ObjectiveTo determine genotype–phenotype correlation in succinic semialdehyde dehydrogenase (SSAD... more ObjectiveTo determine genotype–phenotype correlation in succinic semialdehyde dehydrogenase (SSADH) deficiency.MethodsALDH5A1 variants were studied with phenotype correlation in the SSADH natural history study. Assignment of gene variant pathogenicity was based on in silico testing and in vitro enzyme activity after site-directed mutagenesis and expression in HEK293 cells. Phenotypic scoring used a Clinical Severity Score (CSS) designed for the natural history study.ResultsTwenty-four patients were enrolled (10 male, 14 female, median age 8.2 years). There were 24 ALDH5A1 variants, including 7 novel pathogenic variants: 2 missense, 3 splice site, and 2 frameshift. Four previously reported variants were identified in >5% of unrelated families. There was a correlation with age and presence (p = 0.003) and severity (p = 0.002) of epilepsy and with obsessive-compulsive disorder (OCD) (p = 0.016). The median IQ score was 53 (Q25–Q75, 49–61). There was no overall correlation between th...
To determine risk factors and causes for mortality during childhood in patients with infantile sp... more To determine risk factors and causes for mortality during childhood in patients with infantile spasms (IS). We describe the overall goals of care for those who died.
Delineation of resected brain cavities on magnetic resonance images (MRIs) of epilepsy surgery pa... more Delineation of resected brain cavities on magnetic resonance images (MRIs) of epilepsy surgery patients is essential for neuroimaging/neurophysiology studies investigating biomarkers of the epileptogenic zone. The gold standard to delineate the resection on MRI remains manual slice-by-slice tracing by experts. Here, we proposed and validated a semiautomated MRI segmentation pipeline, generating an accurate model of the resection and its anatomical labeling, and developed a graphical user interface (GUI) for user-friendly usage. We retrieved pre- and postoperative MRIs from 35 patients who had focal epilepsy surgery, implemented a region-growing algorithm to delineate the resection on postoperative MRIs and tested its performance while varying different tuning parameters. Similarity between our output and hand-drawn gold standards was evaluated via dice similarity coefficient (DSC; range: 0–1). Additionally, the best segmentation pipeline was trained to provide an automated anatomica...
About 30% of children with drug-resistant epilepsy (DRE) continue to have seizures after epilepsy... more About 30% of children with drug-resistant epilepsy (DRE) continue to have seizures after epilepsy surgery. Since epilepsy is increasingly conceptualized as a network disorder, understanding how brain regions interact may be critical for planning re-operation in these patients. We aimed to estimate functional brain connectivity using scalp EEG and its evolution over time in patients who had repeated surgery (RS-group, n = 9) and patients who had one successful surgery (seizure-free, SF-group, n = 12). We analyzed EEGs without epileptiform activity at varying time points (before and after each surgery). We estimated functional connectivity between cortical regions and their relative centrality within the network. We compared the pre- and post-surgical centrality of all the non-resected (untouched) regions (far or adjacent to resection) for each group (using the Wilcoxon signed rank test). In alpha, theta, and beta frequency bands, the post-surgical centrality of the untouched cortical...
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare genetic disorder caused by inef... more Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare genetic disorder caused by inefficient metabolic breakdown of the major inhibitory neurotransmitter, γ-aminobutyric acid (GABA). Pathologic brain accumulation of GABA and γ-hydroxybutyrate (GHB), a neuroactive by-product of GABA catabolism, leads to a multitude of molecular abnormalities beginning in early life, culminating in multifaceted clinical presentations including delayed psychomotor development, intellectual disability, hypotonia, and ataxia. Paradoxically, over half of patients with SSADHD also develop epilepsy and face a significant risk of sudden unexpected death in epilepsy (SUDEP). Here, we review some of the relevant molecular mechanisms through which impaired synaptic inhibition, astrocytic malfunctions and myelin defects might contribute to the complex SSADHD phenotype. We also discuss the gaps in knowledge that need to be addressed for the implementation of successful gene and enzyme replacement SSAD...
