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Not all SCN1A epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype
Lynette G Sadleir1, Emily I Mountier2, Deepak Gill2
1From the Department of Paediatrics and Child Health (L.G.S., E.I.M.), University of Otago, Wellington, New Zealand; Department of Neurology (D.G.), University of Sydney, Australia; Department of Neurology (S.D.), Starship Children's Health, Auckland, New Zealand; Department of Neurology (C.J.), Children's Hospital Colorado, Anschutz Medical Campus, University of Colorado, Denver; Department of Neurology (C.D.V., M.A.K.), Great Ormond Street Hospital for Children; Developmental Neurosciences (M.A.K.), UCL Great Ormond Street Institute of Child Health, London; Wellcome Trust Sanger Institute (DDD Study Group), Hinxton, Cambridge, UK; Departments of Paediatrics and Radiology (S.M.), University of Melbourne; The Florey Institute of Neuroscience and Mental Health (S.M., I.E.S.); Department of Medical Imaging (S.M.), Royal Children's Hospital, Melbourne, Australia; Department of Neurology (E.W., K.C.N.), Mayo Clinic, Rochester, MN; Department of Neurology (H.R.M.), Marshfield Clinic, WI; Division of Genetic Medicine (G.C., C.T.M., H.C.M.), Department of Pediatrics, University of Washington, Seattle; and Departments of Medicine and Paediatrics (I.E.S.), University of Melbourne, Austin Health and Royal Children's Hospital, Australia. lynette.sadleir@otago.ac.nz scheffer@unimelb.edu.au.
Insights
This study defines a new SCN1A encephalopathy in children, characterized by early onset seizures, profound developmental delays, and movement disorders. A recurrent SCN1A mutation, p.Thr226Met, was identified in most affected individuals.
Area of Science:
- Neurogenetics
- Epilepsy Research
- Developmental Neuroscience
Background:
- SCN1A gene mutations are associated with various epilepsy syndromes.
- Distinguishing between SCN1A-related disorders is crucial for accurate diagnosis and management.
Observation:
- A series of 9 children presented with early-onset profound developmental and epileptic encephalopathy.
- All children exhibited a hyperkinetic movement disorder with dystonia, choreoathetosis, and oral dyskinesia.
- Seizures began between 6-12 weeks of age, with profound developmental impairment noted in all.
Findings:
- A distinct SCN1A encephalopathy phenotype was identified, characterized by early infantile onset, profound impairment, and movement disorder.
- Eight of nine children carried the recurrent SCN1A missense mutation p.Thr226Met.
- This phenotype is distinguishable from Dravet syndrome and genetic epilepsy with febrile seizures plus.
Implications:
- This work establishes a clear phenotype-genotype correlation for a specific SCN1A mutation.
- Early infantile SCN1A encephalopathy represents a distinct clinical entity requiring specific diagnostic approaches.
- Understanding this SCN1A-related disorder aids in differentiating it from other severe early-onset epilepsies.
Objective:
To define a distinct SCN1A developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder.
Methods:
A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and SCN1A mutation.
Results:
We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense SCN1A mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, the mother was negative and the father was unavailable.
Conclusions:
Here, we present a phenotype-genotype correlation for SCN1A. We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met.
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