Douglas E. Crompton
Northern Health
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Publication
Featured researches published by Douglas E. Crompton.
Nature Genetics | 2013
Leanne M. Dibbens; Boukje de Vries; Simona Donatello; Sarah E. Heron; Bree L. Hodgson; Satyan Chintawar; Douglas E. Crompton; James N. Hughes; Susannah T. Bellows; Karl Martin Klein; Petra M.C. Callenbach; Mark Corbett; Alison Gardner; Sara Kivity; Xenia Iona; Brigid M. Regan; Claudia M. Weller; Denis Crimmins; Terence J. O'Brien; Rosa Guerrero-López; John C. Mulley; François Dubeau; Laura Licchetta; Francesca Bisulli; Patrick Cossette; Paul Q. Thomas; Jozef Gecz; José M. Serratosa; Oebele F. Brouwer; Frederick Andermann
The majority of epilepsies are focal in origin, with seizures emanating from one brain region. Although focal epilepsies often arise from structural brain lesions, many affected individuals have normal brain imaging. The etiology is unknown in the majority of individuals, although genetic factors are increasingly recognized. Autosomal dominant familial focal epilepsy with variable foci (FFEVF) is notable because family members have seizures originating from different cortical regions. Using exome sequencing, we detected DEPDC5 mutations in two affected families. We subsequently identified mutations in five of six additional published large families with FFEVF. Study of families with focal epilepsy that were too small for conventional clinical diagnosis with FFEVF identified DEPDC5 mutations in approximately 12% of families (10/82). This high frequency establishes DEPDC5 mutations as a common cause of familial focal epilepsies. Shared homology with G protein signaling molecules and localization in human neurons suggest a role of DEPDC5 in neuronal signal transduction.
Annals of Neurology | 2014
Ingrid E. Scheffer; Sarah E. Heron; Brigid M. Regan; Simone Mandelstam; Douglas E. Crompton; Bree L. Hodgson; Laura Licchetta; Federica Provini; Francesca Bisulli; Lata Vadlamudi; Jozef Gecz; Alan Connelly; Paolo Tinuper; Michael G. Ricos; Samuel F. Berkovic; Leanne M. Dibbens
We recently identified DEPDC5 as the gene for familial focal epilepsy with variable foci and found mutations in >10% of small families with nonlesional focal epilepsy. Here we show that DEPDC5 mutations are associated with both lesional and nonlesional epilepsies, even within the same family. DEPDC5‐associated malformations include bottom‐of‐the‐sulcus dysplasia (3 members from 2 families), and focal band heterotopia (1 individual). DEPDC5 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in cell growth. The clinicoradiological phenotypes associated with DEPDC5 mutations share features with the archetypal mTORopathy, tuberous sclerosis, raising the possibility of therapies targeted to this pathway. Ann Neurol 2014;75:782–787
Annals of Neurology | 2016
Richard D. Bagnall; Douglas E. Crompton; Slavé Petrovski; Lien Lam; Carina Cutmore; Sarah I. Garry; Lynette G. Sadleir; Leanne M. Dibbens; Anita Cairns; Sara Kivity; Zaid Afawi; Brigid M. Regan; Johan Duflou; Samuel F. Berkovic; Ingrid E. Scheffer; Christopher Semsarian
The leading cause of epilepsy‐related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP cases, we performed an exome‐based analysis of rare variants.
Journal of Medical Genetics | 2003
Patrick F. Chinnery; Andrew Curtis; Constanze Fey; Alan Coulthard; Douglas E. Crompton; Ann Curtis; Anne Lombès; John Burn
We recently described a dominantly inherited movement disorder in a large family from Cumbria in the north west of England resulting from an adenine insertion at position 460–461 in the ferritin light polypeptide gene (FTL).1 The disease presented between the ages of 38 and 58 years with chorea in some subjects, focal dystonia in other subjects, and an akinetic rigid parkinsonian syndrome in others. Brain imaging showed basal ganglia cavitation that was confirmed at necropsy. Neuronal loss was accompanied by the formation of neuroaxonal spheroids, with intraneural and extraneural iron deposition. Serum ferritin levels were low in the presence of normal serum iron, transferrin and haemoglobin levels. The results of these investigations provided a direct link between a primary disorder of iron storage metabolism and a late onset neurodegenerative movement disorder.1 Cumbria has a stable, largely white population of Anglo-Saxon and Norman origins. All of the affected subjects described in the original report lived within a 30 mile radius and were traced, using parish records, back to a probable common founder born around 1790.1 A further 10 familial cases with the same mutation were found by screening over 100 patients from northern England with undiagnosed extrapyramidal disease and a small number of other cases referred to us from other parts of the country. The nature of the mutation and our report here of a common haplotype around the gene suggested to us that neuroferritinopathy would be a rare disorder in the UK, likely to have been inherited from a single founder. However, a careful review of published reports identified a number of potentially similar families outside the United Kingdom, including one family from the north of France.
