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(A) Brain section shows a cortical tuber in the left frontal region. (B) Subependymal nodules protruding into the ventricles (arrow). Reproduced with permission from Roach. 8
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Tuberous sclerosis complex (TSC) is a dominantly inherited disorder that variably affects the brain, skin, kidneys, heart, and other organs. Its neurological manifestations include epilepsy, autism, cognitive and behavioral dysfunction, and giant cell tumors. A mutation of either TSC1 or TSC2 can cause tuberous sclerosis complex. Their two gene pro...
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Subependymal giant cell astrocytomas (SEGAs) are histologically benign tumors most frequently associated with tuberous sclerosis complex (TSC). Despite their benign histopathological appearance, they may cause unfavorable outcomes due to their intraventricular location. Rarely, SEGA may be associated with hyperproteinorrhachia (high levels of prote...
Citations
... T uberous sclerosis (TSC), also known as Bourneville disease, 1 is a rare genetic autosomal-dominant disorder. The prevalence of TSC was reported to be 6.8-12.4 per 100,000 population, with no differences in male or female sex. ...
Importance: Tuberous sclerosis is an autosomal dominant genetic disorder that affects multiple organ systems and causes a wide range of physical manifestations. It commonly involves the brain, skin, heart, eyes, kidneys, and lungs. Individuals mostly present with neuropsychiatric symptoms, comprising a noteworthy source of morbidity and mortality. Observation: Ninety percent of individuals with tuberous sclerosis have associated neuropsychiatric manifestations including attention-deficit/hyperactivity disorder, autism spectrum disorder, and intellectual disability, which are typically underidentified and undertreated. Conclusion and Relevance: Lack of specific guidelines for management add to the significant burden of care. An individualized, multifaceted perspective, with particular focus on cognitive and psychosocial comorbidities, is key for managing tuberous sclerosis. Prim Care Companion CNS Disord 2024;26(1):22nr03481. Author affiliations are listed at the end of this article.
... Tuberous sclerosis (TSC) is a multisystem neurocutaneous genetic disease that might be seen in one live birth in 6,000-10,000 (1,2). TSC is inherited in an autosomal dominant manner and 66% of patients have sporadic mutations (3). ...
... This in turn creates a protein complex that is responsible for chaotic cellular hyperplasia and also modifications in a tumor suppressor gene. These mutations may be spontaneous (70%) or inherited autosomally dominant [2,3]. In our index case, antenatal genetic testing was done and the benefits of this antenatal invasive testing were twofold: (1) it helped in accurate fetal counseling and making the family aware of the lifelong implications of this genetic syndrome-an informed decision was taken by the family to continue the pregnancy (2) it prepared the perinatal team including obstetrician, neonatologist, cardiologist and other caregivers to fully prepare for a 'high risk' pregnancy. ...
A 27 year old multigravida, presented with giant left ventricular cardiac rhabdomyoma at the 23rd gestational week. A previous bad obstetric history prompted amniocentesis. A heterozygous, pathogenic, missense variant in exon 40 of the Tuberous Sclerosis (TSC 2) gene with autosomal dominant inheritance was extracted from fetal DNA by targeted gene capture. Sanger’s sequencing confirmed the same. This fetus highlighted the need for genetic assessment in every cardiac rhabdomyoma and a paradigm shift in fetal counseling protocol. We retrospectively reviewed our personal, multi-centric 13 years (2008–2020) database of cardiac rhabdomyomas in the fetal and pediatric cohort. Cardiac rhabdomyoma preceded extra-cardiac manifestations of Tuberous Sclerosis in 87.5% of our cohort. This article underscores this forgotten ominous association. We propose a paradigm shift in fetal counseling in such a scenario, remembering the heterogeneous timing and presentations of this widely variable genetic lesion.
... and the TSC complex subunit 2 gene (TSC2, OMIM 191092) contains 42 exons on chromosome 16p13.3 (Roach, 2016). These two genes encode hamartin (also known as TSC1) and tuberin (also known as TSC2) proteins (Curatolo et al., 2015). ...
... TSC1 or TSC2 pathogenic variants over-activate mTOR-mediated signaling with consequent extensive metabolic reprogramming . This results in uncontrolled cell growth and proliferation and a nervous system imbalance between excitation and inhibition (Curatolo et al., 2015;Roach, 2016). These effects lead to various clinical manifestations including skin, brain, lungs, heart, and kidney tumors and neurological disorders, such as epilepsy, autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD) Roach, 2016;de Vries et al., 2018). ...