Figure S1. Flow chart showing the systematic literature search and number and type of included so... more Figure S1. Flow chart showing the systematic literature search and number and type of included sources. (PPTX 81 kb)
Eishi Asano** Christine Baca** Albert Becker** Ettore Beghi** S andor Beniczky** Luiz Eduardo Bet... more Eishi Asano** Christine Baca** Albert Becker** Ettore Beghi** S andor Beniczky** Luiz Eduardo Betting** Leonardo Bonilha** Gemma Carvill** Fernando Cendes** Ana Coan** Linda de Vries** David Dunn** Rei Enatsu** Jerome Engel Jr.** Dario Englot** Barry E. Gidal** Jean Gotman** Damir Janigro** Barbara Jobst** Cecilie Johannessen Landmark** Csaba Juhasz** Andres Kanner** Jack Lin** Carla Marini** Eric Marsh** Brian Moseley** Marco Mula** Hirokazu Oguni** Sylvain Rheims** Steven Roper** Andrea Rossetti** Ren ee Shellhaas** Gagandeep Singh** Mary Lou Smith** Rainer Surges** Jose Tellez-Zenteno** Jacy Wagnon** Gaetano Zaccara**
SSADHD is a rare inborn metabolic disorder caused by the functional impairment of SSADH (encoded ... more SSADHD is a rare inborn metabolic disorder caused by the functional impairment of SSADH (encoded by the aldh5a1 gene), an enzyme essential for breaking down the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). In SSADHD, pathologic accumulation of GABA results in broad spectrum encephalopathy including developmental delay, ataxia, seizures and a risk of sudden unexpected death in epilepsy (SUDEP). Proof-of-concept systemic SSADH restoration via enzyme replacement therapy (ERT) or aldh5a1 gene transfer increased survival of SSADH knockout mice, suggesting that SSADH restoration might be a viable cure for SSADHD. However, before testing SSADH restoration therapy in patients, we must consider its safety and feasibility in context of the unique SSADHD pathophysiology. Specifically, a profound use-dependent down-regulation of GABA(A) receptors in SSADHD indicates a risk that sudden SSADH restoration might diminish GABAergic tone and provoke seizures. Such risk may be mitigated...
To advance the understanding of KCNQ2 encephalopathy genotype-phenotype relationships and to begi... more To advance the understanding of KCNQ2 encephalopathy genotype-phenotype relationships and to begin to assess the potential of selective KCNQ channel openers as targeted treatments. We retrospectively studied 23 patients with KCNQ2 encephalopathy, including 11 treated with ezogabine (EZO). We analyzed the genotype-phenotype relationships in these and 70 previously described patients. The mean seizure onset age was 1.8 ± 1.6 (SD) days. Of the 20 EEGs obtained within a week of birth, 11 showed burst suppression. When new seizure types appeared in infancy (15 patients), the most common were epileptic spasms (n = 8). At last follow-up, seizures persisted in 9 patients. Development was delayed in all, severely in 14. The KCNQ2 variants identified introduced amino acid missense changes or, in one instance, a single residue deletion. They were clustered in 4 protein subdomains predicted to poison tetrameric channel functions. EZO use (assessed by the treating physicians and parents) was ass...
Crit Care Med 2015 • Volume 43 • Number 12 (Suppl.) Methods: Children (<18 yr) admitted to the... more Crit Care Med 2015 • Volume 43 • Number 12 (Suppl.) Methods: Children (<18 yr) admitted to the PICU for status asthmaticus were eligible for enrollment. Those with neurologic disease or systemic disease other than asthma were excluded from this analysis. Continuous sleep EEG data were collected for a target of 24 hr with a required minimum of 12 hr night time data collection. Standard sleep EEG was done using the international 10–20 system. All data were staged using R&K visual scoring rules. Findings were considered normal if they fell within 2 standard deviations of published norms for age. Data are presented as median (interquartile range). Results: Five children have been studied to date (age: 10.3 [5.5–13.6] yr, 4/5 male). None of the children received sedation. Median study duration was 20.5 (14.8–22.1) hr with a median total sleep time (TST) of 7 hr (6.3–7.6) hr. TST was below normal in 4/5 children. All five had fragmented sleep with a median of 16 (12–17) overnight awakenings. The median value for the average duration of awakening was 5.9 (3.2–6.4) min. The median value for the longest period of uninterrupted sleep was 95 (85–110) min, with a maximum of only 130 min. Remarkably, total min of N3 sleep were normal for 4/5 children whereas total min of REM sleep were reduced for 4/5 children. Conclusions: While PICU care for status asthmaticus was associated with reduced TST, fragmented sleep, and decreased REM sleep, restorative N3 (slow wave) sleep was preserved in the majority of the cohort. This establishes that measurement of sleep architecture is feasible in critically ill children and should be studied in larger and more diverse cohorts to evaluate relationships between sleep and outcomes (including delirium) in the PICU.
