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Eye of the Tiger: Looking Beyond Neurodegeneration with Brain Iron Accumulation Disorders. 老虎之眼:超越脑铁积累障碍的神经变性。
IF 0.4 Pub Date : 2023-06-01 DOI: 10.1055/s-0041-1723959
Prajnya Ranganath, Mallikarjun Patil

The "eye-of-the-tiger" sign in brain magnetic resonance imaging (MRI) is typically associated with neurodegeneration with brain iron accumulation disorders, especially pantothenate kinase-associated neurodegeneration. However, very similar neuroimaging findings may be seen in other neurodegenerative disorders involving the basal ganglia. We report here a patient with fucosidosis who had MRI brain findings closely resembling the "eye-of-the-tiger" sign.

脑磁共振成像(MRI)中的“虎眼”征通常与伴有脑铁积累障碍的神经变性有关,特别是泛酸激酶相关的神经变性。然而,在涉及基底神经节的其他神经退行性疾病中,也可以看到非常相似的神经影像学结果。我们在此报告一位有聚焦病变的患者,他的MRI脑部表现与“虎眼”征非常相似。
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引用次数: 0
The Challenge of Severe Acute Malnutrition in Inborn Errors of Metabolism: Does Medical Food Alone Suffice? 先天代谢缺陷导致严重急性营养不良的挑战:仅靠医疗食品就足够了吗?
IF 0.4 Pub Date : 2023-06-01 DOI: 10.1055/s-0041-1739288
Bhanudeep Singanamalla, Pradip Paria, Renu Suthar, Arushi G Saini, Savita V Attri

Glutaric aciduria type 1 (GA-1) is a treatable inborn error of metabolism caused by glutaryl-CoA dehydrogenase deficiency. This enzyme deficiency leads to accumulation of glutaric acid, 3-hydroxy glutaric acid, and glutaconic acid which are potentially neurotoxic. Patients with GA-1 have characteristic clinical and neuroimaging features that help us to clinch the diagnosis. Early diagnosis by newborn screening helps us to prevent the motor problems such as dystonia and spasticity. Treatment includes low-protein diet along with carnitine supplementation which may lead to deficiency of essential amino acids and hence malnutrition. Managing malnutrition in a child with inborn errors of metabolism (IEM) is challenging. Here, we describe a patient, a case of GA-1 on medical food, presenting with severe acute malnutrition, who improved with a combination of medical and home-made foods along with lysine-free, tryptophan-reduced amino acid supplements.

戊二酸尿1型(GA-1)是由戊二酰辅酶a脱氢酶缺乏引起的一种可治疗的先天性代谢错误。这种酶的缺乏导致戊二酸、3-羟基戊二酸和戊二酸的积累,这些物质具有潜在的神经毒性。GA-1患者具有特征性的临床和神经影像学特征,有助于我们确定诊断。新生儿筛查的早期诊断有助于我们预防运动问题,如肌张力障碍和痉挛。治疗方法包括低蛋白饮食和补充肉碱,这可能导致必需氨基酸缺乏,从而导致营养不良。管理患有先天性代谢缺陷(IEM)儿童的营养不良是一项挑战。在这里,我们描述了一个病人,GA-1在医疗食品的情况下,表现出严重的急性营养不良,谁改善了医疗和自制食品的组合以及赖氨酸,色氨酸减少氨基酸补充剂。
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引用次数: 0
Novel Variants and Clinical Characteristics of 16 Patients from Southeast Asia with Genetic Variants in Neurofibromin-1. 东南亚16例神经纤维蛋白-1基因变异的新变异及其临床特征
IF 0.4 Pub Date : 2023-06-01 DOI: 10.1055/s-0041-1736457
Grace Lin, Heming Wei, Angeline H M Lai, Ee-Shien Tan, Jiin Ying Lim, Breana Cham, Simon Ling, Saumya S Jamuar, Ene-Choo Tan

Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders. It is caused by mutations in the neurofibromin-1 gene ( NF1 ) and affects the formation and growth of nerve tissues. More than 3,600 pathogenic variants in the NF1 gene have been identified from patients with most of the germline variants are from the Western populations. We found 16 patients (15 Chinese and 1 Asian Indian) who had heterozygous variants in NF1 through targeted next-generation sequencing. There were 15 different variants: 4 frameshift, 4 nonsense, 5 missense, and 2 splice variants. One nonsense variant and three frameshift variants had never been reported in any population or patient database. Twelve of the 16 patients met the NF1 diagnostic criteria, and each was found to have a pathogenic or likely pathogenic variant. Three different missense variants of unknown significance were discovered in the other four patients who did not meet NF1 diagnostic criteria. Our findings add four novel variants to the list of genetic mutations linked to NF1's various clinical manifestations.