... This results in uncontrolled cell growth and proliferation and a nervous system imbalance between excitation and inhibition (Curatolo et al., 2015;Roach, 2016). These effects lead to various clinical manifestations including skin, brain, lungs, heart, and kidney tumors and neurological disorders, such as epilepsy, autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD) Roach, 2016;de Vries et al., 2018). There is great symptom variability among affected individuals, even identical twins (Humphrey et al., 2004;Roach, 2016). ...
Background
Tuberous sclerosis complex (TSC) is a genetic, variably expressed, multisystem disease characterized by benign tumors. It is caused by pathogenic variants of the TSC complex subunit 1 gene ( TSC1 ) and the TSC complex subunit 2 gene ( TSC2 ). Genetic testing allows for early diagnosis, genetic counseling, and improved outcomes, but it did not identify a pathogenic variant in up to 25% of all TSC patients. This study aimed to identify the disease-causing variant in a Han-Chinese family with TSC.
Methods
A six-member, three-generation Han-Chinese family with TSC and three unrelated healthy women were recruited. A comprehensive medical examination, a 3-year follow-up, whole exome sequencing, Sanger sequencing, and segregation analysis were performed in the family. The splicing analysis results obtained from six in silico tools, minigene assay, and patients' lymphocyte messenger RNA were compared, and quantitative reverse transcription PCR was used to confirm the pathogenicity of the variant.
Results
Two affected family members had variable clinical manifestations including a rare bilateral cerebellar ataxia symptom. The 3-year follow-up results suggest the effects of a combined treatment of anti-epilepsy drugs and sirolimus for TSC-related epilepsy and cognitive deficits. Whole exome sequencing, Sanger sequencing, segregation analysis, splicing analysis, and quantitative reverse transcription PCR identified the TSC2 gene c.2742+5G>A variant as the genetic cause. This variant inactivated the donor splice site, a cryptic non-canonical splice site was used for different splicing changes in two affected subjects, and the resulting mutant messenger RNA may be degraded by nonsense-mediated decay. The defects of in silico tools and minigene assay in predicting cryptic splice sites were suggested.
Conclusions
This study identified a TSC2 c.2742+5G>A variant as the genetic cause of a Han-Chinese family with TSC and first confirmed its pathogenicity. These findings expand the phenotypic and genetic spectrum of TSC and may contribute to its diagnosis and treatment, as well as a better understanding of the splicing mechanism.
... Туберозный склероз (факоматоз Pringle-Bourneville) представляет собой мультисистемное генетическое заболевание с аутосомно-доминантным наследованием с частотой 1 на 6 000 -10 000 населения [1]. Данное заболевание одинаково часто встречается у представителей мужского и женского полов и всех этнических групп. ...
Tuberous sclerosis is one of the forms of monogenic hereditary pathology related to neurocutaneous diseases (phacomatoses). Diagnostic difficulties are associated with pronounced clinical polymorphism and age-dependent onset of symptoms. The article presents current data on the prevalence and clinical manifestations of tuberous sclerosis. A clinical case of tuberous sclerosis is given in several generations of the same family.
... It is a disease that affects multiple organs and systems and is typified by the presence of cutaneous changes, epilepsy and hamartomas in several tissues and organs (brain, myocardium, teguments, kidneys, eyes) [1]. The prevalence of the disease is between 1 in 6000 to 1 in 10,000 live newborns [2,3]. The disease was first described in 1862 by anatomopathologist Friedrich Daniel von Recklinghausen, who identified the presence of cardiac myomas and sclerotic changes in the brain of a newborn who died immediately after birth. ...
