Pediatric neurology最新文献_第10页

Cenobamate's Efficacy for Seizure Treatment in Tuberous Sclerosis Complex 塞诺巴马特治疗结节性硬化症复合体癫痫发作的疗效。

IF 3.2 3区医学 Q2 CLINICAL NEUROLOGY

Pediatric neurology

Pub Date : 2024-09-26 DOI: 10.1016/j.pediatrneurol.2024.09.023

Gewalin Aungaroon MD , Alexander Cooke BS , David Ritter MD, PhD , Darcy Krueger MD, PhD , Paul Horn PhD , David N. Franz MD

Background

Epilepsy is prevalent, and seizure control is challenging in patients with tuberous sclerosis complex (TSC). Cenobamate (CBM) has proven efficacy in several studies; however, its benefit in the TSC population is not known.

Methods

We performed a retrospective review of patients with TSC who received adjunctive CBM for seizure treatments. We assessed treatment efficacy by comparing seizure frequencies three months before CBM (baseline) and those at 3-, 6-, 12-, and 18- month follow-ups.

Results

We identified 70 patients with TSC receiving CBM and excluded 16 with insufficient data. Fifty-four patients aged 2 to 39 years, with an average baseline seizure of 66.1 ± 88.9 per month, were analyzed. Treatment retention rates at 3, 6, 12, and 18 months were 94.4%, 79.6%, 66.7%, 44.4%, and responder rates (proportions of patients who remained on treatment and had ≥50% seizure reduction) were 38.1%, 51.7%, 53.1%, and 59.1%, respectively. Seizure-free rates at these respective follow-ups were 7.1%, 13.8%, 6.3%, and 9.1%. For patients experiencing reduced seizures, the mean percentage of change ranged from 61.5% to 74.6%. Side effects were common (64.8%), particularly sedation (42.6%), behavioral disturbance (24.1%), and gastrointestinal disturbance (22.2%).

Conclusions

Most patients in this study showed seizure reduction; however, the overall responder and seizure-free rates were lower than the literature, likely due to the unique underlying epileptogenesis in TSC and the challenges of tolerating CBM. The lower treatment retention rates signal areas for improvement in concurrent medication adjustment practices.

背景：在结节性硬化症复合体（TSC）患者中，癫痫是一种常见病，而癫痫发作控制是一项挑战。几项研究已证明塞诺巴马特（CBM）具有疗效，但其对 TSC 患者的益处尚不清楚：我们对接受CBM辅助治疗的TSC患者进行了回顾性研究。我们通过比较CBM治疗前三个月（基线）和随访3个月、6个月、12个月和18个月时的癫痫发作频率来评估治疗效果：我们确定了70名接受CBM治疗的TSC患者，并排除了16名数据不足的患者。对54名年龄在2至39岁之间的患者进行了分析，他们的平均基线发作率为每月66.1±88.9次。3、6、12和18个月的治疗保持率分别为94.4%、79.6%、66.7%和44.4%，应答率（保持治疗且发作减少≥50%的患者比例）分别为38.1%、51.7%、53.1%和59.1%。在这些随访中，无癫痫发作率分别为 7.1%、13.8%、6.3% 和 9.1%。对于发作次数减少的患者，平均变化百分比从61.5%到74.6%不等。副作用很常见（64.8%），尤其是镇静（42.6%）、行为紊乱（24.1%）和胃肠道紊乱（22.2%）：本研究中的大多数患者癫痫发作有所减少，但总体应答率和无发作率低于文献报道，这可能是由于TSC独特的潜在癫痫发生机制以及CBM的耐受性所带来的挑战。较低的治疗保持率预示着同时用药调整实践中需要改进的地方。

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引用次数: 0

Beyond Numbers: A Call to Action for Accurate Estimation of Spinal Muscular Atrophy in the Middle East and North Africa Region 超越数字：呼吁采取行动，准确估计中东和北非地区脊髓性肌肉萎缩症的发病率

IF 3.2 3区医学 Q2 CLINICAL NEUROLOGY

Pediatric neurology

Pub Date : 2024-09-25 DOI: 10.1016/j.pediatrneurol.2024.09.024

Maryam Bemanalizadeh MD , Vahid Mansouri MD

引用次数: 0

Cerebrovascular Injury From Early-Onset Neonatal Escherichia coli Meningitis: Expanding the Clinical-Radiologic Phenotype 早发型新生儿大肠埃希氏菌脑膜炎引起的脑血管损伤：扩展临床放射学表型。