While genetic causes of epilepsy have been hypothesized from the time of Hippocrates, the advent ... more While genetic causes of epilepsy have been hypothesized from the time of Hippocrates, the advent of new genetic technologies has played a tremendous role in elucidating a growing number of specific genetic causes for the epilepsies. This progress has contributed vastly to our recognition of the epilepsies as a diverse group of disorders, the genetic mechanisms of which are heterogeneous. Genotype-phenotype correlation, however, is not always clear. Nonetheless, the developments in genetic diagnosis raise the promise of a future of personalized medicine. Multiple genetic tests are now available, but there is no one test for all possible genetic mutations, and the balance between cost and benefit must be weighed. A genetic diagnosis, however, can provide valuable information regarding comorbidities, prognosis, and even treatment, as well as allow for genetic counseling. In this review, we will discuss the genetic mechanisms of the epilepsies as well as the specifics of particular genetic epilepsy syndromes. We will include an overview of the available genetic testing methods, the application of clinical knowledge into the selection of genetic testing, genotype-phenotype correlations of epileptic disorders, and therapeutic advances as well as a discussion of the importance of genetic counseling.
Epileptic encephalopathy can be induced by inborn metabolic defects that may be rare individually... more Epileptic encephalopathy can be induced by inborn metabolic defects that may be rare individually but in aggregate represent a substantial clinical portion of child neurology. These may present with various epilepsy phenotypes including refractory neonatal seizures, early myoclonic encephalopathy, early infantile epileptic encephalopathy, infantile spasms, and generalized epilepsies which in particular include myoclonic seizures. There are varying degrees of treatability, but the outcome if untreated can often be catastrophic. The importance of early recognition cannot be overemphasized. This paper provides an overview of inborn metabolic errors associated with persistent brain disturbances due to highly active clinical or electrographic ictal activity. Selected diseases are organized by the defective molecule or mechanism and categorized as small molecule disorders (involving amino and organic acids, fatty acids, neurotransmitters, urea cycle, vitamers and cofactors, and mitochondr...
ObjectiveTo determine genotype–phenotype correlation in succinic semialdehyde dehydrogenase (SSAD... more ObjectiveTo determine genotype–phenotype correlation in succinic semialdehyde dehydrogenase (SSADH) deficiency.MethodsALDH5A1 variants were studied with phenotype correlation in the SSADH natural history study. Assignment of gene variant pathogenicity was based on in silico testing and in vitro enzyme activity after site-directed mutagenesis and expression in HEK293 cells. Phenotypic scoring used a Clinical Severity Score (CSS) designed for the natural history study.ResultsTwenty-four patients were enrolled (10 male, 14 female, median age 8.2 years). There were 24 ALDH5A1 variants, including 7 novel pathogenic variants: 2 missense, 3 splice site, and 2 frameshift. Four previously reported variants were identified in >5% of unrelated families. There was a correlation with age and presence (p = 0.003) and severity (p = 0.002) of epilepsy and with obsessive-compulsive disorder (OCD) (p = 0.016). The median IQ score was 53 (Q25–Q75, 49–61). There was no overall correlation between th...
To determine risk factors and causes for mortality during childhood in patients with infantile sp... more To determine risk factors and causes for mortality during childhood in patients with infantile spasms (IS). We describe the overall goals of care for those who died.
Delineation of resected brain cavities on magnetic resonance images (MRIs) of epilepsy surgery pa... more Delineation of resected brain cavities on magnetic resonance images (MRIs) of epilepsy surgery patients is essential for neuroimaging/neurophysiology studies investigating biomarkers of the epileptogenic zone. The gold standard to delineate the resection on MRI remains manual slice-by-slice tracing by experts. Here, we proposed and validated a semiautomated MRI segmentation pipeline, generating an accurate model of the resection and its anatomical labeling, and developed a graphical user interface (GUI) for user-friendly usage. We retrieved pre- and postoperative MRIs from 35 patients who had focal epilepsy surgery, implemented a region-growing algorithm to delineate the resection on postoperative MRIs and tested its performance while varying different tuning parameters. Similarity between our output and hand-drawn gold standards was evaluated via dice similarity coefficient (DSC; range: 0–1). Additionally, the best segmentation pipeline was trained to provide an automated anatomica...
