Linear Nevus Sebaceous Syndrome in a Child With Infantile Spasms and Focal Cortical Dysplasia.
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ABSTRACT:
SUBMITTER: Salman S
PROVIDER: S-EPMC8487669 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundLinear nevus sebaceous syndrome (LNSS) is a multisystem disorder that includes nevus sebaceous and central nervous system, ocular and skeletal anomalies. We report the first case of a KRAS G12D mosaic mutation in a patient diagnosed with LNSS.Case presentationA 3-month-old female with a clinical diagnosis of LNSS presented with intermittent epilepsy. Her mother carefully collected a skin lesion sample from scratched-off scurf obtained from the patient's nails. DNA was extracted, and long-range PCR was performed to amplify the KRAS gene, which was then analyzed by next-generation sequencing. The results revealed the presence of a low-level heterozygous mutation in the KRAS gene (c.35C>T; p.G12D, 5 %).ConclusionsThese findings suggest that the KRAS somatic mosaic mutation in this patient may have caused her skin and eye lesions and epilepsy. With this correct diagnosis, the infant can be effectively treated.
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Project description:BackgroundLinear nevus sebaceous syndrome (LNSS) is a rare genetic disease characterized by large linear sebaceous nevus typically on the face, scalp, or neck. LNSS could be accompanied by multisystem disorders including the central nervous system. Herein, we report gene mutational profile via whole exome sequencing of both lesional and non-lesional skin samples in a LNSS patient.Case presentationA 17-year-old girl presented with multisystem abnormalities, including large skin lesions, ocular disorders, abnormal bone development and neurological symptoms. A diagnosis of LNSS was established based on clinical manifestations, histopathological and imaging findings. The skin lesions were resected and no recurrence was noted at the time of drafting this report. Whole exome sequencing of genomic DNA revealed the following 3 mutations in the lesions of the index patient: KRAS (c.35G > A, p.G12D), PRKRIR (c.A1674T, p.R558S), and RRP7A (c. C670T, p.R224W), but no mutation was found in the healthy skin and peripheral blood sample of the index patient, or in the blood samples of her parents and sibling. PCR-mediated Sanger sequencing of DNA derived from lesional skin sample of the index patient verified KRAS mutation, but not PRKRIR (c.A1674T, p.R558S) and RRP7A (c. C670T, p.R224W). None of the 3 mutations was found in Sanger sequencing in skin lesions of 60 other cases of nevus sebaceous patients.ConclusionsOur findings show the relevance of KRAS mutation to LNSS, providing new clues in understanding related genetic heterogeneity which could aid genetic counselling for LNSS patients.
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Project description:Infantile spasms are characterized by age-specific expression of epileptic spasms and hypsarrhythmia and often result in significant cognitive impairment. Other epilepsies or autism often ensue especially in symptomatic IS (SIS). Cortical or subcortical damage, including white matter, have been implicated in the pathogenesis of SIS. To generate a model of SIS, we recreated this pathology by injecting rats with lipopolysaccharide and doxorubicin intracerebrally at postnatal day (P) 3 and with p-chlorophenylalanine intraperitoneally at P5. Spasms occurred between P4 and 13 and were associated with ictal EEG correlates, interictal EEG abnormalities and neurodevelopmental decline. After P9 other seizures, deficits in learning and memory, and autistic-like behaviors (indifference to other rats, increased grooming) were observed. Adrenocorticotropic hormone (ACTH) did not affect spasms. Vigabatrin transiently suppressed spasms at P5. This new model of SIS will be useful to study the neurobiology and treatment of SIS, including those that are refractory to ACTH.
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Project description:We generated cortical organoids from four FCD patients. To generate cortical organoids, we used induced pluriplotent stem cells (iPSCs) obtained from skin biopsy from these FCD selected patients and healthy controls. We extrated RNA samples from the cortical organoids to do customized panel of gene expression. Gene expression using NanoString Human Neuropathology Panel from four FCD patients and four controls
2022-01-01 | GSE174605 | GEO
Project description:Focal cortical dysplasias (FCDs) constitute a prevalent cause of intractable epilepsy in children, and is one of the leading conditions requiring epilepsy surgery. Despite recent advances in the cellular and molecular biology of these conditions, the pathogenetic mechanisms of FCDs remain largely unknown. The purpose if this work is to review the molecular underpinnings of FCDs and to highlight potential therapeutic targets. A systematic review of the literature regarding the histologic, molecular, and electrophysiologic aspects of FCDs was conducted. Disruption of the mammalian target of rapamycin (mTOR) signaling comprises a common pathway underlying the structural and electrical disturbances of some FCDs. Other mechanisms such as viral infections, prematurity, head trauma, and brain tumors are also posited. mTOR inhibitors (i.e., rapamycin) have shown positive results on seizure management in animal models and in a small cohort of patients with FCD. Encouraging progress has been achieved on the molecular and electrophysiologic basis of constitutive cells in the dysplastic tissue. Despite the promising results of mTOR inhibitors, large-scale randomized trials are in need to evaluate their efficacy and side effects, along with additional mechanistic studies for the development of novel, molecular-based diagnostic and therapeutic approaches.
| S-EPMC4107035 | biostudies-literature
Project description:A 55-year-old man presented with seizures characterized by "tightening" of the right side and variable loss of awareness. EEG showed focal epileptogenic abnormalities over left and midline central regions. MRI showed left frontal focal cortical dysplasia (figure 1). He had multiple skin lesions (figure 2) and colonoscopy revealed gastrointestinal mucosal ganglioneuromas. Genetic testing of PTEN gene confirmed a diagnosis of Cowden syndrome (CS).
