References of "Johnson, Michael R"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailUltra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals
Feng, Yen-Chen Anne; Howrigan, Daniel P.; Abbott, Liam E. et al

in American Journal of Human Genetics (2019)

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared ... [more ▼]

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology. [less ▲]

Detailed reference viewed: 64 (3 UL)
Full Text
Peer Reviewed
See detailGenomic and clinical predictors of lacosamide response in refractory epilepsies
Heavin, Sinéad B.; McCormack, Mark; Wolking, Stefan et al

in Epilepsia Open (2019), 0(0),

Abstract Objective Clinical and genetic predictors of response to antiepileptic drugs (AEDs) are largely unknown. We examined predictors of lacosamide response in a real-world clinical setting. Methods We ... [more ▼]

Abstract Objective Clinical and genetic predictors of response to antiepileptic drugs (AEDs) are largely unknown. We examined predictors of lacosamide response in a real-world clinical setting. Methods We tested the association of clinical predictors with treatment response using regression modeling in a cohort of people with refractory epilepsy. Genetic assessment for lacosamide response was conducted via genome-wide association studies and exome studies, comprising 281 candidate genes. Results Most patients (479/483) were treated with LCM in addition to other AEDs. Our results corroborate previous findings that patients with refractory genetic generalized epilepsy (GGE) may respond to treatment with LCM. No clear clinical predictors were identified. We then compared 73 lacosamide responders, defined as those experiencing greater than 75% seizure reduction or seizure freedom, to 495 nonresponders (<25% seizure reduction). No variants reached the genome-wide significance threshold in our case-control analysis. Significance No genetic predictor of lacosamide response was identified. Patients with refractory GGE might benefit from treatment with lacosamide. [less ▲]

Detailed reference viewed: 37 (0 UL)
Full Text
Peer Reviewed
See detailComparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy
Silvennoinen, Katri; de Lange, Nikola Maria UL; Zagaglia, Sara et al

in Epilepsia Open (2019), 0(0),

Abstract Objective To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). Methods People with JME were identified from a large ... [more ▼]

Abstract Objective To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). Methods People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. Results We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7\%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1\%) was not significant. The rates of ADRs were highest for topiramate (45.5\%) and valproate (37.5\%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13], P < 0.001) and female sex (1.41 [1.07-1.85], P = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15-5.02], P < 0.001 and 1.93 [1.31-2.86], P < 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2 vs 92.6\%, P = 0.001). Significance In people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place, valproate should remain available as a therapy, including as an alternative for women of childbearing potential whose seizures are resistant to other treatments. [less ▲]

Detailed reference viewed: 58 (1 UL)
Full Text
Peer Reviewed
See detailRare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study
May, Patrick UL; Girard, Simon; Harrer, Merle et al

in Lancet Neurology (2018), 17(8), 699-708

Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We ... [more ▼]

Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. Methods For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes. Findings Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41–4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05–2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02–2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors. Interpretation Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy. [less ▲]

Detailed reference viewed: 68 (17 UL)
Full Text
Peer Reviewed
See detailGenetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients.
McCormack, Mark; Gui, Hongsheng; Ingason, Andres et al

in Neurology (2017)

OBJECTIVE: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. METHODS ... [more ▼]

OBJECTIVE: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. METHODS: We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. RESULTS: We report an association between a rare variant in the complement factor H-related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 x 10(-11); odds ratio [95% confidence interval] 7 [3.2-16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. CONCLUSIONS: The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H-related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients. [less ▲]

Detailed reference viewed: 112 (2 UL)
Full Text
Peer Reviewed
See detailApplication of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data
Allen, Andrew S.; Berkovic, Samuel F.; Bridgers, Joshua et al

in European Journal of Human Genetics (2017)

The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox–Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly ... [more ▼]

The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox–Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients with IS or LGS. The contribution of autosomal recessive genetic variation, however, is less well understood. We implemented a rare variant transmission disequilibrium test (TDT) to search for autosomal recessive epileptic encephalopathy genes in a cohort of 320 outbred patient–parent trios that were generally prescreened for rare metabolic disorders. In the current sample, our rare variant transmission disequilibrium test did not identify individual genes with significantly distorted transmission over expectation after correcting for the multiple tests. While the rare variant transmission disequilibrium test did not find evidence of a role for individual autosomal recessive genes, our current sample is insufficiently powered to assess the overall role of autosomal recessive genotypes in an outbred epileptic encephalopathy population. [less ▲]

Detailed reference viewed: 124 (10 UL)
Full Text
Peer Reviewed
See detailDe Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies.
Appenzeller, Silke; Balling, Rudi UL; Barisic, Nina et al

in American Journal of Human Genetics (2017), 100(1), 179-

In the list of consortium members for the Epilepsy Phenome/Genome Project, member Dina Amrom’s name was misspelled as Amron. The authors regret the error.

Detailed reference viewed: 96 (3 UL)