Pub Date : 2023-12-21DOI: 10.1016/j.braindev.2023.12.003
Sareh Hosseinpour , Ehsan Razmara , Morteza Heidari , Zahra Rezaei , Mahmoud Reza Ashrafi , Ali Zare Dehnavi , Reyhaneh Kameli , Ali Hosseini Bereshneh , Hassan Vahidnezhad , Reza Azizimalamiri , Zahra Zamani , Neda Pak , Maryam Rasulinezhad , Bahram Mohammadi , Homa Ghabeli , Mohammad Ghafouri , Mahmoud Mohammadi , Gholam Reza Zamani , Reza Shervin Badv , Sasan Saket , Ali Reza Tavasoli
Objective
Mitochondrial leukodystrophies (MLs) are mainly caused by impairments of the mitochondrial respiratory chains. This study reports the mutation and phenotypic spectrum of a cohort of 41 pediatric patients from 39 distinct families with MLs among 320 patients with a molecular diagnosis of leukodystrophies.
Methods
This study summarizes the clinical, imaging, and molecular data of these patients for five years.
Results
The three most common symptoms were neurologic regression (58.5%), pyramidal signs (58.5%), and extrapyramidal signs (43.9%). Because nuclear DNA mutations are responsible for a high percentage of pediatric MLs, whole exome sequencing was performed on all patients. In total, 39 homozygous variants were detected. Additionally, two previously reported mtDNA variants were identified with different levels of heteroplasmy in two patients. Among 41 mutant alleles, 33 (80.4%) were missense, 4 (9.8%) were frameshift (including 3 deletions and one duplication), and 4 (9.8%) were splicing mutations. Oxidative phosphorylation in 27 cases (65.8%) and mtDNA maintenance pathways in 8 patients (19.5%) were the most commonly affected mitochondrial pathways. In total, 5 novel variants in PDSS1, NDUFB9, FXBL4, SURF1, and NDUSF1 were also detected. In silico analyses showed how each novel variant may contribute to ML pathogenesis.
Conclusions
The findings of this study suggest whole-exome sequencing as a strong diagnostic genetic tool to identify the causative variants in pediatric MLs. In comparison between oxidative phosphorylation (OXPHOS) and mtDNA maintenance groups, brain stem and periaqueductal gray matter (PAGM) involvement were more commonly seen in OXPHOS group (P value of 0.002 and 0.009, respectively), and thinning of corpus callosum was observed more frequently in mtDNA maintenance group (P value of 0.042).
{"title":"A comprehensive study of mutation and phenotypic heterogeneity of childhood mitochondrial leukodystrophies","authors":"Sareh Hosseinpour , Ehsan Razmara , Morteza Heidari , Zahra Rezaei , Mahmoud Reza Ashrafi , Ali Zare Dehnavi , Reyhaneh Kameli , Ali Hosseini Bereshneh , Hassan Vahidnezhad , Reza Azizimalamiri , Zahra Zamani , Neda Pak , Maryam Rasulinezhad , Bahram Mohammadi , Homa Ghabeli , Mohammad Ghafouri , Mahmoud Mohammadi , Gholam Reza Zamani , Reza Shervin Badv , Sasan Saket , Ali Reza Tavasoli","doi":"10.1016/j.braindev.2023.12.003","DOIUrl":"10.1016/j.braindev.2023.12.003","url":null,"abstract":"<div><h3>Objective</h3><p><span>Mitochondrial leukodystrophies (MLs) are mainly caused by impairments of the mitochondrial </span>respiratory chains<span>. This study reports the mutation and phenotypic spectrum of a cohort of 41 pediatric<span> patients from 39 distinct families with MLs among 320 patients with a molecular diagnosis<span> of leukodystrophies.</span></span></span></p></div><div><h3>Methods</h3><p>This study summarizes the clinical, imaging, and molecular data of these patients for five years.</p></div><div><h3>Results</h3><p><span>The three most common symptoms<span><span><span><span> were neurologic regression (58.5%), pyramidal signs (58.5%), and </span>extrapyramidal signs (43.9%). Because nuclear </span>DNA mutations<span> are responsible for a high percentage of pediatric MLs, whole exome sequencing<span> was performed on all patients. In total, 39 homozygous variants were detected. Additionally, two previously reported mtDNA variants were identified with different levels of heteroplasmy in two patients. Among 41 mutant alleles, 33 (80.4%) were missense, 4 (9.8%) were frameshift (including 3 deletions and one duplication), and 4 (9.8%) were splicing mutations. </span></span></span>Oxidative phosphorylation in 27 cases (65.8%) and mtDNA maintenance pathways in 8 patients (19.5%) were the most commonly affected mitochondrial pathways. In total, 5 novel variants in </span></span><em>PDSS1, NDUFB9, FXBL4, SURF1</em>, and <em>NDUSF1</em><span> were also detected. In silico analyses showed how each novel variant may contribute to ML pathogenesis.</span></p></div><div><h3>Conclusions</h3><p><span><span>The findings of this study suggest whole-exome sequencing as a strong diagnostic genetic tool to identify the causative variants in pediatric MLs. In comparison between oxidative phosphorylation (OXPHOS) and mtDNA maintenance groups, brain stem and </span>periaqueductal gray matter (PAGM) involvement were more commonly seen in OXPHOS group (P value of 0.002 and 0.009, respectively), and thinning of </span>corpus callosum was observed more frequently in mtDNA maintenance group (P value of 0.042).</p></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138823742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Post-encephalopathic epilepsy (PEE) is a serious complication of acute encephalopathy syndromes, and is more frequent in patients with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) than in children with acute encephalopathy. However, a risk factor analysis using laboratory findings in the acute phase of AESD has not yet been performed. Therefore, the present study examined risk factors of AESD-related PEE using laboratory parameters in the acute phase of AESD.