IF 3.2 3区医学 Q2 CLINICAL NEUROLOGY

Pediatric neurology

Pub Date : 2024-09-24 DOI: 10.1016/j.pediatrneurol.2024.09.020

Francesca G. García MD , Yi Li MD , Rachel Vassar MD , Cheryl Hawkins MD , Mark Petersen MD , Dawn Gano MD, MAS

引用次数: 0

Exploring the Genetic Landscape of Epilepsy With Eyelid Myoclonia: A Comprehensive Review on Clinical Features and Diagnostic Challenges 探索眼睑肌张力障碍性癫痫的遗传规律：临床特征和诊断难题的全面回顾。

IF 3.2 3区医学 Q2 CLINICAL NEUROLOGY

Pediatric neurology

Pub Date : 2024-09-23 DOI: 10.1016/j.pediatrneurol.2024.09.018

Samia Aziz Sulaiman MD , Ihda Bani Khalaf MD , Ahmad E. Saeed MD , Waseem Hoshan MD , Ahmed W. Hageen MBBCh , Jatin Motwani MBBS , Aman Goyal MBBS

Jeavons syndrome (JS), also known as epilepsy with eyelid myoclonia (EEM), is an idiopathic epileptic syndrome that primarily affects children. JS constitutes a significant portion of idiopathic generalized epilepsies and overall epileptic conditions and is characterized by frequent eyelid myoclonia. JS is often triggered by factors such as eyelid closure and exposure to light, leading to absence seizures with photoparoxysmal responses. Although previous studies indicate that some genes have demonstrated an association with the syndrome, no definitive causative gene has yet been identified. The current review therefore aims to shed emphasis on the potential value genetic testing holds in the context of EEM, as well as the need to investigate potential early diagnosis and management strategies in future research.

杰文斯综合征（JS），又称眼睑肌阵挛癫痫（EEM），是一种主要影响儿童的特发性癫痫综合征。JS 在特发性全身癫痫和整体癫痫中占很大比例，其特征是频繁出现眼睑肌张力障碍。JS 常常由眼睑闭合和光线照射等因素诱发，导致失神发作和光敏反应。尽管以往的研究表明，一些基因与该综合征有关联，但尚未发现明确的致病基因。因此，本综述旨在强调基因检测在 EEM 方面的潜在价值，以及在未来研究中调查潜在早期诊断和管理策略的必要性。

引用次数: 0

Severe Epilepsy in an Individual With a TSC2 R905Q Variant Prompting Late Diagnosis in Affected Family Members 一名 TSC2 R905Q 变异患者的严重癫痫导致受影响家庭成员的晚期诊断。

IF 3.2 3区医学 Q2 CLINICAL NEUROLOGY

Pediatric neurology

Pub Date : 2024-09-21 DOI: 10.1016/j.pediatrneurol.2024.09.014

Alice Man BSc , Matteo Di Scipio BSc , Breanne Dale MSc, CGC , Paula Teixeira Marques MD , Cynthia Sloan Birbeck BScN, RN, MN , Puneet Jain MBBS, MD, DM , Elisabetta Trinari MD, MSc , Resham Ejaz MD , Robyn Whitney MD

Background

Tuberous sclerosis complex (TSC) is a multisystemic disorder caused by inactivating variants in the mTOR pathway inhibitor genes TSC1 and TSC2. Individuals with TSC are predisposed to benign tumors in multiple organs as well as TSC-associated neuropsychiatric disorders (TAND) and epilepsy. Pathogenic variants in TSC2 are typically associated with a more severe phenotype compared with TSC1; the TSC2 R905Q variant has been shown to be an exception, where patients have been reported to present with unusually mild TSC features that may be undetected.

Methods

We studied the TSC phenotype of a 13-year-old individual and three family members with a TSC2 c.2714G>A (R905Q) pathogenic variant.

Results

Patient 1 presented with severe medically refractory epilepsy without tubers or subependymal nodules and only mild dermatologic features of TSC missed on virtual examinations. Her mother and maternal aunt (Patients 2 and 3–diagnosed after age 50 years) presented with a mild phenotype, with dermatologic features and TAND. Her maternal uncle (Patient 4–diagnosed at age 47 years) displayed the most severe phenotype, presenting with intellectual disability, medically refractory epilepsy, obsessive-compulsive disorder, post-traumatic stress disorder, and psychosis.