| S-EPMC3795595 | biostudies-literature
Project description:Hemiconvulsion-hemiplegia-epilepsy syndrome (HHES) is a subset of acute encephalopathy characterized by infantile-onset with acute hemiconvulsive febrile status and subsequent unilateral cerebral atrophy and hemiparesis. In the chronic phase, patients with HHES develop epilepsy, typically displayed as intractable focal seizures. The patients are often intractable with antiepileptic drugs and need surgical treatment. Although viral encephalitis and genetic abnormalities are presumed to be the underlying etiology, the pathogenesis remains mostly unknown. We describe three cases of successful functional hemispherotomy for intractable epilepsy in HHES. Patients developed acute asymmetrical convulsive status following viral infections during the ages of 17-30 months. Their seizures were intractable with antiepileptic drugs and required hemispherotomy. On the basis of the pathological findings, all cases were diagnosed as focal cortical dysplasia (FCD) type IIId. The epileptogenic mild cortical malformations may be the cause of HHES.
| S-EPMC6879674 | biostudies-literature
Project description:The treatment of infantile spasms is challenging, especially in the context of the following: (1) a severe phenotype with high morbidity and mortality; (2) the urgency of diagnosis and successful early response to therapy; and (3) the paucity of effective, safe, and well-tolerated therapies. Even after initially successful treatment, relapse risk is substantial and the most effective therapies pose considerable risk with long-term administration. In evaluating any treatment for infantile spasms, the key short-term outcome measure is freedom from both epileptic spasms and hypsarrhythmia. In contrast, the most important long-term outcomes are enduring seizure-freedom and measures of intellectual performance in later childhood and adulthood. First-line treatment options-namely hormonal therapy and vigabatrin-display moderate to high efficacy but also exhibit substantial side-effect burdens. Data on efficacy and safety of each class of therapy, as well as the combination of these therapies, are reviewed in detail. Specific hormonal therapies (adrenocorticotropic hormone and various corticosteroids) are contrasted. Those etiologies that prompt specific therapies are reviewed briefly, as are an array of second-line therapies supported by less-compelling data. The ketogenic diet is discussed in greater detail, with a focus on the limitations of numerous available studies that generally suggest that it is efficacious. Special discussion is allocated to cannabidiol-the investigational therapy that has received the most attention, and which is already in use in the form of various artisanal cannabis extracts. Finally, a treatment algorithm reflecting the concepts and controversies discussed in this review is presented.
| S-EPMC6293071 | biostudies-literature
Project description:AimTo estimate the prevalence, and evaluate presentation, treatment response, treatment side effects, and long-term seizure outcomes in all known cases of children with Down syndrome and infantile spasms on the island of Ireland.MethodThis was a 10-year retrospective multicentre review of clinical records and investigations, focusing on treatment response, side effects, and long-term outcomes.ResultsThe prevalence of infantile spasms in Down syndrome was 3.0% during the study period. Fifty-four infants were identified with median age of spasm onset at 201 days (interquartile range [IQR] 156-242). Spasm cessation was achieved in 88% (n=46) at a median of 110 days (IQR 5-66). The most common first-line medications were prednisolone (n=20, 37%), vigabatrin (n=18, 33.3%), and sodium valproate (n=9, 16.7%). At follow-up (median age 23.7mo; IQR 13.4-40.6), 25% had ongoing seizures and 85% had developmental concerns. Treatment within 60 days did not correlate with spasm cessation. Seventeen children (31%) experienced medication side effects, with vigabatrin accounting for 52%.InterpretationPrednisolone is an effective and well-tolerated medication for treating infantile spasms in Down syndrome. Despite the high percentage of spasm cessation, developmental concerns and ongoing seizures were common.
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Project description:Rett syndrome is a severe neurodevelopmental disorder, almost exclusively affecting females and characterised by a wide spectrum of clinical manifestations. Both the classic form and preserved speech variant of Rett syndrome are due to mutations in the MECP2 gene. Several other variants of Rett syndrome have been described. In 1985, Hanefeld described a variant with the early appearance of convulsions. In this variant, the normal perinatal period is soon followed by the appearance of seizures, usually infantile spasms. We have observed two patients with signs of Rett syndrome showing acquired microcephaly and stereotypic midline hand movements. The disease started with generalised convulsions and myoclonic fits at 1.5 months in the first patient and with spasms at 10 days in the other, suggesting a diagnosis of the Hanefeld variant. In these patients, MECP2 point mutations and gross rearrangements were excluded by denaturing high performance liquid chromatography and real time quantitative PCR. The ARX and CDKL5 genes have been associated with West syndrome (infantile spasms, hypsarrhythmia, and mental retardation).Based on the clinical overlap between the Hanefeld variant and West syndrome, we analysed ARX and CDKL5 in the two girls.We found frameshift deletions in CDKL5 in both patients; one in exon 5 (c.163_166delGAAA) and the other in exon 18 (c.2635_2636delCT). CDKL5 was then analysed in 19 classic Rett and 15 preserved speech variant patients, all MECP2 negative, but no mutations were found.Our results show that CDKL5 is responsible for a rare variant of Rett syndrome characterised by early development of convulsions, usually of the spasm type.
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