Tuberous Sclerosis Research Articles

Kidney transplantation in patients with tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a disorder of the mammalian target of the rapamycin (mTOR) pathway associated with the development of multisystem tumors, including renal angiomyolipoma (AML). These renal tumors are benign by nature but locally invasive and carry a risk for the progression of chronic kidney disease (CKD) to end stage kidney disease (ESKD). The frequency of subsequent renal transplantation in this population is largely uncharacterized, although single-center data suggests that 5%-15% of adult TSC patients are kidney transplant recipients. This retrospective cohort study utilized United Network for Organ Sharing (UNOS) data. We included candidates waitlisted between 1987 and 2020 for a first kidney transplant with TSC-associated kidney failure. We utilized descriptive statistics to characterize the frequency of first-time kidney transplant waitlisting and transplantation among persons with TSC and the Fine-Gray subdistribution hazard model to evaluate characteristics associated with progression from waitlist. We identified 200 TSC-associated kidney failure patients within the waitlist cohort. Of these, 12 were pediatric patients. Two-thirds (N = 134) of waitlisted persons were female. One hundred forty patients received a transplant with a median waitlist time of 2 years. Younger age at waitlisting was associated with a greater probability of progressing to transplant (HR 0.98 [95% CI: 0.96-0.99]). 91.8% of kidney transplant recipients survived 1-year post-transplant with a functioning allograft. The majority of patients with TSC who are waitlisted for a kidney transplant progress onto transplantation with excellent 1-year post transplant patient and allograft survival.

Diagnosis of tuberous sclerosis in the prenatal period: a retrospective study of 240 cases and review of the literature.

Tuberous sclerosis complex (TSC) is a rare multisystemic disorder caused by a pathogenic variant in the TSC1 or TSC2 gene. A great phenotypic variability characterises TSC. The condition predisposes to the formation of hamartomas in various tissues, neurologic and neurodevelopmental disorders such as epilepsy, psychiatric disorders, as well as intellectual disability in 50%. TSC may be responsible for cardiac rhabdomyomas (CRs), cortical tubers, or subependymal nodules during foetal life. Detecting multiple CRs is associated with a very high risk of TSC, but the CR could be single and isolated. Few data exist to estimate the risk of TSC in these cases. We report the largest series of prenatal genetic tests for TSC with a retrospective study of 240 foetuses presenting with suggestive antenatal signs. We also provide a review of the literature to specify the probability of clinical or genetic diagnosis of TSC in case of detection of single or multiple CRs. Indeed, an early diagnosis is crucial for the counselling of the couple and their families. In this series, a definite diagnosis was assessed in 50% (41/82) of foetuses who initially presented with a single CR and 80.3% (127/158) in cases of multiple CRs. The prevalence of parental germinal mosaicism was 2.6% (3/115).

Exposome on skeletal muscle system: a mini-review.

Exposomics is an ever-expanding field which captures the cumulative exposures to chemical, biological, physical, lifestyle, and social factors associated with biological responses. Since skeletal muscle is currently considered as the largest secretory organ and shows substantial plasticity over the life course, this reviews addresses the topic of exposome and skeletal muscle by reviewing the state-of-the-art evidence and the most intriguing perspectives. Muscle stem cells react to stressors via phosphorylated eukaryotic initiation factor 2α and tuberous sclerosis 1, and are sensible to hormetic factors via sirtuin 1. Microplastics can delay muscle regeneration via p38 mitogen-activated protein kinases and induce transdifferentiation to adipocytes via nuclear factor kappa B. Acrolein can inhibit myogenic differentiation and disrupt redox system. Heavy metals have been associated with reduced muscle strength in children. The deep study of pollutants and biological features can shed new light on neuromuscular pathophysiology. The analysis of a time-varying and dynamic exposome risk score from a panel of exposure and phenotypes of interest is promising. The systematization of hormetic factors and the role of the microbiota in modulating the effects of exposure on skeletal muscle responses are also promising. The comprehensive exposure assessment and its interactions with endogenous processes and the resulting biological effects deserve more efforts in the field of muscle health across the lifespan.