Conclusions

This study expands the possible phenotypic spectrum of TSC2 R905Q variant, demonstrating an association with severe epilepsy without associated neuroradiological stigmata. This presentation highlights the possibility of occult focal cortical dysplasia in TSC and emphasizes the importance of genetic testing in individuals with severe epilepsy. Moreover, a late adult diagnosis was subsequently made in other family members allowing for appropriate TSC surveillance to occur.

背景：结节性硬化症综合征（TSC）是一种多系统疾病，由 mTOR 通路抑制基因 TSC1 和 TSC2 的失活变异引起。TSC患者易患多器官良性肿瘤以及TSC相关神经精神障碍（TAND）和癫痫。与TSC1相比，TSC2的致病变异通常与更严重的表型相关；TSC2 R905Q变异已被证明是一个例外，有报道称患者表现出异常轻微的TSC特征，而这些特征可能未被检测到：方法：我们研究了一名13岁患者和三名家族成员的TSC2 c.2714G>A（R905Q）致病变异的TSC表型：患者 1 患有严重的药物难治性癫痫，无小管或蝶鞍下结节，在虚拟检查中仅发现轻微的 TSC 皮肤特征。她的母亲和姨妈（患者 2 和 3，50 岁后确诊）表现为轻度表型，有皮肤特征和 TAND。她的舅舅（患者4，47岁确诊）的表型最为严重，表现为智力障碍、药物难治性癫痫、强迫症、创伤后应激障碍和精神病：本研究扩展了TSC2 R905Q变异型的可能表型谱，表明该变异型与严重癫痫有关，但没有相关的神经放射学标志。该研究强调了TSC隐匿性局灶性皮质发育不良的可能性，并强调了对严重癫痫患者进行基因检测的重要性。此外，该患者的其他家族成员随后也被确诊为晚期成人患者，因此可以对该患者进行适当的TSC监测。

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引用次数: 0

Rare CCND2 (p.Thr280Ile) Variant Associated With Infantile Spasms in a Patient With Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome 罕见的 CCND2（p.Thr280Ile）变异与巨脑畸形-多发性畸形-多指畸形-脑积水综合征患者的婴儿痉挛有关

IF 3.2 3区医学 Q2 CLINICAL NEUROLOGY

Pediatric neurology

Pub Date : 2024-09-21 DOI: 10.1016/j.pediatrneurol.2024.09.016

Kent M. Mok MD , Jessica L. Carpenter MD , Pamela Herrada MS, CGC , Carol Greene MD , Sandrine Yazbek MD , Gozde Erdemir MD

Background

This report describes a pediatric case of megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome, a rare neurodevelopmental disorder caused by pathogenic variants in the AKT3, CCND2, or PIK3R2 genes. We present a patient with a rare CCND2 variant (c.839C>T, p.Thr280Ile), associated with infantile spasms, ventriculomegaly, polymicrogyria, and intraventricular hemorrhage (IVH).

Methods

A retrospective chart review and literature search were performed using PubMed.

Results

Our patient was found to have ventriculomegaly, grade 3 IVH, bilateral polymicrogyria, and restricted diffusion in the caudate nuclei prenatally. No polydactyly was observed. The patient developed infantile spasms at age 5 months. While high-dose prednisone treatment failed to control the spasms, they resolved with topiramate. By age 2 years, the patient continued to have significant developmental delays, including having poor tone and being nonverbal.

Conclusion

MPPH syndrome remains a rare and challenging diagnosis, with fewer than 100 cases reported. This case highlights the importance of early genetic testing and neuroimaging in the diagnosis and management of MPPH. The unique presentation of IVH and restricted diffusion warrants further investigation into the syndrome’s variable phenotypic spectrum. Early intervention and targeted therapy may help manage seizure activity and improve outcomes.