Methods
We retrospectively screened 27 pediatric patients with AESD for inclusion, and enrolled 20 (“the PEE group”, n = 6; “the non-PEE group”, n = 14) according to inclusion criteria.
Results
The incidence of AESD-related PEE was 30 %, and the median duration from the onset of AESD to the development of PEE was 2.5 months (range, 1–32). The most common types of seizures were focal seizures, epileptic spasms, and startle seizures: 4 out of 6 patients (66.7 %) had intractable epilepsy. The median values of alanine aminotransferase (ALT) in the 1st and 2nd seizure phases of AESD and aspartate aminotransferase (AST) in the 2nd seizure phase were significantly higher in the PEE group than in the non-PEE group (p < 0.01).
Conclusions
This is the first study to report higher serum levels of ALT and AST at the onset of AESD as risk factors for AESD-related PEE. We also provided a detailed description on the clinical characteristics on AESD-related PEE, which are consistent with previous findings.
{"title":"Risk factors for post-encephalopathic epilepsy in patients with acute encephalopathy with biphasic seizures and late reduced diffusion","authors":"Makoto Nishioka , Mitsuo Motobayashi , Tetsuhiro Fukuyama , Yuji Inaba","doi":"10.1016/j.braindev.2023.12.002","DOIUrl":"10.1016/j.braindev.2023.12.002","url":null,"abstract":"<div><h3>Background</h3><p><span>Post-encephalopathic epilepsy (PEE) is a serious complication of acute encephalopathy syndromes, and is more frequent </span>in patients<span> with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) than in children with acute encephalopathy. However, a risk factor analysis using laboratory findings in the acute phase of AESD has not yet been performed. Therefore, the present study examined risk factors of AESD-related PEE using laboratory parameters in the acute phase of AESD.</span></p></div><div><h3>Methods</h3><p>We retrospectively screened 27 pediatric patients with AESD for inclusion, and enrolled 20 (“the PEE group”, n = 6; “the non-PEE group”, n = 14) according to inclusion criteria.</p></div><div><h3>Results</h3><p><span><span><span><span>The incidence of AESD-related PEE was 30 %, and the median duration from the onset of AESD to the development of PEE was 2.5 months (range, 1–32). The most common types of seizures were focal seizures, </span>epileptic spasms, and startle seizures: 4 out of 6 patients (66.7 %) had </span>intractable epilepsy. The median values of </span>alanine aminotransferase (ALT) in the 1st and 2nd seizure phases of AESD and aspartate aminotransferase (AST) in the 2nd seizure phase were significantly higher in the PEE group than in the non-PEE group (</span><em>p</em> < 0.01).</p></div><div><h3>Conclusions</h3><p>This is the first study to report higher serum levels of ALT and AST at the onset of AESD as risk factors for AESD-related PEE. We also provided a detailed description on the clinical characteristics on AESD-related PEE, which are consistent with previous findings.</p></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138818740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Post-encephalopathic epilepsy (PEE) is a serious complication of acute encephalopathy syndromes, and is more frequent in patients with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) than in children with acute encephalopathy. However, a risk factor analysis using laboratory findings in the acute phase of AESD has not yet been performed. Therefore, the present study examined risk factors of AESD-related PEE using laboratory parameters in the acute phase of AESD.
