de novo truncating mutation of the SCN1A gene. Clinical report. The patient was a 13-year-old boy with an IQ of 125 (Wechsler Intelligence Scale for Children–Revised). The family history was negative. At the ages of 6, 10, and 13 months, he had prolonged FS that lasted about 20 minutes. The EEG was normal. Phenobarbital (3 mg/kg/day) was given. Starting at the age of 18 months, afebrile complex partial seizures (CPS) with secondary generalization appeared monthly, on average. At the age of 2 years and 2 months and 2 years and 8 months, he pre- sented in another hospital with two episodes of status epilepticus, one febrile and one afebrile. From ages 2 to 3, serial EEGs showed either focal spike activity (figure, A), bilateral frontal slowing, or diffuse polyspike waves accompanied by myoclonic jerks (figure, B). A brain interictal SPECT showed decreased perfusion in the right temporal and right frontal lobes (for more details, see figure E-1 on the Neurology Web site; go to www.neurology.org). The karyotype, biochemical and metabolic evaluation (for more details, see Appendix E-1), and MRI were normal. Because the afebrile seizures were present daily, all major antiepileptic drugs, includ- ing adrenocorticotropic hormone, were tried in full dosage but were unable to control the seizures. From age 4, in therapy with valproate and vigabatrin, the frequency of seizures gradually de- creased. At age 9 years and 5 months, during a long-term video EEG, valproate therapy was discontinued abruptly. The EEG background was completely normal (figure, C). The patient devel- oped CPS with secondary generalization starting in the right tem- poral region, which lasted 2 minutes (figure, D). At age 13, in therapy with valproate, the patient experienced a similar FS (for more details about the drug used, dosage, and effects, see Appen- dix E-2). A mutational analysis for the SCN1A gene was then performed. 4 Molecular analysis detected a c.2528delG in the pa- tient’s DNA sample. The nucleotide change, which lies within exon 14 and has not been described previously, is predicted to lead to a frame shift after the amino acid 842 residue (out-of-frame deletion) and premature termination at 853 (Gly842fsX853). The molecular analysis of the patient’s parents’ DNA detected normal alleles, suggesting that the mutation arose de novo. Discussion. We report a case of SMEI and a favorable clinical outcome, in which we identified a novel truncating mutation (2528delG) of the SCN1A gene. As the boy matured from infancy to adolescence, his seizures progressively changed from SMEI to FS+ controlled by drug therapy. This is the first report of a mutation predicted to generate a premature stop codon (i.e., a loss-of-function mutation) associated with a benign outcome of SMEI. The diagnosis of SMEI was justified by the presence of prolonged FS that included recurrent status epilepticus and fre- quent and different types of afebrile seizures, including myoclonic seizures, which were resistant to all major antiepileptic drugs. 1,2 The absence of mental retardation can be attributed to the reduc- tion in the frequency of seizures because of therapy after the age of 4 years. 2 In some cases, mental retardation can be very mild, and the diagnosis of SMEI does not depend on the presence or absence of a single clinical sign. 2,3 Moreover, truncating mutations are usually found in SMEI. 2,3 We acknowledge that the presenta- tion of a single case is not sufficient to draw general statements on the issue. The clinical implication of our report is that carriers of devastating ion-channel mutations do not necessarily have a poor prognosis. 5 This may be important in disease management and treatment, because the clinical picture may improve in some cases to the point that the patient is able to lead a normal life. Acknowledgment The authors thank Letizia Corbini, Stefania Lorenzini, and Michela Fal- ciani for their technical assistance. From the Section of Pediatric Neurology (S.B., R.Z.), Department of Pediat- rics, University of Siena, UOC Molecular Medicine (A.O., L.G., V.S.), De- partment of Oncology, Azienda Ospedaliera Universitaria Senese, Policlinico Le Scotte, UOC Nuclear Medicine (L.B.), Azienda Ospedaliera Universitaria Senese, Policlinico Le Scotte, Neuropsychiatric Unit (J.H.), Azienda Osped- aliera Universitaria Senese, and Department of Pediatrics (A.F.), University of Siena, Italy. Disclosure: The authors report no conflicts of interest. Received July 19, 2005. Accepted in final form October 28, 2005. Address correspondence and reprint requests to Dr. S. Buoni or Dr. R. Zannolli, Department of Pediatrics, Section of Pediatric Neurology, Poli- clinico Le Scotte, University of Siena, Siena, Italy; e-mail: zannolli@unisi.it Copyright © 2006 by AAN Enterprises, Inc. Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Con- tents for the February 28 issue to find the title link for this article. Figure. EEGs from the patient. EEGs at the age of 2 years showing normal back- ground activity with sporadic right tem- poral fast spikes (A) and at 3 years myoclonic jerks (B, arrows). At age 9 years and 5 months, a long-term video EEG monitoring 4 days after stopping valproate showed one normal back- ground activity following by a seizure consisting of turning the head to the left side, extension, and hypertonia of the left arm, emission of guttural noises, and generalized rhythmic jerks lasting about 2 minutes (C). Note the initial bioelectri- cal correlate consisting of temporal (pos- terior) sharp theta activity (D). 606 NEUROLOGY 66 February (2 of 2) 2006