背景本报告描述了一例巨脑-多小脑-多乳-脑积水（MPPH）综合征的儿科病例，这是一种由 AKT3、CCND2 或 PIK3R2 基因致病变体引起的罕见神经发育障碍。我们报告了一名患有罕见CCND2变异（c.839C>T, p.Thr280Ile）的患者，该患者伴有婴儿痉挛、脑室肥大、多发性畸形和脑室内出血（IVH）。结果我们发现患者有脑室肥大、3级IVH、双侧多发性畸形和出生前尾状核弥散受限。未发现多指畸形。患者在 5 个月大时出现婴儿痉挛症。虽然大剂量强的松治疗未能控制痉挛，但使用托吡酯后痉挛得到缓解。到 2 岁时，患者仍有明显的发育迟缓，包括音调不佳和不善言语。本病例强调了早期基因检测和神经影像学检查在 MPPH 诊断和治疗中的重要性。IVH和弥散受限的独特表现值得进一步研究该综合征的多变表型谱。早期干预和针对性治疗有助于控制癫痫发作活动和改善预后。

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引用次数: 0

The Face and Features of RNU4-2: A New, Common, Recognizable, Yet Hidden Neurodevelopmental Disorder RNU4-2 的面貌和特征：一种新的、常见的、可识别的但却隐藏的神经发育障碍

IF 3.2 3区医学 Q2 CLINICAL NEUROLOGY

Pediatric neurology

Pub Date : 2024-09-21 DOI: 10.1016/j.pediatrneurol.2024.09.015

Kristen Barbour MD , Matthew N. Bainbridge PhD , Kristen Wigby MD , Aaron D. Besterman MD , Nathaniel A. Chuang MD , Laura E. Tobin MPH , Miguel Del Campo MD , Jerica Lenberg MS , Lynne M. Bird MD , Jennifer Friedman MD

Background

RNU4-2 is a newly identified, noncoding gene responsible for a significant proportion of individuals with neurodevelopmental disorders (NDDs). Diagnosis is hampered by the inability of commonly employed clinical testing methods, including exome sequencing and currently formulated multigene panels, to detect variants in the noncoding region. The relatively high prevalence of this condition, predicted to affect thousands of undiagnosed children with NDDs, makes it even more relevant to have better tools to facilitate diagnosis. The initial report of the gene-disease association outlined aggregate phenotypic features but lacked detailed patient evaluations, potentially under-reporting phenotypic features and failing to highlight unique aspects. We aimed to identify individuals with RNU4-2 gene variants to deeply phenotype the clinical profile. We sought to define key features that may suggest the diagnosis, to highlight individuals for whom specialized testing, able to detect noncoding region variants, may be indicated.

Methods

We reviewed genomic data from 6,734 individuals, identifying five with recurrent de novo RNU4-2 (n.64_65insT) variants. We clinically evaluated four. Findings were compared with those previously reported.

Results

We identify common clinical features, a distinctive dysmorphic facial pattern, and shared imaging abnormalities. We describe novel aspects including longitudinal trajectory and treatment response.

Conclusions

Enhanced recognition of the RNU4-2 (n.64_65insT-common variant) phenotype, particularly the dysmorphic facial features, will facilitate earlier diagnosis. Distinctive characteristics will guide the selection of patients for testing able to detect RNU4-2 variants: genome sequencing or targeted gene testing. Furthermore, health and research systems may identify undiagnosed patients by querying databases for individuals exhibiting the traits described herein.

背景RNU4-2是一种新发现的非编码基因，在神经发育障碍（NDD）患者中占很大比例。由于常用的临床检测方法（包括外显子组测序和目前制定的多基因面板）无法检测到非编码区的变异，因此影响了诊断。这种疾病的发病率相对较高，预计会影响成千上万名未确诊的 NDD 儿童，因此更需要有更好的工具来促进诊断。基因与疾病相关的最初报告概述了综合表型特征，但缺乏对患者的详细评估，因此可能对表型特征报告不足，也未能突出其独特性。我们的目标是识别具有 RNU4-2 基因变异的个体，对临床特征进行深入的表型分析。我们试图定义可能提示诊断的关键特征，以突出可检测非编码区变异的专业检测的适用人群。方法我们回顾了 6,734 例患者的基因组数据，确定了 5 例具有复发性 RNU4-2 (n.64_65insT) 基因变异的患者。我们对其中四人进行了临床评估。结果我们发现了共同的临床特征、独特的面部畸形模式和共同的影像学异常。结论加强对 RNU4-2（n.64_65insT-常见变异体）表型的识别，尤其是畸形面部特征的识别，将有助于早期诊断。通过基因组测序或靶向基因检测，可根据患者的不同特征选择检测RNU4-2变体的方法。此外，医疗和研究系统还可以通过查询数据库中表现出本文所述特征的个体来确定未确诊的患者。