Methods: We retrospectively screened 27 pediatric patients with AESD for inclusion, and enrolled 20 ("the PEE group", n = 6; "the non-PEE group", n = 14) according to inclusion criteria.
Results: The incidence of AESD-related PEE was 30 %, and the median duration from the onset of AESD to the development of PEE was 2.5 months (range, 1-32). The most common types of seizures were focal seizures, epileptic spasms, and startle seizures: 4 out of 6 patients (66.7 %) had intractable epilepsy. The median values of alanine aminotransferase (ALT) in the 1st and 2nd seizure phases of AESD and aspartate aminotransferase (AST) in the 2nd seizure phase were significantly higher in the PEE group than in the non-PEE group (p < 0.01).
Conclusions: This is the first study to report higher serum levels of ALT and AST at the onset of AESD as risk factors for AESD-related PEE. We also provided a detailed description on the clinical characteristics on AESD-related PEE, which are consistent with previous findings.
{"title":"Risk factors for post-encephalopathic epilepsy in patients with acute encephalopathy with biphasic seizures and late reduced diffusion.","authors":"Makoto Nishioka, Mitsuo Motobayashi, Tetsuhiro Fukuyama, Yuji Inaba","doi":"10.1016/j.braindev.2023.12.002","DOIUrl":"https://doi.org/10.1016/j.braindev.2023.12.002","url":null,"abstract":"<p><strong>Background: </strong>Post-encephalopathic epilepsy (PEE) is a serious complication of acute encephalopathy syndromes, and is more frequent in patients with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) than in children with acute encephalopathy. However, a risk factor analysis using laboratory findings in the acute phase of AESD has not yet been performed. Therefore, the present study examined risk factors of AESD-related PEE using laboratory parameters in the acute phase of AESD.</p><p><strong>Methods: </strong>We retrospectively screened 27 pediatric patients with AESD for inclusion, and enrolled 20 (\"the PEE group\", n = 6; \"the non-PEE group\", n = 14) according to inclusion criteria.</p><p><strong>Results: </strong>The incidence of AESD-related PEE was 30 %, and the median duration from the onset of AESD to the development of PEE was 2.5 months (range, 1-32). The most common types of seizures were focal seizures, epileptic spasms, and startle seizures: 4 out of 6 patients (66.7 %) had intractable epilepsy. The median values of alanine aminotransferase (ALT) in the 1st and 2nd seizure phases of AESD and aspartate aminotransferase (AST) in the 2nd seizure phase were significantly higher in the PEE group than in the non-PEE group (p < 0.01).</p><p><strong>Conclusions: </strong>This is the first study to report higher serum levels of ALT and AST at the onset of AESD as risk factors for AESD-related PEE. We also provided a detailed description on the clinical characteristics on AESD-related PEE, which are consistent with previous findings.</p>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138813008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Most long-term affected spinal muscular atrophy (SMA) type 1 patients have severe impairment of motor function and are dependent on mechanical ventilation with tracheostomy. The efficacy and safety of nusinersen in these patients have not been established.
Methods
We retrospectively evaluated the efficacy of intrathecal nusinersen treatment in patients with SMA type 1 who continued treatment for at least 12 months. There were three patients enrolled in our study (3, 4 and 16 years of age) who had severe impairment of gross motor function without head control or the ability to roll over. All three needed mechanical ventilation with tracheostomy and tube feeding. Motor function was assessed using the Children s Hospital of Philadelphia infant test of neuromuscular disorders (CHOP-INTEND) and the caregivers’ evaluations. Concurrently, we examined nerve conduction longitudinally and compared compound motor action potential (CMAP) amplitudes.
Results
All patients continued nusinersen administration without significant adverse events for more than three years. While CHOP-INTEND scores did not remarkably increase, according to the caregivers, all three patients had improved finger or facial muscle movements that enabled them to make their intentions understood. Some CMAPs before treatment were not identified but became traces after nusinersen administration.
Conclusions
The improvement in motor function that leads to smoother communication could be a basis for continuing nusinersen treatment. Currently available motor function scorings are not efficient for assessing therapeutic interventions in SMA patients with medical care complexity. Longitudinal nerve conduction studies could be an objective indicator.