About 30% of children with drug-resistant epilepsy (DRE) continue to have seizures after epilepsy... more About 30% of children with drug-resistant epilepsy (DRE) continue to have seizures after epilepsy surgery. Since epilepsy is increasingly conceptualized as a network disorder, understanding how brain regions interact may be critical for planning re-operation in these patients. We aimed to estimate functional brain connectivity using scalp EEG and its evolution over time in patients who had repeated surgery (RS-group, n = 9) and patients who had one successful surgery (seizure-free, SF-group, n = 12). We analyzed EEGs without epileptiform activity at varying time points (before and after each surgery). We estimated functional connectivity between cortical regions and their relative centrality within the network. We compared the pre- and post-surgical centrality of all the non-resected (untouched) regions (far or adjacent to resection) for each group (using the Wilcoxon signed rank test). In alpha, theta, and beta frequency bands, the post-surgical centrality of the untouched cortical...
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare genetic disorder caused by inef... more Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare genetic disorder caused by inefficient metabolic breakdown of the major inhibitory neurotransmitter, γ-aminobutyric acid (GABA). Pathologic brain accumulation of GABA and γ-hydroxybutyrate (GHB), a neuroactive by-product of GABA catabolism, leads to a multitude of molecular abnormalities beginning in early life, culminating in multifaceted clinical presentations including delayed psychomotor development, intellectual disability, hypotonia, and ataxia. Paradoxically, over half of patients with SSADHD also develop epilepsy and face a significant risk of sudden unexpected death in epilepsy (SUDEP). Here, we review some of the relevant molecular mechanisms through which impaired synaptic inhibition, astrocytic malfunctions and myelin defects might contribute to the complex SSADHD phenotype. We also discuss the gaps in knowledge that need to be addressed for the implementation of successful gene and enzyme replacement SSAD...
Figure S1. Flow chart showing the systematic literature search and number and type of included so... more Figure S1. Flow chart showing the systematic literature search and number and type of included sources. (PPTX 81 kb)
Eishi Asano** Christine Baca** Albert Becker** Ettore Beghi** S andor Beniczky** Luiz Eduardo Bet... more Eishi Asano** Christine Baca** Albert Becker** Ettore Beghi** S andor Beniczky** Luiz Eduardo Betting** Leonardo Bonilha** Gemma Carvill** Fernando Cendes** Ana Coan** Linda de Vries** David Dunn** Rei Enatsu** Jerome Engel Jr.** Dario Englot** Barry E. Gidal** Jean Gotman** Damir Janigro** Barbara Jobst** Cecilie Johannessen Landmark** Csaba Juhasz** Andres Kanner** Jack Lin** Carla Marini** Eric Marsh** Brian Moseley** Marco Mula** Hirokazu Oguni** Sylvain Rheims** Steven Roper** Andrea Rossetti** Ren ee Shellhaas** Gagandeep Singh** Mary Lou Smith** Rainer Surges** Jose Tellez-Zenteno** Jacy Wagnon** Gaetano Zaccara**
SSADHD is a rare inborn metabolic disorder caused by the functional impairment of SSADH (encoded ... more SSADHD is a rare inborn metabolic disorder caused by the functional impairment of SSADH (encoded by the aldh5a1 gene), an enzyme essential for breaking down the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). In SSADHD, pathologic accumulation of GABA results in broad spectrum encephalopathy including developmental delay, ataxia, seizures and a risk of sudden unexpected death in epilepsy (SUDEP). Proof-of-concept systemic SSADH restoration via enzyme replacement therapy (ERT) or aldh5a1 gene transfer increased survival of SSADH knockout mice, suggesting that SSADH restoration might be a viable cure for SSADHD. However, before testing SSADH restoration therapy in patients, we must consider its safety and feasibility in context of the unique SSADHD pathophysiology. Specifically, a profound use-dependent down-regulation of GABA(A) receptors in SSADHD indicates a risk that sudden SSADH restoration might diminish GABAergic tone and provoke seizures. Such risk may be mitigated...