{"title":"The Face and Features of RNU4-2: A New, Common, Recognizable, Yet Hidden Neurodevelopmental Disorder","authors":"Kristen Barbour MD , Matthew N. Bainbridge PhD , Kristen Wigby MD , Aaron D. Besterman MD , Nathaniel A. Chuang MD , Laura E. Tobin MPH , Miguel Del Campo MD , Jerica Lenberg MS , Lynne M. Bird MD , Jennifer Friedman MD","doi":"10.1016/j.pediatrneurol.2024.09.015","DOIUrl":"10.1016/j.pediatrneurol.2024.09.015","url":null,"abstract":"<div><h3>Background</h3><div><em>RNU4</em>-<em>2</em> is a newly identified, noncoding gene responsible for a significant proportion of individuals with neurodevelopmental disorders (NDDs). Diagnosis is hampered by the inability of commonly employed clinical testing methods, including exome sequencing and currently formulated multigene panels, to detect variants in the noncoding region. The relatively high prevalence of this condition, predicted to affect thousands of undiagnosed children with NDDs, makes it even more relevant to have better tools to facilitate diagnosis. The initial report of the gene-disease association outlined aggregate phenotypic features but lacked detailed patient evaluations, potentially under-reporting phenotypic features and failing to highlight unique aspects. We aimed to identify individuals with <em>RNU4</em>-<em>2</em> gene variants to deeply phenotype the clinical profile. We sought to define key features that may suggest the diagnosis, to highlight individuals for whom specialized testing, able to detect noncoding region variants, may be indicated.</div></div><div><h3>Methods</h3><div>We reviewed genomic data from 6,734 individuals, identifying five with recurrent <em>de novo RNU4</em>-<em>2</em> (n.64_65insT) variants. We clinically evaluated four. Findings were compared with those previously reported.</div></div><div><h3>Results</h3><div>We identify common clinical features, a distinctive dysmorphic facial pattern, and shared imaging abnormalities. We describe novel aspects including longitudinal trajectory and treatment response.</div></div><div><h3>Conclusions</h3><div>Enhanced recognition of the <em>RNU4</em>-<em>2</em> (n.64_65insT-common variant) phenotype, particularly the dysmorphic facial features, will facilitate earlier diagnosis. Distinctive characteristics will guide the selection of patients for testing able to detect <em>RNU4</em>-<em>2</em> variants: genome sequencing or targeted gene testing. Furthermore, health and research systems may identify undiagnosed patients by querying databases for individuals exhibiting the traits described herein.</div></div>","PeriodicalId":19956,"journal":{"name":"Pediatric neurology","volume":"161 ","pages":"Pages 188-193"},"PeriodicalIF":3.2,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Precision in Progress: Unraveling the Clinimetric Properties of Beery-Buktenica Developmental Test of Visual-Motor Integration in Children With Cerebral Palsy Across Diverse Motor Severities 精准进行时：揭示Beery-Buktenica视觉-运动整合发展测试在不同运动严重程度脑瘫儿童中的临床测量特性。

IF 3.2 3区医学 Q2 CLINICAL NEUROLOGY

Pediatric neurology

Pub Date : 2024-09-20 DOI: 10.1016/j.pediatrneurol.2024.09.017

Yu-Hsin Chen MD , Chia-Ling Chen MD, PhD , Wei-Hsien Hong PhD , Chung-Yao Chen MD , Chia-Ying Chung MD , Katie P.H. Wu MD , Ching-Yi Wu ScD , Keh-Chung Lin ScD, OTR

Background

In the realm of pediatric cerebral palsy (CP), visual motor challenges often overshadow a child's developmental journey. This study delves into the responsiveness and crucial benchmarks, specifically the minimal clinically important difference (MCID), of the Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI) among children with varying motor severities.