背景大多数长期受影响的脊髓性肌萎缩症(SMA)1型患者运动功能严重受损,需要依靠气管造口术进行机械通气。方法我们回顾性评估了持续治疗至少 12 个月的 1 型 SMA 患者鞘内注射奴西那生的疗效。有三名患者(分别为 3 岁、4 岁和 16 岁)参加了我们的研究,他们的大运动功能严重受损,没有头部控制能力或翻身能力。这三名患者都需要气管插管机械通气和管饲。运动功能的评估采用费城儿童医院婴儿神经肌肉疾病测试(CHOP-INTEND)和护理人员的评估。同时,我们对神经传导进行了纵向检查,并比较了复合运动动作电位(CMAP)的振幅。虽然CHOP-INTEND评分没有显著增加,但据护理人员称,所有三名患者的手指或面部肌肉运动均有所改善,使他们能够表达自己的意图。结论运动功能的改善可使交流更加顺畅,这可能是继续使用纽西奈森治疗的基础。目前可用的运动功能评分并不能有效评估对医疗护理复杂的 SMA 患者的治疗干预。纵向神经传导研究可作为一项客观指标。
{"title":"Nusinersen induces detectable changes in compound motor action potential response in spinal muscular atrophy type 1 patients with severe impairment of motor function","authors":"Yuki Ueda , Kiyoshi Egawa , Kentaro Kawamura , Noriki Ochi , Takeru Goto , Shuhei Kimura , Masashi Narugami , Sachiko Nakakubo , Midori Nakajima , Atsushi Manabe , Hideaki Shiraishi","doi":"10.1016/j.braindev.2023.12.001","DOIUrl":"10.1016/j.braindev.2023.12.001","url":null,"abstract":"<div><h3>Background</h3><p>Most long-term affected spinal muscular atrophy (SMA) type 1 patients have severe impairment of motor function and are dependent on mechanical ventilation with tracheostomy. The efficacy and safety of nusinersen in these patients have not been established.</p></div><div><h3>Methods</h3><p>We retrospectively evaluated the efficacy of intrathecal nusinersen treatment in patients with SMA type 1 who continued treatment for at least 12 months. There were three patients enrolled in our study (3, 4 and 16 years of age) who had severe impairment of gross motor function without head control or the ability to roll over. All three needed mechanical ventilation with tracheostomy and tube feeding. Motor function was assessed using the Children s Hospital of Philadelphia infant test of neuromuscular disorders (CHOP-INTEND) and the caregivers’ evaluations. Concurrently, we examined nerve conduction longitudinally and compared compound motor action potential (CMAP) amplitudes.</p></div><div><h3>Results</h3><p>All patients continued nusinersen administration without significant adverse events for more than three years. While CHOP-INTEND scores did not remarkably increase, according to the caregivers, all three patients had improved finger or facial muscle movements that enabled them to make their intentions understood. Some CMAPs before treatment were not identified but became traces after nusinersen administration.</p></div><div><h3>Conclusions</h3><p>The improvement in motor function that leads to smoother communication could be a basis for continuing nusinersen treatment. Currently available motor function scorings are not efficient for assessing therapeutic interventions in SMA patients with medical care complexity. Longitudinal nerve conduction studies could be an objective indicator.</p></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138691521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-07DOI: 10.1016/j.braindev.2023.11.008
Anna Nikolaidou , Ioannis Beis , Pinelopi Dragoumi , Dimitrios Zafeiriou
Juvenile systemic lupus erythematosus (jSLE) is a chronic multisystem inflammatory disease that manifests before the age of 16 years, following a remitting - relapsing course. The clinical presentation in children is multifaceted, most commonly including constitutional, hematological, cutaneous, renal, and neuropsychiatric symptoms. Neuropsychiatric manifestations range widely, affecting approximately 14–95 % of jSLE patients. They are associated with high morbidity and mortality, particularly at a younger age. Headaches, seizures, cognitive dysfunction, and mood disorders are the most frequent neuropsychiatric manifestations. The pathophysiological mechanism is quite complex and has not yet been fully investigated, with autoantibodies being the focus of research. The diagnosis of neuropsychiatric jSLE remains challenging and exclusionary. In this article we review the clinical neuropsychiatric manifestations associated with jSLE with the aim that early diagnosis and prompt treatment is achieved in children and adolescents with the disease.