Movement Disorders | 2005
Douglas E. Crompton; Patrick F. Chinnery; David W. Bates; Timothy J. Walls; Margaret Jackson; Andrew R.J. Curtis; John Burn
Neuroferritinopathy is a recently recognized, dominantly inherited movement disorder caused by a mutation of the ferritin light chain gene. We present video case reports of 4 individuals with neuroferritinopathy chosen to illustrate how this disorder can present and subsequently progress clinically. The clinical phenotype of this disorder is highly variable with symptoms beginning in the third to sixth decades. Chorea, dystonia, or an akinetic‐rigid syndrome can predominate in different individuals. Neuroferritinopathy is not restricted to the UK and it has been described in apparently sporadic cases. The diagnosis should therefore be considered in patients with a wide variety of different movement disorders. Characteristic neuroimaging assists in identifying affected individuals.
Epilepsy Research | 2016
Monica Sophie Cooper; Anne M. McIntosh; Douglas E. Crompton; Jacinta M. McMahon; Amy Schneider; Kevin Farrell; Vijeya Ganesan; Deepak Gill; Sara Kivity; Tally Lerman-Sagie; Ailsa McLellan; James T. Pelekanos; Venkateswaran Ramesh; Lynette G. Sadleir; Elaine C. Wirrell; Ingrid E. Scheffer
We measured the mortality rate and the rate of Sudden Unexpected Death in Epilepsy (SUDEP) in Dravet Syndrome (DS). We studied a cohort of 100 consecutively recruited, unrelated patients with DS; 87 had SCN1A mutations. Living cases had a median follow-up of 17 years. Seventeen patients died, at a median age of seven years (inter-quartile range 3-11 years) with causes of death: 10 SUDEP, four status epilepticus, two drowning and one asphyxia. The SUDEP classification included three Definite, one Definite Plus and six Probable. The Dravet-specific mortality rate/1000-person-years was 15.84 (98% CI 9.01-27.85). The Dravet-specific SUDEP rate was 9.32/1000-person-years (98% CI 4.46-19.45). The Dravet-specific SUDEP rate is the only documented syndrome-specific SUDEP rate. SUDEP in DS occurs mainly in childhood. It is also the highest SUDEP rate, considerably higher than the recent 5.1 SUDEP rate/1000-person-years for adults with refractory epilepsy.
Neurology | 2009
Saul A. Mullen; Douglas E. Crompton; Patrick W. Carney; Ingo Helbig; Samuel F. Berkovic
Genome-wide association studies are utilized for gene discovery in common diseases. Genotypes of large groups of unrelated patients are compared to controls. This has become feasible due to the recent technical advances in genomics and convincing positive results are now regularly being published. This review is an accessible introduction to the genetic and technical knowledge needed to interpret such studies. Genome-wide association studies are being applied to many neurologic diseases. Here we use idiopathic generalized epilepsy as an example to highlight the phenotyping, sample size, and statistical issues that must be addressed in such studies. These studies are likely to transform our understanding of complex neurologic diseases in the next few years. CAE = childhood absence epilepsy; CDCV = common disease-common variant; CDMRV = common disease-multiple rare variant; CNV = copy number variation; GTCS = generalized tonic-clonic seizures; GWAS = genome-wide association studies; IGE = idiopathic generalized epilepsy; JAE = juvenile absence epilepsy; JME = juvenile myoclonic epilepsy; LD = linkage disequilibrium; MS = multiple sclerosis; RLS = restless legs syndrome; RR = relative risk; SNP = single nucleotide polymorphism.
Journal of Neurology, Neurosurgery, and Psychiatry | 2005
R Padmanabhan; Douglas E. Crompton; D Burn; Daniel Birchall
An important but not widely recognised complication of lumboperitoneal shunting is the development of a Chiari 1 deformity and syringomyelia. We present a case of a patient who developed symptomatic cerebellar tonsillar descent and syrinx formation following treatment of pseudotumour cerebri with lumboperitoneal shunting. A 31 year old woman was diagnosed with pseudotumour cerebri following development of headaches, loss of vision, and papilloedema, in association with a cerebrospinal fluid (CSF) opening pressure of 36 cm H2O. Cranial imaging showed an attenuated ventricular system and no other abnormality. In particular, the posterior fossa was …
Neurology Genetics | 2015
Gemma L. Carvill; Douglas E. Crompton; Brigid M. Regan; Jacinta M. McMahon; Julia Saykally; Matthew Zemel; Amy Schneider; Leanne M. Dibbens; Katherine B. Howell; Simone Mandelstam; Richard J. Leventer; A. Simon Harvey; Saul A. Mullen; Samuel F. Berkovic; Joseph Sullivan; Ingrid E. Scheffer; Mefford Hc
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.
Clinical and Experimental Ophthalmology | 2007
Patrick Yu‐Wai‐Man; Douglas E. Crompton; James Y Graham; Fiona M Black; Margaret R Dayan
Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology and establishing the correct diagnosis can be challenging. Although dysfunction of the anterior visual pathways is uncommon, it is the most common neuro‐ophthalmological manifestation of this condition and given the potential for irreversible, severe visual loss, prompt diagnosis and treatment are essential. We describe a patient with optic perineuritis as a rare initial presentation of sarcoidosis and discuss the underlying pathophysiology and management.