Tuberous sclerosis complex (TSC) is a rare autosomal dominant neurocutaneous syndrome. It is manifested mainly in cutaneous lesions, epilepsy and the emergence of hamartomas in several tissues and organs. The disease sets in due to mutations in two tumor suppressor genes: TSC1 and TSC2. The authors present the case of a 33-year-old female patient registered with the Bihor County Regional Center of Medical Genetics (RCMG) since 2021 with a TSC diagnosis. She was diagnosed with epilepsy at eight months old. At 18 years old she was diagnosed with tuberous sclerosis and was referred to the neurology department. Since 2013 she has been registered with the department for diabetes and nutritional diseases with a type 2 diabetes mellitus (T2DM) diagnosis. The clinical examination revealed: growth delay, obesity, facial angiofibromas, sebaceous adenomas, depigmented macules, papillomatous tumorlets in the thorax (bilateral) and neck, periungual fibroma in both lower limbs, frequent convulsive seizures; on a biological level, high glycemia and glycated hemoglobin levels. Brain MRI displayed a distinctive TS aspect with five bilateral hamartomatous subependymal nodules associating cortical/subcortical tubers with the frontal, temporal and occipital distribution. Molecular diagnosis showed a pathogenic variant in the TSC1 gene, exon 13, c.1270A>T (p. Arg424*). Current treatment targets diabetes (Metformin, Gliclazide and the GLP-1 analog semaglutide) and epilepsy (Carbamazepine and Clonazepam). This case report presents a rare association between type 2 diabetes mellitus and Tuberous Sclerosis Complex. We suggest that the diabetes medication Metformin may have positive effects on both the progression of the tumor associated with TSC and the seizures specific to TSC and we assume that the association of TSC and T2DM in the presented cases is accidental, as there are no similar cases reported in the literature.
... 3 It is an autosomal dominant disorder which its neuropathological findings were first described by Bourneville in 1880, when he observed masses in both kidneys in a child with epilepsy. 4 With the advance of molecular techniques, TSC1 and TSC2 were cloned in the 1990s, and genotype-phenotype correlations were made possible. 1 Tuberous sclerosis complex is caused by mutations in TSC1 5 at 9q34, which produces hamartin, 6 and mutations in TSC2 at 16p13, 7 which produces tuberin. ...
Background Tuberous sclerosis complex (TSC) is a multisystemic disorder. Its clinical features manifest differently in several organs, prompting the need for better knowledge.
Objective The goal of the present study is to evaluate the neurological findings of TSC, such as cerebral lesions and epilepsy, and to raise awareness of non-neurological findings that could contribute to an earlier diagnosis and treatment.
Methods This was a natural history study of patients with a definitive diagnosis of TSC who were referred to a specialized outpatient clinic and followed-up for 2 years with clinical and radiological exams.
Results A total of 130 TSC patients (59 males [45.4%], mean age 20.4 years old [1 to 56 years old]); 107 patients (82.3%) were diagnosed with epilepsy. Seizures predominantly began at < 1 year old (72.8%); focal seizures predominated (86.9%); epileptic spasms occurred in 34.5% of patients, and refractory epilepsy was present in 55.1%. Neuropsychiatric disorders, cortical tubers and cerebellar tubers were significantly more frequent in the epilepsy group. Moreover, rhabdomyomas were significantly more frequent in the epilepsy group ( p = 0.044), while lymphangioleiomyomatosis was significantly less frequent in the epilepsy group ( p = 0.009). Other non-neurological findings did not differ significantly between the groups with and without epilepsy.
Conclusions The present study of TSC patients demonstrated the predominantly neurological involvement and significantly higher proportion of TSC-associated neuropsychiatric disorders in the epilepsy group. Higher proportions of cortical and cerebellar tubers may be a risk factor for epilepsy and neurodevelopmental disorders.
... and the mutation types included point mutations, frameshift mutations, large fragment deletions, and splicing site mutations, etc. The inactivating variants of the two genes cause hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and consequently result in hamartomas in multiorgans including brain, skin, heart, lungs, kidneys, and eyes (Peron et al., 2018;Roach, 2016). ...
... The mutational spectra of this study consisted of missense mutations, nonsense mutations, frameshift mutations, and splice-site variants, these represented the largest number of variants in TSC patients (Salussolia et al., 2019). The inheritances included 11 de-novo variants (78.57%), one paternal variant (7.14%), and two maternal variants (14.29%), consistent with the previously reported inheritance characteristics of TSC (i.e., 67%-75% of patients have spontaneous mutations and the rest inherit the mutation from their parents in an autosomal dominant manner) (Ehninger, 2013;Roach, 2016). Although the most common variants of the patients are de novo in nature, parents are likely to have another TSC child because of the possible mosaic or intronic germ line mutations (Rose et al., 1999;Verhoef et al., 1999). ...
Background:
Noninvasive prenatal diagnosis (NIPD) based on cell-free DNA (cfDNA) has been introduced into the clinical application for some monogenic disorders but not for tuberous sclerosis (TSC) yet, which is an autosomal dominant disease caused by various variations in TSC1 or TSC2 gene. We aimed to explore the feasibility of NIPD on TSC.