1型神经纤维瘤病(NF1)是最常见的遗传性疾病之一。它是由神经纤维蛋白-1基因(NF1)突变引起的,并影响神经组织的形成和生长。已从患者中鉴定出超过3600种NF1基因的致病变异,其中大多数种系变异来自西方人群。通过靶向下一代测序,我们发现16例患者(15例中国人和1例亚洲印度人)具有NF1杂合变异体。有15个不同的变体:4个移码,4个无义,5个错义和2个拼接变体。一种无义变异和三种移码变异从未在任何人群或患者数据库中报道过。16例患者中有12例符合NF1诊断标准,并且每个患者都被发现有致病性或可能致病性变异。在其他4例不符合NF1诊断标准的患者中发现了三种不同的意义未知的错义变异。我们的发现在与NF1的各种临床表现相关的基因突变列表中增加了四种新的变异。
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引用次数: 0
Three Cases of Joubert Syndrome in a Consanguineous Syrian Family and a Interesting Case of Multinational Collaboration. 一个叙利亚近亲家庭的Joubert综合征三例及一个有趣的跨国合作案例。
IF 0.4 Pub Date : 2023-06-01 DOI: 10.1055/s-0040-1721826
Davor Petrović, Vida Čulić, Zofia Swinderek-Alsayed

Joubert syndrome (JS) is a rare congenital, autosomal recessive disorder characterized by a distinctive brain malformation, developmental delay, ocular motor apraxia, breathing abnormalities, and high clinical and genetic heterogeneity. We are reporting three siblings with JS from consanguineous parents in Syria. Two of them had the same homozygous c.2172delA (p.Trp725Glyfs*) AHI1 mutation and the third was diagnosed prenatally with magnetic resonance imaging. This pathogenic variant is very rare and described in only a few cases in the literature. Multinational collaboration could be of benefit for the patients from undeveloped, low-income countries that have a low-quality health care system, especially for the diagnosis of rare diseases.

Joubert综合征(JS)是一种罕见的先天性常染色体隐性遗传病,其特征是明显的大脑畸形、发育迟缓、眼运动失用症、呼吸异常,且具有高度的临床和遗传异质性。我们报告在叙利亚有三名父母是近亲的兄弟姐妹患有JS。其中两人具有相同的纯合子c.2172delA (p.Trp725Glyfs*) AHI1突变,第三人在产前通过磁共振成像诊断。这种致病变异是非常罕见的,在文献中只有少数病例被描述。跨国合作可能有利于来自卫生保健系统质量较低的不发达低收入国家的患者,特别是在罕见疾病的诊断方面。
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引用次数: 0
RHOBTB2 p.Arg511Trp Mutation in Early Infantile Epileptic Encephalopathy-64: Review and Case Report. 早期婴儿癫痫性脑病RHOBTB2 p.a g511trp突变-64:回顾和病例报告。
IF 0.4 Pub Date : 2023-06-01 DOI: 10.1055/s-0040-1722288
Jacinta Fonseca, C Melo, C Ferreira, M Sampaio, R Sousa, M Leão

Early infantile epileptic encephalopathy-64 (EIEE 64), also called RHOBTB2-related developmental and epileptic encephalopathy (DEE), is caused by heterozygous pathogenic variants (EIEE 64; MIM#618004) in the Rho-related BTB domain-containing protein 2 ( RHOBTB2 ) gene. To date, only 13 cases with RHOBTB2-related DEE have been reported. We add to the literature the 14th case of EIEE 64, identified by whole exome sequencing, caused by a heterozygous pathogenic variant in RHOBTB2 (c.1531C > T), p.Arg511Trp. This additional case supports the main features of RHOBTB2-related DEE: infantile-onset seizures, severe intellectual disability, impaired motor functions, postnatal microcephaly, recurrent status epilepticus, and hemiparesis after seizures.