{"title":"Neuropsychiatric manifestations associated with Juvenile Systemic Lupus Erythematosus: An overview focusing on early diagnosis","authors":"Anna Nikolaidou , Ioannis Beis , Pinelopi Dragoumi , Dimitrios Zafeiriou","doi":"10.1016/j.braindev.2023.11.008","DOIUrl":"10.1016/j.braindev.2023.11.008","url":null,"abstract":"<div><p>Juvenile systemic lupus erythematosus (jSLE) is a chronic multisystem inflammatory disease that manifests before the age of 16 years, following a remitting - relapsing course. The clinical presentation in children is multifaceted, most commonly including constitutional, hematological, cutaneous, renal, and neuropsychiatric symptoms. Neuropsychiatric manifestations range widely, affecting approximately 14–95 % of jSLE patients. They are associated with high morbidity and mortality, particularly at a younger age. Headaches, seizures, cognitive dysfunction, and mood disorders are the most frequent neuropsychiatric manifestations. The pathophysiological mechanism is quite complex and has not yet been fully investigated, with autoantibodies being the focus of research. The diagnosis of neuropsychiatric jSLE remains challenging and exclusionary. In this article we review the clinical neuropsychiatric manifestations associated with jSLE with the aim that early diagnosis and prompt treatment is achieved in children and adolescents with the disease.</p></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138566864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-06DOI: 10.1016/j.braindev.2023.11.005
Josef Finsterer
{"title":"In patients with neurological complications, SARS-CoV-2 infection must be confirmed by PCR","authors":"Josef Finsterer","doi":"10.1016/j.braindev.2023.11.005","DOIUrl":"10.1016/j.braindev.2023.11.005","url":null,"abstract":"","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138500355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-03DOI: 10.1016/j.braindev.2023.11.007
Mai Samejima , Mitsuko Nakashima , Jun Shibasaki , Hirotomo Saitsu , Mitsuhiro Kato
Background
Neurooculocardiogenitourinary syndrome (NOCGUS), a multisystemic syndrome characterized by motor disorder, intellectual disability, seizures, abnormal brain structure, ocular diseases, and cardiac diseases, has been reported with missense variant of WD repeat-containing protein 37 (WDR37) in humans. This report aimed to identify the cause of NOCGUS in an affected patient.
Case presentation
We identified a de novo intronic 4-bp deletion of WDR37, c.727-27_727-24del, which were predicted to cause abnormal splicing by SpliceAI, in the patient with NOCGUS. Reverse transcription polymerase chain reaction (RT-PCR) revealed intron retention of 63 base pairs before exon 10 in messenger RNA, which was predicted to insert 21 additional aberrant amino acids (p.S242_I243insLCQKKLKISRKCLFWPSLWQQ). The patient had novel phenotypes, anal atresia, and polycystic kidney, in addition to intellectual disability, seizures, cerebellar vermian anomaly, and coloboma, which are typical in NOCGUS. We did not observe motor impairments or cardiovascular anomalies.
Conclusion
This is the first reported case of NOCGUS with the splicing variant of WDR37, which manifests with distinctive but variable features. Our findings may expand a possible phenotypic expression of NOCGUS.
{"title":"Splicing variant of WDR37 in a case of Neurooculocardiogenitourinary syndrome","authors":"Mai Samejima , Mitsuko Nakashima , Jun Shibasaki , Hirotomo Saitsu , Mitsuhiro Kato","doi":"10.1016/j.braindev.2023.11.007","DOIUrl":"10.1016/j.braindev.2023.11.007","url":null,"abstract":"<div><h3>Background</h3><p>Neurooculocardiogenitourinary syndrome (NOCGUS), a multisystemic syndrome characterized by motor disorder, intellectual disability, seizures, abnormal brain structure, ocular diseases, and cardiac diseases, has been reported with missense variant of WD repeat-containing protein 37 (WDR37) in humans. This report aimed to identify the cause of NOCGUS in an affected patient.</p></div><div><h3>Case presentation</h3><p>We identified a <em>de novo</em> intronic 4-bp deletion of <em>WDR37</em>, c.727-27_727-24del, which were predicted to cause abnormal splicing by SpliceAI, in the patient with NOCGUS. Reverse transcription polymerase chain reaction (RT-PCR) revealed intron retention of 63 base pairs before exon 10 in messenger RNA, which was predicted to insert 21 additional aberrant amino acids (p.S242_I243insLCQKKLKISRKCLFWPSLWQQ). The patient had novel phenotypes, anal atresia, and polycystic kidney, in addition to intellectual disability, seizures, cerebellar vermian anomaly, and coloboma, which are typical in NOCGUS. We did not observe motor impairments or cardiovascular anomalies.</p></div><div><h3>Conclusion</h3><p>This is the first reported case of NOCGUS with the splicing variant of <em>WDR37</em>, which manifests with distinctive but variable features. Our findings may expand a possible phenotypic expression of NOCGUS.</p></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2023-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138479438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-03DOI: 10.1016/j.braindev.2023.11.009
Victoria Elizabeth De Knegt , Malene Landbo Børresen , Marianne Knudsen , Katrine Moe Thomsen , Peter Vilhelm Uldall , Anne Vagner Jakobsen , Christina Engel Hoei-Hansen
Objective
To evaluate outcomes from hemispherectomy and callosotomy related to the need for anti-seizure medication (ASM), seizure frequency, and cognition.
