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Epileptic Spasms Are a Feature of DEPDC5 Mtoropathy Epileptic spasms are a feature of DEPDC5 mTORopathy Gemma L. Carvill, PhD ABSTRACT Douglas E. Crompton, Objective: To assess the presence of DEPDC5 mutations in a cohort of patients with epileptic PhD, MBBS spasms. Brigid M. Regan, BSc Methods: We performed DEPDC5 resequencing in 130 patients with spasms, segregation anal- (Hons) ysis of variants of interest, and detailed clinical assessment of patients with possibly and likely Jacinta M. McMahon, pathogenic variants. BSc (Hons) DEPDC5 Julia Saykally Results: We identified 3 patients with variants in in the cohort of 130 patients with DEPDC5 Matthew Zemel, BS spasms. We also describe 3 additional patients with alterations and epileptic spasms: 2 Amy L. Schneider, MGen from a previously described family and a third ascertained by clinical testing. Overall, we describe DEPDC5 Couns 6 patients from 5 families with spasms and variants; 2 arose de novo and 3 were Leanne Dibbens, PhD familial. Two individuals had focal cortical dysplasia. Clinical outcome was highly variable. Katherine B. Howell, Conclusions: While recent molecular findings in epileptic spasms emphasize the contribution of de MBBS (Hons), novo mutations, we highlight the relevance of inherited mutations in the setting of a family history BMedSc of focal epilepsies. We also illustrate the utility of clinical diagnostic testing and detailed pheno- Simone Mandelstam, typic evaluation in characterizing the constellation of phenotypes associated with DEPDC5 alter- MBChB ations. We expand this phenotypic spectrum to include epileptic spasms, aligning DEPDC5 Richard J. Leventer, epilepsies more with the recognized features of other mTORopathies. Neurol Genet 2015;1:e17; MBBS, PhD doi: 10.1212/NXG.0000000000000016 A. Simon Harvey, MD Saul A. Mullen, MBBS, GLOSSARY PhD ExAC 5 Exome Aggregation Consortium; FCD 5 focal cortical dysplasia; FFEVF 5 familial focal epilepsy with variable foci; 5 5 5 Samuel F. Berkovic, MD, MAF minor allele frequency; mTOR mammalian target of rapamycin; TSC tuberous sclerosis complex. FRS Autosomal dominant mutations in DEPDC5 cause familial focal epilepsy with variable foci Joseph Sullivan, MD 1,2 Ingrid E. Scheffer, MBBS, (FFEVF). FFEVF is characterized by seizures arising from different cortical regions in dif- 1,3–7 PhD* ferent family members, and onset ranges from infancy to adulthood. Clinical presentation 1,2 Heather C. Mefford, MD, is highly variable and reduced penetrance of ;66%isusual. Families may show patterns PhD* that are effectively subsets of FFEVF, such as a phenotypically homogeneous pattern of autosomal dominant nocturnal frontal lobe epilepsy; individuals with rolandic epilepsy have also been described.1,2,8–10 Recently, DEPDC5 mutations were reported in patients with var- Correspondence to Dr. Mefford: ious brain malformations, challenging the long-held distinction between lesional and nonle- – [email protected] or sional epilepsies.11 13 Dr. Scheffer: [email protected] DEPDC5 forms part of the GATOR1 complex, a negative regulator of the mammalian target 14 Supplemental data of rapamycin (mTOR) pathway. Mutations in other mTOR pathway proteins TSC1 and at Neurology.org/ng *These authors contributed equally to the manuscript. From the Division of Genetic Medicine (G.L.C., J. Saykally, M.Z., H.C.M.), Department of Pediatrics, University of Washington, Seattle; Epilepsy Research Centre (D.E.C., B.M.R., J.M.M., A.L.S., S.A.M., S.F.B., I.E.S.), Department of Medicine, The University of Melbourne, Austin Health, Melbourne, Australia; Neurology Department (D.E.C.), Northern Health, Melbourne, Australia; Epilepsy Research Program (L.D.), School of Pharmacy and Medical Sciences, and Sansom Institute for Health Research (L.D.), University of South Australia, Adelaide, Australia; Department of Neurology (K.B.H., R.J.L., A.S.H., I.E.S.), Royal Children’s Hospital, Melbourne, Australia; Florey Institute of Neuroscience and Mental Health (K.B.H., S.M., R.J.L., A.S.H., S.A.M., I.E.S.), Melbourne, Australia; Murdoch Childrens Research Institute (K.B.H., R.J.L., A.S.H.), Melbourne, Australia; Department of Paediatrics (S.M., R.J.L., A.S.H.) and Department of Radiology (S.M.), The University of Melbourne, Melbourne, Australia; and Epilepsy Division (J. Sullivan), Department of Neurology and Pediatrics, University of California, San Francisco. Funding information and disclosures are provided at the end of the article. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was paid by the authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially. Neurology.org/ng © 2015 American Academy of Neurology 1 ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 2 Table 1 Clinical and molecular features in patients with DEPDC5 variants and epileptic spasms Protein change Age cDNA change (PolyPhen-2, SIFT, studied, Epilepsy Seizure Seizure Other Ped Ref (GERP) Grantham) sex syndrome onset offset Development Seizure types (onset) EEG/video EEG, age MRI Treatment features A:III:2 c.2390delA p.Gln797Argfs*18; 3 y, M IS 2 mo Ongoing Global DD; IS, asymmetric (2 mo); 4 mo: interictal GSW and low-voltage fast Right Improved with ASD (NA) NA regression FDS (9 mo) activity. In spasms: high-voltage biphasic temporal prednisolone. Refractory slow waves then low-voltage fast activity. FCD to PB, CZP, and VGB. FDS: improved with TPM and CBZ. Right anterior temporal lobectomy Neurology: Genetics scheduled. 4–24 mo: right focal slowing, right temporal Mild left interictal epileptiform discharges leg weakness 2 y 2 mo: as at 4–24 mo plus subclinical electrographic seizures arising from right anterior temporal region B:III:2 c.1555C.T p.Gln519*; NA 30 y, M IS 6 wk Ongoing Global DD; IS (6 wk); FDS (3 y); 28 y: generalized background slowing, ND Refractory to CBZ, CZP, Autistic (6.01) regression; FDS/TCS (3 y); multifocal interictal sharp-slow discharges, LEV, LTG, prednisolone, features moderate- myoclonus maximal centrally and posteriorly, usually and VPA severe ID bisynchronous, sometimes with background attenuation. Similar discharges with asymmetric myoclonic jerks and negative myoclonus. C:III:3 c.3092C.A p.Pro1031His; 16 y, F Late-onset 2 y 8 mo Ongoing Speech and Asymmetric flexor 7 y 4 mo: interictal epileptiform spikes and Normal Refractory to CBZ, CLB, Nil (5.31) 0.971, 0.01, 23 epileptic language delay; spasms (2 y 8 mo); sharp waves from both temporal and ETX, KD, LCM, LTG, NZP, spasms regression; mild reflex tonic seizures posterior regions in sleep. GSW, GPSW, and TPM, VGB, VPA, and ZSM ID precipitated by startle GPFA in slow wave sleep. Ictal EEG: (1) with (10 y); atypical spasms: polyphasic, rhythmic 2 Hz delta, absences (11 y); TCS maximal in midline, often with superimposed (12 y) fast beta; (2) with reflex tonic seizures: generalized decrements and LVFA; and (3) with absences: GSW at 2–3 Hz. 9 y 5 mo: as above plus background slowing, 10 y: left lateral temporal interictal left central sharp-slow trains and corticectomy, normal frontotemporal delta, GSW with left histopathology, no temporal lead-in improvement D:II:1 c.842A.T Tyr281Phe; 0.997, 5 y, F IS 3 mo Ongoing Speech and IS; tonic seizures 14 mo: hypsarrhythmia with focal fast Left Refractory to B6, ACTH, Right HP (5.05) 0.02, 22 (rare) language delay, (27 mo) activity in left frontocentral regions. frontal PB, VGB, and KD s/p hemispherotomy Electroclinical spasms with generalized FCD spike/wave and pseudonormalization. 27 mo: (s/p left frontal lobectomy) hypsarrhythmia. Head drops, brief tonic seizures, and tonic eye deviation associated with low-amplitude fast activity. E:IV:21 c.19311G.A NA 34 y, F IS, OLE 2 mo FDS Normal IS (8 wk); FDS (11 y) 5 mo: multifocal and generalized interictal Normal Spasms: ceased with Nil ongoing, polyspike-wave discharges prednisolone; FDS: partial spasms response to CBZ ceased at 6 mo 8 mo: normal 34 y: nonspecific episodic generalized slowing, otherwise normal Continued ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Table 1 Continued ª Protein change Age cDNA change (PolyPhen-2, SIFT, studied, Epilepsy Seizure Seizure Other 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Ped Ref (GERP) Grantham) sex syndrome onset offset Development Seizure types (onset) EEG/video EEG, age MRI Treatment features E:IV:41 c.19311G.A NA 16 y, M IS 6 wk 6 mo Global DD; ID IS (6 wk) 5 mo: background slowing, multifocal Normal Controlled on VGB Autistic spike-wave and polyspike-wave activity, features left occipital electrographic seizure 3 y 7 mo: within normal limits Infantile esotropia Abbreviations: ACTH 5 adrenocorticotropic hormone; ASD 5 autistic spectrum disorder; B6 5 pyridoxine; CBZ 5 carbamazepine; CLB 5 clobazam; CZP 5 clonazepam; DD 5 developmental delay; ETX 5 ethosuxamide; FCD 5 focal cortical dysplasia; FDS 5 focal dyscognitive seizure; FDS/TCS 5 focal dyscognitive seizure evolving to a bilateral convulsive/tonic-clonic seizure; FSRA 5 focal seizure with retained awareness; GERP 5 Genome Evolutionary Rate Profiling; GPFA 5 generalized paroxysmal fast activity; GPSW 5 generalized polyspike-wave; GSW 5 generalized spike-wave; HP 5 hemiparesis; ID 5 intellectual disability; IS 5 infantile spasms; KD 5 ketogenic diet; LCM 5 lacosamide; LEV 5 levetiracetam; LTG 5 lamotrigine; LVFA 5 low-voltage fast activity; NA 5 not applicable; ND 5 not done; NZP 5 nitrazepam; OLE 5 occipital lobe epilepsy; PB 5 phenobarbitone; Ped Ref 5 pedigree reference; s/p 5 status post; TCS 5 tonic-clonic seizure; TPM 5 topiramate; VGB 5 vigabatrin; VNS 5 vagal nerve stimulator; VPA 5 valproate; ZSM 5 zonisamide.
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