早期婴儿癫痫性脑病-64 (eie64),也称为rhobtb2相关发育性和癫痫性脑病(DEE),是由杂合致病性变异引起的(eie64;MIM#618004)在RHOBTB2相关结构域蛋白2 (RHOBTB2)基因中表达。迄今为止,仅报道了13例与rhobtb2相关的DEE。我们在文献中增加了第14例eie64,通过全外显子组测序鉴定,由RHOBTB2 (c.1531C > T)的杂合致病变异p.Arg511Trp引起。这一新增病例支持了rhobtb2相关DEE的主要特征:婴儿期癫痫发作、严重智力残疾、运动功能受损、产后小头畸形、反复发作的癫痫持续状态和癫痫发作后偏瘫。
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引用次数: 0
6q13q14.3 Microdeletion Syndrome with Severe Hypotonia and Facial Dysmorphism: Genotype-Phenotype Correlation. 微缺失综合征伴严重低张力和面部畸形:基因型-表型相关性。
IF 0.4 Pub Date : 2023-06-01 DOI: 10.1055/s-0040-1721739
Manisha Goyal, Mohammed Faruq, Ashok Gupta, Divya Shrivastava, Uzma Shamim

Hypotonia is a symptom of diminished tone of skeletal muscle and can be nongenetic or a part of genetic syndrome. Hypotonia, developmental delay, and facial dysmorphism are nonspecific findings observed in many genetic syndromes mostly in chromosomal microdeletion and duplication. Here we report a case with severe hypotonia and facial dysmorphism, diagnosed with deletion at 6q13q14.3 by array comparative genomic hybridization (CGH) at very early age. Recent genetic diagnostic technologies such as array CGH may enable clinicians to diagnose chromosomal abnormalities earlier and provide appropriate medical management.

肌张力减退是骨骼肌张力减退的一种症状,可以是非遗传性的,也可以是遗传综合征的一部分。低张力、发育迟缓和面部畸形是许多遗传综合征的非特异性发现,主要表现在染色体微缺失和重复。在这里,我们报告一个严重张力低下和面部畸形的病例,在很小的时候通过阵列比较基因组杂交(CGH)诊断为6q13q14.3缺失。最近的基因诊断技术,如阵列CGH,可以使临床医生更早地诊断染色体异常,并提供适当的医疗管理。
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引用次数: 1
Variant in CACNA1G as a Possible Genetic Modifier of Neonatal Epilepsy in an Infant with a De Novo SCN2A Mutation. CACNA1G变异可能是新生儿癫痫SCN2A新生突变婴儿的遗传修饰因子
IF 0.4 Pub Date : 2023-06-01 DOI: 10.1055/s-0041-1723958
Juan Jose Nieto-Barcelo, Noelia Gonzalez Montes, Isabel Gonzalo Alonso, Francisco Martinez, Maria Jose Aparisi, Marina Martinez-Matilla, Ana Victoria Marco Hernandez, Miguel Tomás Vila

Mutations in SCN2A genes have been described in patients with epilepsy, finding a large phenotypic variability, from benign familial epilepsy to epileptic encephalopathy. To explain this variability, it was proposed the existence of dominant modifier alleles at one or more loci that contribute to determine the severity of the epilepsy phenotype. One example of modifier factor may be the CACNA1G gene, as proved in animal models. We present a 6-day-old male newborn with recurrent seizures in which a mutation in the SCN2A gene is observed, in addition to a variant in CACNA1G gene. Our patient suffered in the first days of life myoclonic seizures, with pathologic intercritical electroencephalogram pattern, requiring multiple drugs to achieve adequate control of them. During the next weeks, the patient progressively improved until complete remission at the second month of life, being possible to withdraw the antiepileptic treatment. We propose that the variant in CACNA1G gene could have acted as a modifier of the epilepsy syndrome produced by the mutation in SCN2A gene in our patient.