Method

Eighty-eight children with CP (50 males, 38 females; aged three to 12 years) with Gross Motor Function Classification System (GMFCS) levels I to III were recruited from the rehabilitation department of Chang Gung Memorial Hospital in Taiwan. Each participant received the Beery VMI tests at baseline and at one-year follow-up. The standardized response mean (SRM) was calculated to determine the responsiveness of Beery VMI, and a distribution-based approach was used to estimate MCID.

Results

The Beery VMI exhibited remarkable responsiveness across GMFCS levels I to III (SRM = 0.98-2.36). MCIDs for Beery VMI varied across severities, with ranges of 2.93 to 4.41 (0.2 S.D.), 7.31 to 11.49 (0.5 S.D.), and 11.70 to 18.38 (0.8 S.D.). Notably, in the visual perception subset, MCIDs were 3.93 to 4.03 (0.2 S.D.), 9.83 to 10.07 (0.5 S.D.), and 15.73 to 16.11 (0.8 S.D.). In the supplemental motor coordination subtest, MCIDs spanned 1.67 to 4.87 (0.2 S.D.), 4.18 to 12.17 (0.5 S.D.), and 6.68 to 19.47 (0.8 S.D.).

Conclusions

Beery VMI demonstrates robust responsiveness in children with CP. Motor-severity-tailored MCIDs offer a guide for clinicians and researchers, hinting at treatment efficacy. Particularly, lower change scores in VMI and motor coordination subtests may signal effective interventions for moderate motor disability over mild cases.

背景：在小儿脑瘫（CP）领域，视觉运动方面的挑战往往给儿童的成长历程蒙上阴影。本研究探讨了不同运动严重程度的儿童对 Beery-Buktenica 视觉-运动整合发育测试（Beery VMI）的反应能力和关键基准，特别是最小临床重要差异（MCID）：方法：从台湾长庚纪念医院康复科招募了88名患有CP的儿童（男50名，女38名；年龄在3至12岁之间），他们的粗大运动功能分级系统（GMFCS）处于I至III级。每位受试者在基线和一年随访时均接受了 Beery VMI 测试。通过计算标准化反应平均值（SRM）来确定比瑞 VMI 的反应性，并采用基于分布的方法来估计 MCID：结果：Beery VMI 在 GMFCS I 至 III 级（SRM = 0.98-2.36）中表现出显著的反应性。不同严重程度的 Beery VMI 的 MCID 各不相同，范围分别为 2.93 至 4.41（0.2 S.D.）、7.31 至 11.49（0.5 S.D.）和 11.70 至 18.38（0.8 S.D.）。值得注意的是，在视觉感知子测试中，MCID 分别为 3.93 至 4.03（0.2 S.D.）、9.83 至 10.07（0.5 S.D.）和 15.73 至 16.11（0.8 S.D.）。在补充运动协调分测验中，MCID 的范围分别为 1.67 至 4.87（0.2 S.D.）、4.18 至 12.17（0.5 S.D.）和 6.68 至 19.47（0.8 S.D.）：结论：Beery VMI 对患有 CP 的儿童具有很强的反应能力。运动性定制的 MCID 为临床医生和研究人员提供了指导，暗示了治疗效果。特别是，VMI 和运动协调分测验中较低的变化分可能预示着对中度运动障碍的干预比轻度病例有效。

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引用次数: 0

Cortical Gyrification Is Associated With the Clinical Phenotype in Tuberous Sclerosis Complex 皮质回旋与结节性硬化症复合体的临床表型有关。

IF 3.2 3区医学 Q2 CLINICAL NEUROLOGY

Pediatric neurology

Pub Date : 2024-09-19 DOI: 10.1016/j.pediatrneurol.2024.09.012

Nicolò Trevisan PhD , Francesco Brunello MD , Fabio Sambataro MD, PhD , Gaia Biscalchin MD , Margherita Nosadini MD, PhD , Stefano Sartori MD, PhD , Concetta Luisi MD, PhD , Maria Federica Pelizza MD , Renzo Manara MD , Irene Toldo MD, PhD

Background

Tuberous sclerosis complex (TSC) is characterized by cortical tubers, determining cortical disarrangement and consequently drug-resistant epilepsy, intellectual disability, and TSC-associated neuropsychiatric disorders (TAND).

Aim of the study

To establish whether gyrification index (GI), a software-based neuroradiological parameter, could be associated with the severity of phenotype in TSC, identifying the cortical regions that are more associated with the severity of the main clinical manifestations.