Methods:
We recruited singleton pregnancies at risk of TSC from 14 families with a proband child. Definitive NIPD for TSC was performed using targeted next-generation sequencing of cfDNA in parallel with maternal white blood cell DNA (wbcDNA). The NIPD results were validated by amniocentesis or postnatal gene testing and follow-up of the born children.
Results:
Missense mutations, nonsense mutations, frameshift mutations, and splice-site variants which were obtained through de-novo, maternal, or paternal inheritance were included. The mean and minimum gestational weeks of NIPD were 17.18 ± 5.83 and 8 weeks, respectively. The NIPD results were 100% consistent with the amniocentesis or postnatal gene testing and follow-up of the born children.
Conclusion:
This study demonstrates that NIPD based on cfDNA is feasible for TSC, but required to be confirmed with more samples. Studies on TSC can contribute to the application and promotion of NIPD for monogenic disorders.
... Tuberous Sclerosis Complex (TSC) is an autosomal dominant multisystem disorder with an estimated incidence of 1:6000-10,000 live births and a prevalence of 1:20,000 in the general population [1,2]. ...
Epilepsy surgery is recommended in selected patients with Tuberous Sclerosis Complex (TSC). However, reports on predictive factors of seizure outcome are variable.
Here we report on seizure and cognitive outcome of 35 TSC patients who received surgery for refractory epilepsy in 7 Italian centers over a period of 22 years (1997–2019). The rate of seizure-free individuals at last follow-up (mean 7.5 years, range 1–21 years) was 51%. Patients with longer follow-up (≥10 years) had a lower rate of Engel I outcome (11.1%) than those who received surgery in the last 10 years (65.4%, p = 0.003). Factors associated with Engel II, III, IV outcome in our cohort included: high number of cortical tubers (≥5); presence of subependymal nodules (SENs); seizure onset before age 1 year; and multifocal interictal epileptic discharges (IEDs) on electroencephalogram (EEG). A subset of patients evaluated with Vineland Adaptive Behaviour Scales (VABS) showed developmental gains, in line with their developmental trajectories, but no improvement in standard scores after surgery was noted. Our study demonstrates that the rates of successful seizure outcome of epilepsy surgery in TSC have improved in the last 10 years. More than half of the patients achieved seizure freedom, and a high proportion of affected individuals experienced a reduction in seizure burden and in antiseizure medications. A comprehensive assessment after surgery should be performed in TSC patients to evaluate the overall neurodevelopmental outcome, as measures that are based only on seizure control do not adequately identify the benefits of surgery on global functioning in these patients.
... Tuberous sclerosis complex (TSC) is an autosomal dominant disease with an incidence of 1:6,000 to 1:10,000 live births that affects many organs, including skin, brain, lungs, kidneys and heart [1]. TSC is caused by mutations in either TSC complex subunit 1 (TSC1) or subunit 2 (TSC2) [2,3]. Alternatively known as hamartin and tuberin, respectively, both proteins are widely expressed throughout normal tissues and are involved in the mammalian target of rapamycin (mTOR) pathway. ...
Objective
We describe the clinical and genetic features, drug use and neuropsychiatric disorders of infants diagnosed with tuberous sclerosis complex (TSC) within 3 months of age at a neonatal intensive care unit (NICU) to better understand the different outcomes from early screening.
Methods
In this retrospective study, we consisted of 42 infants with a definitive TSC diagnosis by genetic criteria (TSC1 = 8, TSC2 = 34). The different phenotypes and outcomes between patients with TSC1 and TSC2 mutations were analyzed.
Results
The most common initial presenting features of TSC were cortical tubers on magnetic resonance imaging (50%), hypomelanotic macules on skin (47.61%) and spasm (42.85%), when they were diagnosed. Following disease progression to time of follow-up 1 year later, we found that the rate of epilepsy increased from 42.85% to 75.61% and that of cardiac rhabdomyoma increased from 28.57% to 43.9%. The median age at first presentation was 7.84 ± 1.88 months. We also found that 54.83% of patients on medication were seizure free for over 1 year, and that 43.9% of patients have intellectual disability. In total, 42 variants of TSC were detected, including 12 novel variants. We found no evidence of an association between different clinical features and their outcomes among patients with different gene mutations.
Conclusion
Early diagnosis of TSC in NICU opens a window of opportunity for early, more effective treatment of epilepsy as well as reduces the risk of neurological conditions.