Malignant tumors in tuberous sclerosis complex: a case report and review of the literature

BackgroundTuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disease that arises from TSC1 or TSC2 genetic mutations. These genetic mutations can induce the development of benign tumors in any organ system with significant clinical implications in morbidity and mortality. In rare instances, patients with TSC can have malignant tumors, including renal cell carcinoma (RCC) and pancreatic neuroendocrine tumor (PNET). It is considered a hereditary renal cancer syndrome despite the low incidence of RCC in TSC patients. TSC is typically diagnosed in prenatal and pediatric patients and frequently associated with neurocognitive disorders and seizures, which are often experienced early in life. However, penetrance and expressivity of TSC mutations are highly variable. Herein, we present a case report, with associated literature, to highlight that there exist undiagnosed adult patients with less penetrant features, whose clinical presentation may contain non-classical signs and symptoms, who have pathogenic TSC mutations.Case presentationA 31-year-old female with past medical history of leiomyomas status post myomectomy presented to the emergency department for a hemorrhagic adnexal cyst. Imaging incidentally identified a renal mass suspicious for RCC. Out of concern for hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome, the mass was surgically removed and confirmed as RCC. Discussion with medical genetics ascertained a family history of kidney cancer and nephrectomy procedures and a patient history of ungual fibromas on the toes. Genetic testing for hereditary kidney cancer revealed a 5’UTR deletion in the TSC1 gene, leading to a diagnosis of TSC. Following the diagnosis, dermatology found benign skin findings consistent with TSC. About six months after the incidental finding of RCC, a PNET in the pancreatic body/tail was incidentally found on chest CT imaging, which was removed and determined to be a well-differentiated PNET. Later, a brain MRI revealed two small cortical tubers, one in each frontal lobe, that were asymptomatic; the patient’s history and family history did not contain seizures or learning delays. The patient presently shows no evidence of recurrence or metastatic disease, and no additional malignant tumors have been identified.ConclusionsTo our knowledge, this is the first report in the literature of a TSC patient without a history of neurocognitive disorders with RCC and PNET, both independently rare occurrences in TSC. The patient had a strong family history of renal disease, including RCC, and had several other clinical manifestations of TSC, including skin and brain findings. The incidental finding and surgical removal of RCC prompted the genetic evaluation and diagnosis of TSC, leading to a comparably late diagnosis for this patient. Reporting the broad spectrum of disease for TSC, including more malignant phenotypes such as the one seen in our patient, can help healthcare providers better identify patients who need genetic evaluation and additional medical care.

Sturge Weber syndrome: journey of 10 years

Sturge-Weber syndrome is the third most prevalent neurocutaneous condition after neurofibromatosis and tuberous sclerosis. It is characterized by alterations in the brain, skin, and eyes vasculature, caused by abnormal fetal vein growth. Symptoms include port wine nevi on the upper face and eye-lid than rest of the body. Neurological manifestations include atonic, tonic or myoclonic type of seizures which are refractory to usual treatment. Authors present case of a 9-year-old female suffering from seizures since many years without any definitive diagnosis, to increase awareness among pediatricians for early diagnosis and better management for this syndrome.

Tuberous sclerosis complex combined with primary lymphedema: A case report

Tuberous sclerosis complex combined with primary lymphedema: A case report

Population-based study of rare epilepsy incidence in a US urban population.

This study was undertaken to estimate incidence of rare epilepsies and compare with literature. We used electronic health record text search to identify children with 28 rare epilepsies in New York City (2010-2014). We estimated cumulative incidence and compared with literature. Eight of 28 rare epilepsies had five or more prior estimates, and our measurements were within the published range for all. The most common were infantile epileptic spasms syndrome (1 in 2920 live births), Lennox-Gastaut syndrome (1 in 9690), and seizures associated with tuberous sclerosis complex (1 in 14 300). Fifteen of 28 had fewer than five prior estimates, and of these, we provided additional estimates for early infantile developmental and epileptic encephalopathy (1 in 32 700), epilepsy with myoclonic-atonic seizures (1 in 34 100), Sturge-Weber syndrome plus seizures/epilepsy (1 in 40 900), epilepsy in infancy with migrating focal seizures (1 in 54 500), Aicardi syndrome plus seizures/epilepsy (1 in 71 600), hypothalamic hamartoma with seizures (1 in 225 000), and Rasmussen syndrome (1 in 450 000). Five of 28 rare epilepsies had no prior estimates, and of these, we provided a new estimate for developmental/epileptic encephalopathy with spike-and-wave activation in sleep and/or continuous spikes and waves during sleep (1 in 34 100). Data were limited for the remaining 12 rare epilepsies, which were all genetic epilepsies, including PCDH19, CDKL5, Alpers disease, SCN8A, KCNQ2, SCN2A, GLUT1 deficiency, Phelan-McDermid syndrome, myoclonic epilepsy with ragged-red fibers, dup15q syndrome, ring chromosome 14, and ring chromosome 20. We estimated the incidence of rare epilepsies using population-based electronic health record data and literature review. More research is needed to better estimate the incidence of genetic epilepsies with nonspecific clinical features. Electronic health records may be a valuable data source for studying rare epilepsies and other rare diseases, particularly as genetic testing becomes more widely adopted.

