Early diagnosis of tuberous sclerosis complex: a race against time. How to make the diagnosis before seizures?

Słowińska, Monika; Jóźwiak, Sergiusz; Peron, Angela; Borkowska, Julita; Chmielewski, Dariusz; Sadowski, Krzysztof; Jurkiewicz, Elżbieta; Vignoli, Aglaia; Briola, Francesca La; Canevini, Maria Paola; Kotulska-Jóźwiak, Katarzyna

doi:10.1186/s13023-018-0764-z

Cited by 66 publications

(43 citation statements)

References 34 publications

(91 reference statements)

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“…Most of the cases examined herein were diagnosed before 10 years of age (N = 51/66; 77%); this was similar to a previous study with a larger sample size (N = 197/243; 81%) 23 performed at two different Hospitals in Boston, and there was no statistically significant difference in the age of diagnosis between the two studies (P = 0.48, Fisher's exact test, 2-tailed). However, as only four of our TSC cases were diagnosed in the first 6 months of life, it could be useful for clinicians in Mexico to monitor specific clinical signs that have recently been reported to be useful for an earlier TSC diagnosis (before 6 months) 1,24 .…”

Section: Discussionmentioning

confidence: 99%

First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants

Reyna-Fabián

Hernández‐Martínez

Alcántara-Ortigoza

et al. 2020

Sci Rep

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echavarría 4 , carlos G. todd-Quiñones 5,6 & Ariadna González-del Angel 1* the aim of this study was to improve knowledge of the mutational spectrum causing tuberous sclerosis complex (tSc) in a sample of Mexican patients, given the limited information available regarding this disease in Mexico and Latin America. Four different molecular techniques were implemented to identify from single nucleotide variants to large rearrangements in the TSC1 and TSC2 genes of 66 unrelated Mexican-descent patients that clinically fulfilled the criteria for a definitive TSC diagnosis. The mutation detection rate was 94%, TSC2 pathogenic variants (pV) prevailed over TSC1 PV (77% vs. 23%) and a recurrent mutation site (hotspot) was observed in TSC1 exon 15. Interestingly, 40% of the identified mutations had not been previously reported. The wide range of novels PV made it difficult to establish any genotype-phenotype correlation, but most of the pV conditioned neurological involvement (intellectual disability and epilepsy). Our 3D protein modeling of two variants classified as likely pathogenic demonstrated that they could alter the structure and function of the hamartin (TSC1) or tuberin (TSC2) proteins. Molecular analyses of parents and first-degree affected family members of the index cases enabled us to distinguish familial (18%) from sporadic (82%) cases and to identify one case of apparent gonadal mosaicism. Tuberous sclerosis complex (TSC; MIM #191100, MIM #613254) is an autosomal dominant syndrome characterized by the presence of multiple hamartomas in different organs and systems. The incidence is about 0.1-1/10,000 births and the prevalence varies from 1/6,000 to 1/10,000 among different populations 1-3. The manifestations of TSC are highly variable among individuals and even within the same family 4 , but the most common clinical features are localized in skin and central nervous system 5-7. TSC is caused by pathogenic variants (PV) in the tumor suppressor-genes, TSC1 (tuberous sclerosis complex 1, MIM *605284, 9q34.13) and TSC2 (tuberous sclerosis complex 2, MIM *191092, 16p13.3). These PV can be detected by various molecular techniques, such as single-strand conformational polymorphism (SSCP), direct Sanger sequencing (SS), multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS). There are currently more than 2,000 pathogenic TSC1/TSC2 variants described in the Leiden Open Variation Database (www.lovd.nl/TSC1 and www.lovd.nl/TSC2) 8 ; of them, 21-26% are located in TSC1 and 69-79% in TSC2 9,10. In approximately 5-25% of the analyzed TSC cases, a PV could not be identified in either gene 9,11,12. The emergence of new techniques, such as NGS, has significantly increased the mutation detection rate

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Section: Discussionmentioning

confidence: 99%

First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants

Reyna-Fabián

Hernández‐Martínez

Alcántara-Ortigoza

et al. 2020

Sci Rep

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“…Recent developments in early or even prenatal diagnosis of TSC have led to treatment of an increasing number of young infants with TSC before clinical seizures. 248 In the study of Jóźwiak et al, 14 infants diagnosed with TSC by the end of the second month of age were followed with video-EEG until 24 months of age and treated with vigabatrin (100-150 mg/kg) if paroxysmal EEG activity appeared. 249 Ten of 14 developed paroxysmal activity and were treated with vigabatrin before clinical seizure onset.…”

Section: Vigabatrinmentioning

confidence: 99%

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%‐20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease‐modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N‐acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially “repurposable” medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury–treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose–blood level relationship, brain target engagement, and dose‐response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

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“…Prenatal diagnosis of TSC and early postnatal diagnosis, mainly before the onset of seizures, improves neurological outcome as preventive treatment can be implemented . Additionally, neonatal treatment with everolimus can reduce the large rhabdomyomas detected by prenatal imaging …”

Section: Other Genetic Syndromes Associated With Cardiac Anomaliesmentioning

confidence: 99%

Fetal cardiac abnormalities: Genetic etiologies to be considered

et al. 2019

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Congenital heart diseases are a common prenatal finding. The prenatal identification of an associated genetic syndrome or a major extracardiac anomaly helps to understand the etiopathogenic diagnosis. Besides, it also assesses the prognosis, management, and familial recurrence risk while strongly influences parental decision to choose termination of pregnancy or postnatal care. This review article describes the most common genetic diagnoses associated with a prenatal finding of a congenital heart disease and a suggested diagnostic process.

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Early diagnosis of tuberous sclerosis complex: a race against time. How to make the diagnosis before seizures?

Cited by 66 publications

References 34 publications

First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants

First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Fetal cardiac abnormalities: Genetic etiologies to be considered

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