Radiology - Research Publications

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    Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45
    Carvill, GL ; Liu, A ; Mandelstam, S ; Schneider, A ; Lacroix, A ; Zemel, M ; McMahon, JM ; Bello-Espinosa, L ; Mackay, M ; Wallace, G ; Waak, M ; Zhang, J ; Yang, X ; Malone, S ; Zhang, Y-H ; Mefford, HC ; Scheffer, IE (WILEY, 2018-01)
    Heterozygous de novo variants in the autophagy gene, WDR45, are found in beta-propeller protein-associated neurodegeneration (BPAN). BPAN is characterized by adolescent onset dementia and dystonia; 66% patients have seizures. We asked whether WDR45 was associated with developmental and epileptic encephalopathy (DEE). We performed next generation sequencing of WDR45 in 655 patients with developmental and epileptic encephalopathies. We identified 3/655 patients with DEE plus 4 additional patients with de novo WDR45 pathogenic variants (6 truncations, 1 missense); all were female. Six presented with DEE and 1 with early onset focal seizures and profound regression. Median seizure onset was 12 months, 6 had multiple seizure types, and 5/7 had focal seizures. Three patients had magnetic resonance susceptibility-weighted imaging; blooming was noted in the globus pallidi and substantia nigra in the 2 older children aged 4 and 9 years, consistent with iron accumulation. We show that de novo pathogenic variants are associated with a range of developmental and epileptic encephalopathies with profound developmental consequences.
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    Mosaic uniparental disomy results in GM1 gangliosidosis with normal enzyme assay
    Myers, KA ; Bennett, MF ; Chow, CW ; Carden, SM ; Mandelstam, SA ; Bahlo, M ; Scheffer, IE (WILEY, 2018-01)
    Inherited metabolic disorders are traditionally diagnosed using broad and expensive panels of screening tests, often including invasive skin and muscle biopsy. Proponents of next-generation genetic sequencing have argued that replacing these screening panels with whole exome sequencing (WES) would save money. Here, we present a complex patient in whom WES allowed diagnosis of GM1 gangliosidosis, caused by homozygous GLB1 mutations, resulting in β-galactosidase deficiency. A 10-year-old girl had progressive neurologic deterioration, macular cherry-red spot, and cornea verticillata. She had marked clinical improvement with initiation of the ketogenic diet. Comparative genomic hybridization microarray showed mosaic chromosome 3 paternal uniparental disomy (UPD). GM1 gangliosidosis was suspected, however β-galactosidase assay was normal. Trio WES identified a paternally-inherited pathogenic splice-site GLB1 mutation (c.75+2dupT). The girl had GM1 gangliosidosis; however, enzymatic testing in blood was normal, presumably compensated for by non-UPD cells. Severe neurologic dysfunction occurred due to disruptive effects of UPD brain cells.
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    Epileptic spasms are a feature of DEPDC5 mTORopathy
    Carvill, GL ; Crompton, DE ; Regan, BM ; McMahon, JM ; Saykally, J ; Zemel, M ; Schneider, AL ; Dibbens, L ; Howell, KB ; Mandelstam, S ; Leventer, RJ ; Harvey, AS ; Mullen, SA ; Berkovic, SF ; Sullivan, J ; Scheffer, IE ; Mefford, HC (LIPPINCOTT WILLIAMS & WILKINS, 2015-08)
    OBJECTIVE: To assess the presence of DEPDC5 mutations in a cohort of patients with epileptic spasms. METHODS: We performed DEPDC5 resequencing in 130 patients with spasms, segregation analysis of variants of interest, and detailed clinical assessment of patients with possibly and likely pathogenic variants. RESULTS: We identified 3 patients with variants in DEPDC5 in the cohort of 130 patients with spasms. We also describe 3 additional patients with DEPDC5 alterations and epileptic spasms: 2 from a previously described family and a third ascertained by clinical testing. Overall, we describe 6 patients from 5 families with spasms and DEPDC5 variants; 2 arose de novo and 3 were familial. Two individuals had focal cortical dysplasia. Clinical outcome was highly variable. CONCLUSIONS: While recent molecular findings in epileptic spasms emphasize the contribution of de novo mutations, we highlight the relevance of inherited mutations in the setting of a family history of focal epilepsies. We also illustrate the utility of clinical diagnostic testing and detailed phenotypic evaluation in characterizing the constellation of phenotypes associated with DEPDC5 alterations. We expand this phenotypic spectrum to include epileptic spasms, aligning DEPDC5 epilepsies more with the recognized features of other mTORopathies.