Incidence and Characteristics of Cerebellar Atrophy/Volume Loss in Children with Confirmed Diagnosis Tuberous Sclerosis Complex

Objectives: The goal of our study was to determine the incidence of cerebellar atrophy, assess the imaging findings in the posterior fossa and determine the incidence of hippocampal sclerosis in a cohort of pediatric patients with confirmed tuberous sclerosis complex (TSC). Material and methods: MRI studies of 98 TSC pediatric patients (mean age 7.67 years) were evaluated for cerebellar atrophy, cerebral/cerebellar tubers, white matter lesions, subependymal nodules, subependymal giant cell astrocytomas, ventriculomegaly, and hippocampal sclerosis. Clinical charts were revisited for clinical symptoms suggesting cerebellar involvement, for seizures and treatment for seizures, behavioral disorders and autism. Results: Cerebral tubers were present in 97/98 cases. In total, 97/98 had subependymal nodules, 15/98 had SEGA, 8/98 had ventriculomegaly and 4/98 had hippocampal sclerosis. Cerebellar tubers were found in 8/98 patients (8.2%), whereas cerebellar atrophy was described in 38/98 cases (38.8%). In 37/38 patients, cerebellar volume loss was mild and diffuse, and only one case presented with left hemi-atrophy. Briefly, 32/38 presented with seizures and were treated with anti-seizure drugs. In total, 8/38 (21%) presented with behavioral disorders, 10/38 had autism and 2/38 presented with seizures and behavioral disorders and autism. Conclusions: Several studies have demonstrated cerebellar involvement in patients with TSC. Cerebellar tubers differ in shape compared with cerebral tubers and are associated with cerebellar volume loss. Cerebellar atrophy may be focal and diffuse and one of the primary cerebellar manifestations of TSC, especially if a TSC2 mutation is present. Cerebellar degeneration may, however, also be secondary/acquired due to cellular damage resulting from seizure activity, the effects of anti-seizure drugs and anoxic–ischemic injury from severe seizure activity/status epilepticus. Further, prospective studies are required to identify and establish the pathogenic mechanism of cerebellar atrophy in patients with TSC.

Multiple recurrent supraventricular tachycardia in infantile tuberous sclerosis complex: management requiring triple-drug therapy.

We report the case of a female neonate admitted to the neonatal ICU with a rapid, narrow-complex tachyarrhythmia determined to be supraventricular tachycardia. Multimodality imaging and genetic testing confirmed a diagnosis of tuberous sclerosis complex with multiple cardiac rhabdomyomas. At 13 days of age, the patient was readmitted, exhibiting recurrent supraventricular tachycardia non-responsive to first-line treatment. Management required triple-drug therapy, whereafter the patient remained stable without recurrences. This is a rare report of supraventricular tachycardia in a functionally normal heart with the occurrence of supraventricular tachycardia due to structural abnormalities, with the possibility of multiple concealed accessory pathways.