To advance the understanding of KCNQ2 encephalopathy genotype-phenotype relationships and to begi... more To advance the understanding of KCNQ2 encephalopathy genotype-phenotype relationships and to begin to assess the potential of selective KCNQ channel openers as targeted treatments. We retrospectively studied 23 patients with KCNQ2 encephalopathy, including 11 treated with ezogabine (EZO). We analyzed the genotype-phenotype relationships in these and 70 previously described patients. The mean seizure onset age was 1.8 ± 1.6 (SD) days. Of the 20 EEGs obtained within a week of birth, 11 showed burst suppression. When new seizure types appeared in infancy (15 patients), the most common were epileptic spasms (n = 8). At last follow-up, seizures persisted in 9 patients. Development was delayed in all, severely in 14. The KCNQ2 variants identified introduced amino acid missense changes or, in one instance, a single residue deletion. They were clustered in 4 protein subdomains predicted to poison tetrameric channel functions. EZO use (assessed by the treating physicians and parents) was ass...
Crit Care Med 2015 • Volume 43 • Number 12 (Suppl.) Methods: Children (<18 yr) admitted to the... more Crit Care Med 2015 • Volume 43 • Number 12 (Suppl.) Methods: Children (<18 yr) admitted to the PICU for status asthmaticus were eligible for enrollment. Those with neurologic disease or systemic disease other than asthma were excluded from this analysis. Continuous sleep EEG data were collected for a target of 24 hr with a required minimum of 12 hr night time data collection. Standard sleep EEG was done using the international 10–20 system. All data were staged using R&K visual scoring rules. Findings were considered normal if they fell within 2 standard deviations of published norms for age. Data are presented as median (interquartile range). Results: Five children have been studied to date (age: 10.3 [5.5–13.6] yr, 4/5 male). None of the children received sedation. Median study duration was 20.5 (14.8–22.1) hr with a median total sleep time (TST) of 7 hr (6.3–7.6) hr. TST was below normal in 4/5 children. All five had fragmented sleep with a median of 16 (12–17) overnight awakenings. The median value for the average duration of awakening was 5.9 (3.2–6.4) min. The median value for the longest period of uninterrupted sleep was 95 (85–110) min, with a maximum of only 130 min. Remarkably, total min of N3 sleep were normal for 4/5 children whereas total min of REM sleep were reduced for 4/5 children. Conclusions: While PICU care for status asthmaticus was associated with reduced TST, fragmented sleep, and decreased REM sleep, restorative N3 (slow wave) sleep was preserved in the majority of the cohort. This establishes that measurement of sleep architecture is feasible in critically ill children and should be studied in larger and more diverse cohorts to evaluate relationships between sleep and outcomes (including delirium) in the PICU.
While genetic causes of epilepsy have been hypothesized from the time of Hippocrates, the advent ... more While genetic causes of epilepsy have been hypothesized from the time of Hippocrates, the advent of new genetic technologies has played a tremendous role in elucidating a growing number of specific genetic causes for the epilepsies. This progress has contributed vastly to our recognition of the epilepsies as a diverse group of disorders, the genetic mechanisms of which are heterogeneous. Genotype-phenotype correlation, however, is not always clear. Nonetheless, the developments in genetic diagnosis raise the promise of a future of personalized medicine. Multiple genetic tests are now available, but there is no one test for all possible genetic mutations, and the balance between cost and benefit must be weighed. A genetic diagnosis, however, can provide valuable information regarding comorbidities, prognosis, and even treatment, as well as allow for genetic counseling. In this review, we will discuss the genetic mechanisms of the epilepsies as well as the specifics of particular genetic epilepsy syndromes. We will include an overview of the available genetic testing methods, the application of clinical knowledge into the selection of genetic testing, genotype-phenotype correlations of epileptic disorders, and therapeutic advances as well as a discussion of the importance of genetic counseling.
Epileptic encephalopathy can be induced by inborn metabolic defects that may be rare individually... more Epileptic encephalopathy can be induced by inborn metabolic defects that may be rare individually but in aggregate represent a substantial clinical portion of child neurology. These may present with various epilepsy phenotypes including refractory neonatal seizures, early myoclonic encephalopathy, early infantile epileptic encephalopathy, infantile spasms, and generalized epilepsies which in particular include myoclonic seizures. There are varying degrees of treatability, but the outcome if untreated can often be catastrophic. The importance of early recognition cannot be overemphasized. This paper provides an overview of inborn metabolic errors associated with persistent brain disturbances due to highly active clinical or electrographic ictal activity. Selected diseases are organized by the defective molecule or mechanism and categorized as small molecule disorders (involving amino and organic acids, fatty acids, neurotransmitters, urea cycle, vitamers and cofactors, and mitochondr...
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Papers by Phillip Pearl