Methods

This was a retrospective cross-sectional study. Magnetic resonance imaging was acquired on a 1.5-T scanner. CAT12 toolbox was used for the estimation of GI. Data analysis was performed with Jamovi. The level of significance was set to P < 0.05 for all tests.

Results

Forty-five patients with TSC and 42 healthy controls were included. Patients with TSC were characterized by higher total GI (P = 0.002) compared with healthy controls. Among patients with TSC, a higher total GI was associated with impaired neurological examination (P = 0.039), epilepsy (P = 0.017), intellectual disability (P = 0.013), TAND (P = 0.013), and higher number of cortical tubers (P < 0.001). An increased local GI in specific cortical areas was associated with TAND and autism spectrum disorders.

Conclusions

GI is a software-based neuroradiological parameter that could represent a reliable overall prognostic marker in TSC. Local GI can be used to identify phenotype-specific gyrification patterns allowing an early characterization of patients with TSC.

背景：结节性硬化综合征（TSC）的特点是皮质管状结构，决定了皮质的错乱，进而导致耐药性癫痫、智力障碍和TSC相关神经精神障碍（TAND）：研究目的：确定回旋指数（GI）这一基于软件的神经放射学参数是否与TSC表型的严重程度相关，从而确定与主要临床表现的严重程度更相关的皮质区域：这是一项回顾性横断面研究。磁共振成像由 1.5-T 扫描仪采集。CAT12 工具箱用于估算 GI。使用 Jamovi 进行数据分析。显著性水平设定为 P 结果：共纳入 45 名 TSC 患者和 42 名健康对照者。与健康对照组相比，TSC 患者的总消化道指数较高（P = 0.002）。在 TSC 患者中，较高的总 GI 与神经系统检查受损（P = 0.039）、癫痫（P = 0.017）、智力障碍（P = 0.013）、TAND（P = 0.013）和较多的皮质管数量（P 结论：总 GI 是一种基于软件的神经网络成像技术：GI是一种基于软件的神经放射学参数，可作为TSC可靠的总体预后标志。局部 GI 可用于识别表型特异性回旋模式，从而对 TSC 患者进行早期定性。

{"title":"Cortical Gyrification Is Associated With the Clinical Phenotype in Tuberous Sclerosis Complex","authors":"Nicolò Trevisan PhD , Francesco Brunello MD , Fabio Sambataro MD, PhD , Gaia Biscalchin MD , Margherita Nosadini MD, PhD , Stefano Sartori MD, PhD , Concetta Luisi MD, PhD , Maria Federica Pelizza MD , Renzo Manara MD , Irene Toldo MD, PhD","doi":"10.1016/j.pediatrneurol.2024.09.012","DOIUrl":"10.1016/j.pediatrneurol.2024.09.012","url":null,"abstract":"<div><h3>Background</h3><div>Tuberous sclerosis complex (TSC) is characterized by cortical tubers, determining cortical disarrangement and consequently drug-resistant epilepsy, intellectual disability, and TSC-associated neuropsychiatric disorders (TAND).</div></div><div><h3>Aim of the study</h3><div>To establish whether gyrification index (GI), a software-based neuroradiological parameter, could be associated with the severity of phenotype in TSC, identifying the cortical regions that are more associated with the severity of the main clinical manifestations.</div></div><div><h3>Methods</h3><div>This was a retrospective cross-sectional study. Magnetic resonance imaging was acquired on a 1.5-T scanner. CAT12 toolbox was used for the estimation of GI. Data analysis was performed with Jamovi. The level of significance was set to <em>P</em> < 0.05 for all tests.</div></div><div><h3>Results</h3><div>Forty-five patients with TSC and 42 healthy controls were included. Patients with TSC were characterized by higher total GI (<em>P</em> = 0.002) compared with healthy controls. Among patients with TSC, a higher total GI was associated with impaired neurological examination (<em>P</em> = 0.039), epilepsy (<em>P</em> = 0.017), intellectual disability (<em>P</em> = 0.013), TAND (<em>P</em> = 0.013), and higher number of cortical tubers (<em>P</em> < 0.001). An increased local GI in specific cortical areas was associated with TAND and autism spectrum disorders.</div></div><div><h3>Conclusions</h3><div>GI is a software-based neuroradiological parameter that could represent a reliable overall prognostic marker in TSC. Local GI can be used to identify phenotype-specific gyrification patterns allowing an early characterization of patients with TSC.</div></div>","PeriodicalId":19956,"journal":{"name":"Pediatric neurology","volume":"161 ","pages":"Pages 170-175"},"PeriodicalIF":3.2,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Biallelic Variants in LIPT2 as a Cause of Infantile-Onset Dystonia: Expanding the Clinical and Molecular Spectrum LIPT2的双拷贝变异是婴儿期发病肌张力障碍的病因之一：扩展临床和分子谱系。