#2242 mTORi: edging closer to targeted therapy in tuberous sclerosis complex

Abstract Background and Aims Tuberous sclerosis complex (TSC) is an autosomal dominant condition with an estimated incidence of 1 in 6000 births. TSC is caused mostly by mutations in either TSC1 or TSC2 genes, with 70–80% of cases resulting from sporadic mutations; however in 10-15% of cases no mutations are identified. A dysregulation of these genes that encode the hamartin and tuberin proteins, respectively, results in an aberrant signaling of the mammalian target of the rapamycin (mTOR) pathway and subsequent tumor growth. Indeed, the clinical features of TSC are characterized by the proliferation of different types of hamartomas in various organs, including brain, heart, skin, lungs, eyes, bone, kidneys and less frequently pancreas. TSC is mainly diagnosed clinically according to diagnostic criteria with genetic testing performed in cases of diagnostic uncertainty or/and to support the clinic diagnosis. Renal angiomyolipomas (AMLs), observed in more than 80% of patients with TSC, are benign, mostly bilateral tumors, composed of immature smooth muscle cells, abnormal blood vessels and fat cells in variable portions. Their size and the prevalence of their vascular component are directly associated with risk of acute bleeding that in 25% of cases may require embolization or nephrectomy. As a consequence, renal complications are the leading cause of death in adult TSC patients and AML-related surgery is performed in a high percentage of these patients. In the last decade, mTOR inhibitor (mTOR-i) therapy has demonstrated to be a potential alternative to embolization and nephrectomy for managing TSC-AML. The aim of this study was to evaluate over time, potential changes in the relative tissue composition of renal AMLs and their overall size following the initiation of mTOR-i therapy based on MRI measurements. Method From August 2011 to May 2023, 86 potentially eligible adult TSC patients with AML, across a great part of Italy were referred for assessment and monitoring at our center. 14 of these patients were eligible for mTOR-i therapy. An ethics committee approved its use as a compassionate therapy as mTOR-is are not approved as a conventional therapy for renal AMLs in Italy. These patients underwent baseline renal magnetic resonance imaging (MRI) assessment and a regular follow-up with MRI scan every 6-9 months after initiation of therapy. Dose titration was guided by trough levels, side effects and lesion radiological responsiveness on MRI. Results No AML bleeding events were documented during the study. None of the 14 patients on treatment discontinued therapy. Overall, 5 of them (35.7%) required dose adjustments during the course of treatment due to adverse events (40%), sub-optimal trough levels (40%) or minimal radiological response (20%). Radiologic assessment with MRI confirmed a halted growth trend in all treatment-naive cases (100%) and in 64% of them, a regression in AML volume and a reduction of their vascular component within the first year of treatment. Conclusion Our experience confirmed results that emerged from different clinical studies evaluating mTOR inhibition in TSC patients conducted in the last decade. For renal angiomyolipoma, mTOR-i treatment, carefully monitored, fundamentally changed the approach from preventive embolization or even partial nephrectomy to pharmacological treatment; drastically limiting the number of urgent interventional procedures that TSC patients often might undergo. In conclusion, mTOR-i therapy represents a valid and important therapeutic strategy to arrest the growth or regress of renal AMLs.

Vitamin D in tuberous sclerosis complex-associated tumors

Mammalian target of rapamycin inhibitors (mTORi) have been used to treat pediatric tuberous sclerosis complex (TSC)-associated tumors, particularly in cases with contraindications to surgery or difficulties in complete tumor resection. However, some patients experience side effects and tumor regression after discontinuation of the treatment. Therefore, there is an urgent need to develop drugs that can be used in combination with mTORi to increase their efficacy and minimize their side effects. 1,25-Dihydroxyvitamin D3 (1,25-D), which has anticancer properties, may be a promising candidate for adjuvant or alternative therapy because TSC and cancer cells share common mechanisms, including angiogenesis, cell growth, and proliferation. Vitamin D receptor-mediated signaling can be epigenetically modified and plays an important role in susceptibility to 1,25-D. Therefore, vitamin D signaling may be a promising drug target, and in vitro studies are required to evaluate the efficacy of 1,25-D in TSC-associated tumors, brain development, and core symptoms of psychiatric disorders.