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    Not all SCN1A epileptic encephalopathies are Dravet syndrome
    Sadleir, LG ; Mountier, EI ; Gill, D ; Davis, S ; Joshi, C ; DeVile, C ; Kurian, MA ; Mandelstam, S ; Wirrell, E ; Nickels, KC ; Murali, HR ; Carvill, G ; Myers, CT ; Mefford, HC ; Scheffer, IE (LIPPINCOTT WILLIAMS & WILKINS, 2017-09-05)
    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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    Epidemiology and etiology of infantile developmental and epileptic encephalopathies in Tasmania
    Ware, TL ; Huskins, SR ; Grinton, BE ; Liu, Y-C ; Bennett, MF ; Harvey, M ; McMahon, J ; Andreopoulos-Malikotsinas, D ; Bahlo, M ; Howell, KB ; Hildebrand, MS ; Damiano, JA ; Rosenfeld, A ; Mackay, MT ; Mandelstam, S ; Leventer, RJ ; Harvey, AS ; Freeman, JL ; Scheffer, IE ; Jones, DL ; Berkovic, SF (WILEY, 2019-09)
    We sought to determine incidence, etiologies, and yield of genetic testing in infantile onset developmental and epileptic encephalopathies (DEEs) in a population isolate, with an intensive multistage approach. Infants born in Tasmania between 2011 and 2016, with seizure onset <2 years of age, epileptiform EEG, frequent seizures, and developmental impairment, were included. Following review of EEG databases, medical records, brain MRIs, and other investigations, clinical genetic testing was undertaken with subsequent research interrogation of whole exome sequencing (WES) in unsolved cases. The incidence of infantile DEEs was 0.44/1000 per year (95% confidence interval 0.25 to 0.71), with 16 cases ascertained. The etiology was structural in 5/16 cases. A genetic basis was identified in 6 of the remaining 11 cases (3 gene panel, 3 WES). In two further cases, WES identified novel variants with strong in silico data; however, paternal DNA was not available to support pathogenicity. The etiology was not determined in 3/16 (19%) cases, with a candidate gene identified in one of these. Pursuing clinical imaging and genetic testing followed by WES at an intensive research level can give a high diagnostic yield in the infantile DEEs, providing a solid base for prognostic and genetic counseling.
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    Second-hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA
    Lee, WS ; Stephenson, SEM ; Howell, KB ; Pope, K ; Gillies, G ; Wray, A ; Maixner, W ; Mandelstam, SA ; Berkovic, SF ; Scheffer, IE ; MacGregor, D ; Harvey, AS ; Lockhart, PJ ; Leventer, RJ (WILEY, 2019-07)
    Focal cortical dysplasia (FCD) causes drug-resistant epilepsy and is associated with pathogenic variants in mTOR pathway genes. How germline variants cause these focal lesions is unclear, however a germline + somatic "2-hit" model is hypothesized. In a boy with drug-resistant epilepsy, FCD, and a germline DEPDC5 pathogenic variant, we show that a second-hit DEPDC5 variant is limited to dysmorphic neurons, and the somatic mutation load correlates with both dysmorphic neuron density and the epileptogenic zone. These findings provide new insights into the molecular and cellular correlates of FCD determining drug-resistant epilepsy and refine conceptualization of the epileptogenic zone.
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    CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures
    Thomas, RH ; Zhang, LM ; Carvill, GL ; Archer, JS ; Heavin, SB ; Mandelstam, SA ; Craiu, D ; Berkovic, SF ; Gill, DS ; Mefford, HC ; Scheffer, IE (LIPPINCOTT WILLIAMS & WILKINS, 2015-03-03)
    OBJECTIVE: To delineate the phenotype of early childhood epileptic encephalopathy due to de novo mutations of CHD2, which encodes the chromodomain helicase DNA binding protein 2. METHODS: We analyzed the medical history, MRI, and video-EEG recordings of 9 individuals with de novo CHD2 mutations and one with a de novo 15q26 deletion encompassing CHD2. RESULTS: Seizures began at a mean of 26 months (12-42) with myoclonic seizures in all 10 cases. Seven exhibited exquisite clinical photosensitivity; 6 self-induced with the television. Absence seizures occurred in 9 patients including typical (4), atypical (2), and absence seizures with eyelid myoclonias (4). Generalized tonic-clonic seizures occurred in 9 of 10 cases with a mean onset of 5.8 years. Convulsive and nonconvulsive status epilepticus were later features (6/10, mean onset 9 years). Tonic (40%) and atonic (30%) seizures also occurred. In 3 cases, an unusual seizure type, the atonic-myoclonic-absence was captured on video. A phenotypic spectrum was identified with 7 cases having moderate to severe intellectual disability and refractory seizures including tonic attacks. Their mean age at onset was 23 months. Three cases had a later age at onset (34 months) with relative preservation of intellect and an initial response to antiepileptic medication. CONCLUSION: The phenotypic spectrum of CHD2 encephalopathy has distinctive features of myoclonic epilepsy, marked clinical photosensitivity, atonic-myoclonic-absence, and intellectual disability ranging from mild to severe. Recognition of this genetic entity will permit earlier diagnosis and enable the development of targeted therapies.
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    Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5
    Scerri, T ; Riseley, JR ; Gillies, G ; Pope, K ; Burgess, R ; Mandelstam, SA ; Dibbens, L ; Chow, CW ; Maixner, W ; Harvey, AS ; Jackson, GD ; Amor, DJ ; Delatycki, MB ; Crino, PB ; Berkovic, SF ; Scheffer, IE ; Bahlo, M ; Lockhart, PJ ; Leventer, RJ (WILEY, 2015-05)
    Whole-exome sequencing of two brothers with drug-resistant, early-onset, focal epilepsy secondary to extensive type IIA focal cortical dysplasia identified a paternally inherited, nonsense variant of DEPDC5 (c.C1663T, p.Arg555*). This variant has previously been reported to cause familial focal epilepsy with variable foci in patients with normal brain imaging. Immunostaining of resected brain tissue from both brothers demonstrated mammalian target of rapamycin (mTOR) activation. This report shows the histopathological features of cortical dysplasia associated with a DEPDC5 mutation, confirms mTOR dysregulation in the malformed tissue and expands the spectrum of neurological manifestations of DEPDC5 mutations to include severe phenotypes with large areas of cortical malformation.