IF 3.2 3区医学 Q2 CLINICAL NEUROLOGY

Pediatric neurology

Pub Date : 2024-09-18 DOI: 10.1016/j.pediatrneurol.2024.09.013

Kuntal Sen MD , Alonso Zea Vera MD , Anna Puronurmi MD , Andrea Gropman MD , Parith Wongkittichote MD , Rebecca Ganetzky MD , Kaija Autio PhD , Alexander Kastaniotis PhD

Background

Lipoyl transferase 2 is involved in the biosynthesis of lipoate. Lipoate is the cofactor for the glycine cleavage system and four dehydrogenase enzymes. Biallelic variants in LIPT2 causing severe neonatal encephalopathy was first described in 2017.

Methods

Clinical data were collected by retrospective chart review after obtaining consent from parents. The pathogenicity of these variants was further delineated using a yeast model. The YEp352-LIPT2 plasmid was used as a template to generate the two patient variants using QuickChange Lightning Site-Directed Mutagenesis Kit.

Results

The patient was a 15-month-old female who presented at one month with dystonia, developmental delay, and feeding difficulties. Brain magnetic resonance imaging showed cortical malformations including colpocephaly, polymicrogyria, and heterotopia. Patient had elevations in lactate (6.1 mmol/L) and glycine. Exome sequencing showed two variants of uncertain significance in trans in the LIPT2 gene: c.346 G>T and c.418C>T. Patient was started on lipoic acid, thiamine, and COQ10. Yeast complementation experiments indicate that both patient mutant variants result in diminished function versions of the LIPT2 protein.

Conclusion

We report the fourth case of LIPT2-related disorder. Proband shared significant overlap with previous patients; however, there was a distinct movement disorder and brain malformations, which have not been previously described. Unlike most neurometabolic disorders where dystonia develops later after metabolic stroke in basal ganglia, LIPT2-related disorder seems unique due to early onset of dystonia due to energy deficit in the developing brain. Lipoic acid supplementation has not led to significant clinical improvement. Analyses in yeast indicate that novel variants are deleterious but have retained some functionality.

背景：脂酰转移酶 2 参与脂酸的生物合成。脂酸是甘氨酸裂解系统和四种脱氢酶的辅助因子。2017年首次描述了导致严重新生儿脑病的LIPT2双唇变异：在征得家长同意后，通过回顾性病历审查收集临床数据。利用酵母模型进一步确定了这些变异的致病性。以YEp352-LIPT2质粒为模板，使用QuickChange Lightning定点突变试剂盒生成患者的两个变体：患者是一名15个月大的女性，一个月大时出现肌张力障碍、发育迟缓和喂养困难。脑磁共振成像显示大脑皮层畸形，包括头盖骨畸形、多小脑畸形和异位畸形。患者的乳酸（6.1毫摩尔/升）和甘氨酸升高。外显子组测序显示，LIPT2 基因有两个意义不确定的反式变异：c.346 G>T 和 c.418C>T。患者开始服用硫辛酸、硫胺素和 COQ10。酵母互补实验表明，患者的两个突变变体都会导致 LIPT2 蛋白的功能减弱：我们报告了第四例 LIPT2 相关疾病。我们报告了第四例 LIPT2 相关疾病患者，该病例与之前的患者有明显的重叠；但是，患者有明显的运动障碍和脑部畸形，这在之前的病例中还没有出现过。与大多数神经代谢性疾病不同的是，肌张力障碍是在基底节发生代谢中风后才出现的，而LIPT2相关障碍则是由于发育中的大脑能量不足而导致肌张力障碍提前出现。补充硫辛酸并不能显著改善临床症状。在酵母中进行的分析表明，新的变体是有害的，但保留了一些功能。

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引用次数: 0