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High-resolution molecular genomic autopsy reveals complex sudden unexpected death in epilepsy risk profile.

ABSTRACT: Advanced variant detection in genes underlying risk of sudden unexpected death in epilepsy (SUDEP) can uncover extensive epistatic complexity and improve diagnostic accuracy of epilepsy-related mortality. However, the sensitivity and clinical utility of diagnostic panels based solely on established cardiac arrhythmia genes in the molecular autopsy of SUDEP is unknown. We applied the established clinical diagnostic panels, followed by sequencing and a high density copy number variant (CNV) detection array of an additional 253 related ion channel subunit genes to analyze the overall genomic variation in a SUDEP of the 3-year-old proband with severe myoclonic epilepsy of infancy (SMEI). We uncovered complex combinations of single nucleotide polymorphisms and CNVs in genes expressed in both neurocardiac and respiratory control pathways, including SCN1A, KCNA1, RYR3, and HTR2C. Our findings demonstrate the importance of comprehensive high-resolution variant analysis in the assessment of personally relevant SUDEP risk. In this case, the combination of de novo single nucleotide polymorphisms (SNPs) and CNVs in the SCN1A and KCNA1 genes, respectively, is suspected to be the principal risk factor for both epilepsy and premature death. However, consideration of the overall biologically relevant variant complexity with its extensive functional epistatic interactions reveals potential personal risk more accurately.

SUBMITTER: Klassen TL

PROVIDER: S-EPMC4195652 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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High-resolution molecular genomic autopsy reveals complex sudden unexpected death in epilepsy risk profile.

Klassen Tara L TL Bomben Valerie C VC Patel Ankita A Drabek Janice J Chen Tim T TT Gu Wenli W Zhang Feng F Chapman Kevin K Lupski James R JR Noebels Jeffrey L JL Goldman A M AM

Epilepsia 20131224 2

Advanced variant detection in genes underlying risk of sudden unexpected death in epilepsy (SUDEP) can uncover extensive epistatic complexity and improve diagnostic accuracy of epilepsy-related mortality. However, the sensitivity and clinical utility of diagnostic panels based solely on established cardiac arrhythmia genes in the molecular autopsy of SUDEP is unknown. We applied the established clinical diagnostic panels, followed by sequencing and a high density copy number variant (CNV) detect ...[more]

PMID: 24372310

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Project description:Sudden unexpected death in epilepsy is the leading category of epilepsy-related death and the underlying mechanisms are incompletely understood. Risk factors can include a recent history and high frequency of generalized tonic-clonic seizures, which can depress brain activity postictally, impairing respiration, arousal and protective reflexes. Neuropathological findings in sudden unexpected death in epilepsy cases parallel those in other epilepsy patients, with no implication of novel structures or mechanisms in seizure-related deaths. Few large studies have comprehensively reviewed whole brain examination of such patients. We evaluated 92 North American Sudden unexpected death in epilepsy Registry cases with whole brain neuropathological examination by board-certified neuropathologists blinded to the adjudicated cause of death, with an average of 16 brain regions examined per case. The 92 cases included 61 sudden unexpected death in epilepsy (40 definite, 9 definite plus, 6 probable, 6 possible) and 31 people with epilepsy controls who died from other causes. The mean age at death was 34.4 years and 65.2% (60/92) were male. The average age of death was younger for sudden unexpected death in epilepsy cases than for epilepsy controls (30.0 versus 39.6 years; P = 0.006), and there was no difference in sex distribution respectively (67.3% male versus 64.5%, P = 0.8). Among sudden unexpected death in epilepsy cases, earlier age of epilepsy onset positively correlated with a younger age at death (P = 0.0005) and negatively correlated with epilepsy duration (P = 0.001). Neuropathological findings were identified in 83.7% of the cases in our cohort. The most common findings were dentate gyrus dysgenesis (sudden unexpected death in epilepsy 50.9%, epilepsy controls 54.8%) and focal cortical dysplasia (FCD) (sudden unexpected death in epilepsy 41.8%, epilepsy controls 29.0%). The neuropathological findings in sudden unexpected death in epilepsy paralleled those in epilepsy controls, including the frequency of total neuropathological findings as well as the specific findings in the dentate gyrus, findings pertaining to neurodevelopment (e.g. FCD, heterotopias) and findings in the brainstem (e.g. medullary arcuate or olivary dysgenesis). Thus, like prior studies, we found no neuropathological findings that were more common in sudden unexpected death in epilepsy cases. Future neuropathological studies evaluating larger sudden unexpected death in epilepsy and control cohorts would benefit from inclusion of different epilepsy syndromes with detailed phenotypic information, consensus among pathologists particularly for more subjective findings where observations can be inconsistent, and molecular approaches to identify markers of sudden unexpected death in epilepsy risk or pathogenesis.

Project description:Sudden unexpected death in epilepsy (SUDEP) is a leading cause of premature death in patients with epilepsy. One hypothesis proposes that sudden death is mediated by post-ictal central respiratory depression, which could relate to underlying pathology in key respiratory nuclei and/or their neuromodulators. Our aim was to investigate neuronal populations in the ventrolateral medulla (which includes the putative human pre-Bötzinger complex) and the medullary raphe. Forty brainstems were studied comprising four groups: 14 SUDEP, six epilepsy controls, seven Dravet syndrome cases and 13 non-epilepsy controls. Serial sections through the medulla (from obex 1 to 10 mm) were stained for Nissl, somatostatin, neurokinin 1 receptor (for pre-Bötzinger complex neurons) and galanin, tryptophan hydroxylase and serotonin transporter (neuromodulatory systems). Using stereology total neuronal number and densities, with respect to obex level, were measured. Whole slide scanning image analysis was used to quantify immunolabelling indices as well as co-localization between markers. Significant findings included reduction in somatostatin neurons and neurokinin 1 receptor labelling in the ventrolateral medulla in sudden death in epilepsy compared to controls (P < 0.05). Galanin and tryptophan hydroxylase labelling was also reduced in sudden death cases and more significantly in the ventrolateral medulla region than the raphe (P < 0.005 and P < 0.05). With serotonin transporter, reduction in labelling in cases of sudden death in epilepsy was noted only in the raphe (P ? 0.01); however, co-localization with tryptophan hydroxylase was significantly reduced in the ventrolateral medulla. Epilepsy controls and cases with Dravet syndrome showed less significant alterations with differences from non-epilepsy controls noted only for somatostatin in the ventrolateral medulla (P < 0.05). Variations in labelling with respect to obex level were noted of potential relevance to the rostro-caudal organization of respiratory nuclear groups, including tryptophan hydroxylase, where the greatest statistical difference noted between all epilepsy cases and controls was at obex 9-10 mm (P = 0.034), the putative level of the pre-Bötzinger complex. Furthermore, there was evidence for variation with duration of epilepsy for somatostatin and neurokinin 1 receptor. Our findings suggest alteration to neuronal populations in the medulla in SUDEP with evidence for greater reduction in neuromodulatory neuropeptidergic and mono-aminergic systems, including for galanin, and serotonin. Other nuclei need to be investigated to evaluate if this is part of more widespread brainstem pathology. Our findings could be a result of previous seizures and may represent a pathological risk factor for SUDEP through impaired respiratory homeostasis during a seizure.

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High-resolution molecular genomic autopsy reveals complex sudden unexpected death in epilepsy risk profile.

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High-resolution molecular genomic autopsy reveals complex sudden unexpected death in epilepsy risk profile.

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