SCN2A基因突变已在癫痫患者中被描述,发现从良性家族性癫痫到癫痫性脑病有很大的表型变异。为了解释这种变异性,有人提出在一个或多个基因座上存在显性修饰等位基因,这些等位基因决定了癫痫表型的严重程度。CACNA1G基因可能是修饰因子的一个例子,已在动物模型中得到证实。我们报告了一个6天大的男性新生儿复发性癫痫发作,其中SCN2A基因突变以及CACNA1G基因突变被观察到。我们的患者在出生的第一天就出现了肌阵挛性发作,伴有病理性的临界间期脑电图模式,需要多种药物来达到适当的控制。在接下来的几周内,患者逐渐好转,直到生命第二个月完全缓解,可以停止抗癫痫治疗。我们提出,CACNA1G基因的变异可能是我们患者的SCN2A基因突变所产生的癫痫综合征的修饰因子。
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引用次数: 2
The HBG2 rs7482144 (C > T) Polymorphism is Linked to HbF Levels but not to the Severity of Sickle Cell Anemia. HBG2 rs7482144 (C > T)多态性与HbF水平有关,但与镰状细胞性贫血的严重程度无关。
IF 0.4 Pub Date : 2023-06-01 DOI: 10.1055/s-0041-1733950
Bhaskar V K S Lakkakula, Smaranika Pattnaik

Sickle cell anemia (SCA) is a severe disease characterized by anemia, acute clinical complications, and a relatively short life span. In this disease, abnormal hemoglobin makes the red blood cells deformed, rigid, and sticky. Fetal hemoglobin (HbF) is one of the key modulators of SCA morbidity and mortality. Interindividual HbF variation is a heritable trait that is controlled by polymorphism in genes linked and unlinked to the hemoglobin β gene (HBB). The genetic polymorphisms that determine HbF levels are known to ameliorate acute clinical events. About 190 well-characterized homozygous SCA patients were included in this study. Complete blood count (CBC), high-performance liquid chromatography (HPLC), and clinical investigations were obtained from patient's records. Severity scores were determined by using the combination of anemia, complications, total leucocyte count, and transfusion scores. HBG2 rs7482144 polymorphism was genotyped by using the polymerase chain reaction and restriction fragment length polymorphism. The association between HBG2 rs7482144 polymorphism and HbF levels as well as the disease severity of SCA were assessed. SCA patients carrying TT genotype were found to have higher HbF levels. In addition, SCA patients with increased severity showed significantly lower levels of hemoglobin, HbF, and hematocrit values. However, the genotypes of HBG2 rs7482144 polymorphism were not found to be associated with the risk of disease severity. In summary, this study demonstrated that HBG2 rs7482144 polymorphism is linked with HbF levels, but it does not affect disease severity. The sample sizes used and the pattern of association deduced from our small sample size prevents us from extrapolating our findings further.

镰状细胞性贫血(SCA)是一种以贫血、急性临床并发症和相对较短的寿命为特征的严重疾病。在这种疾病中,异常的血红蛋白使红细胞变形、僵硬和粘稠。胎儿血红蛋白(HbF)是SCA发病率和死亡率的关键调节因子之一。个体间HbF变异是一种遗传性状,由与血红蛋白β基因(HBB)相关和非相关基因的多态性控制。已知决定HbF水平的遗传多态性可以改善急性临床事件。本研究纳入了约190例特征良好的纯合子SCA患者。全血细胞计数(CBC)、高效液相色谱(HPLC)和临床调查从患者的记录。严重程度评分由贫血、并发症、总白细胞计数和输血评分联合确定。采用聚合酶链反应和限制性片段长度多态性对HBG2 rs7482144多态性进行基因分型。评估HBG2 rs7482144多态性与HbF水平以及SCA疾病严重程度之间的关系。携带TT基因型的SCA患者HbF水平较高。此外,严重程度增加的SCA患者血红蛋白、HbF和红细胞压积值水平显著降低。然而,未发现HBG2 rs7482144多态性的基因型与疾病严重程度的风险相关。综上所述,本研究表明HBG2 rs7482144多态性与HbF水平相关,但不影响疾病严重程度。使用的样本量和从我们的小样本量推断出的关联模式使我们无法进一步推断我们的发现。
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引用次数: 3
Variable Presentation and Reduced Penetrance in Autosomal Dominant Acute Necrotizing Encephalopathy Related to RANBP2 Variant. 与RANBP2变异相关的常染色体显性急性坏死性脑病的不同表现和外显率降低。
IF 0.4 Pub Date : 2023-06-01 DOI: 10.1055/s-0040-1721802
Daniel R Carvalho, Carlos E Speck-Martins, Bernardo J A F Martins, Ana Paula Izumi, Alessandra La Rocque-Ferreira