Methods
A review of the medical charts of all Danish pediatric patients who underwent hemispherectomy or callosotomy from January 1996 to December 2019 for preoperative and postoperative ASM use, seizure frequency, and cognitive data.
Results
The median age of epilepsy onset was two years (interquartile range (IQR): 0.0–5.3) for the hemispherectomy patients (n = 16) and one year (IQR: 0.6–1.7) for callosotomy patients (n = 5). Median time from onset to final surgery was 3.4 years for hemispherectomy and 10.2 years for callosotomy, while the median follow-up time was 6.9 years and 9.0 years, respectively. Preoperatively, all patients had daily seizures and were treated with ≥ 2 ASM. Hemispherectomy resulted in a reduction in seizure frequency in 87.5 % of patients, with 78.6 % achieving seizure freedom. Furthermore, 81.3 % experienced a reduction in ASM use and 56.3 % stopped all ASM. Median IQ/developmental quotient (IQ/DQ) was low preoperatively (44.0 [IQR: 40.0–55.0]) and remained unchanged postoperatively (IQ change: 0.0 [IQR: −10.0–+4.0]). Callosotomy resulted in a seizure reduction of 86–99 % in four patients, and ASM could be reduced in three patients. Median IQ/DQ was 20.0 preoperatively (IQR: 20.0–30.0) and remained unchanged postoperatively (IQ change: 0.0 [IQR: 0.0]).
Conclusion
Hemispherectomy and callosotomy result in a substantial reduction in seizure frequency and ASM use without deterioration of IQ. Extensive epilepsy surgery should be considered early in children with drug-resistant epilepsy.
{"title":"Current state of hemispherectomy and callosotomy for pediatric refractory epilepsy in Denmark","authors":"Victoria Elizabeth De Knegt , Malene Landbo Børresen , Marianne Knudsen , Katrine Moe Thomsen , Peter Vilhelm Uldall , Anne Vagner Jakobsen , Christina Engel Hoei-Hansen","doi":"10.1016/j.braindev.2023.11.009","DOIUrl":"10.1016/j.braindev.2023.11.009","url":null,"abstract":"<div><h3>Objective</h3><p>To evaluate outcomes from hemispherectomy and callosotomy related to the need for anti-seizure medication (ASM), seizure frequency, and cognition.</p></div><div><h3>Methods</h3><p>A review of the medical charts of all Danish pediatric patients who underwent hemispherectomy or callosotomy from January 1996 to December 2019 for preoperative and postoperative ASM use, seizure frequency, and cognitive data.</p></div><div><h3>Results</h3><p>The median age of epilepsy onset was two years (interquartile range (IQR): 0.0–5.3) for the hemispherectomy patients (n = 16) and one year (IQR: 0.6–1.7) for callosotomy patients (n = 5). Median time from onset to final surgery was 3.4 years for hemispherectomy and 10.2 years for callosotomy, while the median follow-up time was 6.9 years and 9.0 years, respectively. Preoperatively, all patients had daily seizures and were treated with ≥ 2 ASM. Hemispherectomy resulted in a reduction in seizure frequency in 87.5 % of patients, with 78.6 % achieving seizure freedom. Furthermore, 81.3 % experienced a reduction in ASM use and 56.3 % stopped all ASM. Median IQ/developmental quotient (IQ/DQ) was low preoperatively (44.0 [IQR: 40.0–55.0]) and remained unchanged postoperatively (IQ change: 0.0 [IQR: −10.0–+4.0]). Callosotomy resulted in a seizure reduction of 86–99 % in four patients, and ASM could be reduced in three patients. Median IQ/DQ was 20.0 preoperatively (IQR: 20.0–30.0) and remained unchanged postoperatively (IQ change: 0.0 [IQR: 0.0]).</p></div><div><h3>Conclusion</h3><p>Hemispherectomy and callosotomy result in a substantial reduction in seizure frequency and ASM use without deterioration of IQ. Extensive epilepsy surgery should be considered early in children with drug-resistant epilepsy.</p></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2023-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138479437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}