Acute necrotizing encephalopathy (ANE) is clinically characterized by fever, acute alteration of consciousness, seizures, and rapid progression to coma within days of onset of a viral illness occurring in healthy children without evidence of central nervous system infection. Brain magnetic resonance imaging (MRI) shows multiple symmetrical lesions affecting primarily the thalami but also brain stem, putamina, periventricular white matter, and cerebellum. Most cases of ANE are sporadic and nonrecurrent. However, a missense variant in RANBP2 has been identified in some families with recurrent ANE (OMIM # 608033), also named autosomal dominant ANE (ADANE). Clinical manifestation, clinical course, and brain MRI imaging findings of six affected members of two distinct families with ADANE were described. Sequencing revealed heterozygous c.1754C > T variant in RANBP2 (p.Thr585Met) in affected and asymptomatic family members. Only few ADANE families have been reported and it is the first description in South America. Differential diagnosis of Leigh disease and acute disseminated encephalomyelitis is discussed. Our report reinforces incomplete penetrance of ADANE and intrafamilial phenotypic variability of outcome.

急性坏死性脑病(ANE)的临床特征是在没有中枢神经系统感染证据的健康儿童中发生的一种病毒性疾病,发病数天内表现为发热、急性意识改变、癫痫发作和迅速发展为昏迷。脑磁共振成像(MRI)显示多发对称病变,主要影响丘脑,也影响脑干、壳层、脑室周围白质和小脑。大多数ANE病例是散发性和非复发性的。然而,在一些复发性ANE (omim# 608033)家族中发现了RANBP2的错义变体,也称为常染色体显性ANE (ADANE)。本文描述了来自两个不同家族的6名ADANE患者的临床表现、临床病程和脑MRI成像结果。测序结果显示,在感染和无症状的家族成员中,RANBP2基因(p. thr558met)存在c.1754C > T杂合变异。只有少数ADANE家族被报道,这是南美洲的第一次描述。讨论Leigh病与急性播散性脑脊髓炎的鉴别诊断。我们的报告强调了ADANE的不完全外显率和结果的家族内表型变异性。
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引用次数: 0
Digenic Inheritance in Juvenile Open-Angle Glaucoma. 青少年开角型青光眼的基因遗传。
IF 0.4 Pub Date : 2023-06-01 DOI: 10.1055/s-0040-1722213
Bindu I Somarajan, Shikha Gupta, Karthikeyan Mahalingam, Kishan Azmira, Viney Gupta

Juvenile open-angle glaucoma (JOAG) is an uncommon subset of primary glaucoma with an onset before the age of 40 years. In this case report, we describe the cosegregation of MYOC , p.Pro370Leu and LTBP2 , p.Pro432Leu mutations in a family with JOAG. The family with autosomal dominant JOAG belonged to Northern India. The samples of proband and her parents were evaluated by whole exome sequencing. Sanger sequencing was conducted in all the study participants to check the mutations identified. Both MYOC and LTBP2 mutations were found to cosegregate in affected individuals leading to a severe JOAG phenotype, thereby suggesting a digenic inheritance of MYOC with LTBP2 in this family.

青少年开角型青光眼(JOAG)是一种罕见的原发性青光眼,发病年龄在40岁之前。在这个病例报告中,我们描述了MYOC, p.p pro370leu和LTBP2, p.p pro432leu突变在JOAG家族中的共分离。常染色体显性JOAG家族来自印度北部。先证者及其父母的样本采用全外显子组测序进行评估。对所有研究参与者进行了桑格测序,以检查确定的突变。在受影响的个体中发现MYOC和LTBP2突变共分离,导致严重的JOAG表型,从而提示该家族存在MYOC与LTBP2的基因遗传。
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引用次数: 2
期刊
Journal of pediatric genetics
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