#2259 Preimplantation genetic testing in inherited kidney diseases

Abstract Background and Aims Identifying the underlying genetic cause in individuals with monogenic kidney disease allow counselling to provide prognosis and therapeutic options. In addition, discussions may extend to assessing the risk of having affected children and exploring family planning alternatives. Pre-conception counselling covers a wide range of considerations, including the expected pregnancy outcome for both mother and child, the risk of recurrence, invasive prenatal diagnosis, and the option of pre-implantation genetic testing (PGT). In this study we provide a clinical overview of PGT for monogenic kidney disease in our centre. Methods This is a retrospective cohort study of individuals with monogenic kidney disease counselled on our fertility clinic for PGT, in the Fundació Puigvert—Hospital de Sant Pau, Barcelona-Spain from January 2016 to 2023. Results During the study period, 751 visits were made to the fertility clinic, of which 8.3% (63/751) had a monogenic inherited kidney disease (IKD). Regarding the baseline characteristics of individuals with monogenic conditions, most were females (70%; 44/63). The mean age of the women was 33 years, most had no history of pregnancy prior to the first visit (73%). The mean anti-Mullerian hormone (AMH) level was 2.67 ng/ml, with 22% having levels below 1.1 ng/ml. Most cases (84%; 53/63) showed an autosomal dominant pattern of inheritance, with autosomal dominant polycystic kidney disease (ADPKD) being the primary cause in 66% of cases (42/63), followed by tuberous sclerosis complex in 8% (5/63). Autosomal recessive and X-linked disorders were each present in 8% (5/63). Table 1 shows the complete list of genetic kidney disease cases that consulted the fertility clinic. In terms of renal function, affected women had a mean renal function measured by estimated glomerular filtration rate (eGFR) of 90 mil/min/1.73 m2, with 74% having chronic kidney disease (CKD) category G1. Affected male had mean eGFR of 65 mL/min/1.73 m2, with only 38% (6/19 patients) having CKD-G1. Two (13%; 2/19) of the affected men had received a kidney transplant. Of the 63 couples who were counseled, 51% (32/63) agreed to proceed with PGT; 81% (26/32) underwent at least one cycle of ovarian stimulation, in vitro fertilization, and PGT. Fifty per cent (13/26) had a live birth child and 19% (5/26) are currently pregnant. Six couples (10%; 6/32) have pending tests. Among patients who decided not to proceed with PGT (31/63), the main reason for not doing so was that they had a spontaneous pregnancy before the first PGT cycle (35%; 11/31). Low ovarian reserve and couple´s refusal to proceed with PGT were the second most common reasons, each accounting for 22.5% of cases. In 10% (3/31) of cases, the indication for PGT was not yet approved in Spain (mainly because these patients already had a healthy living child). Maternal age over 40 years and the age of the prospective father were the reasons for not performing PGT in 6% and 3% respectively. Of note, a patient with ADPKD presented with a ruptured hepatic cyst after ovarian hormone stimulation. Therefore, PGT was discontinued after two cycles. Conclusion Women with IKD are most likely to request PGT than affected males. The most frequent condition is, by far, ADPKD. Once the technique is explained less than 50% of couples keep wishing to undergo PGT. Low ovarian reserve (which correlates quite well with age) is an important reason that impedes to go through PGT. Larger international studies are needed to understand the patient's uptake of PGT for IKD as well as the access to this technique depending on the country.

#2862 Genetics and electron microscopy: complementary tools for management of focal segmental glomerulosclerosis?

Abstract Background and Aims Focal segmental glomerular sclerosis (FSGS) defines a histologic lesion that represents a pattern of injury associated to different pathologic conditions affecting both children and adults. It is classified into primary forms, presumably immune-mediated, secondary forms, determined by a maladaptive response to different conditions, genetic and undetermined forms. According to Mayo Clinic classification, primary and secondary forms can de differentiated using electron microscopy (EM), with a podocytes foot process effacement (FPE) ≥80% identifying primary forms. Better understanding the role of Genetics in FSGS and response to treatment in different forms is of vital importance in this rare and multifaceted condition. We analyzed a discrete cohort of patients with FSGS examined both with EM and genetic testing (GT). Main aims of our study were: 1) assessment of GT in primary and secondary forms; 2) analysis of response to therapy according to histologic and genetic classification. Method This is a retrospective observational study on patients that received a histological diagnosis of FSGS, including EM, and underwent NGS genetic testing from January 2020 to June 2023. Primary and secondary forms of FSGS were distinguished by degree of pedicle fusion at EM, according to Mayo Clinic classification. Clinical, laboratory, genetic data and used therapies were recorded. Complete response (CR) to therapy was defined as a reduction of proteinuria to 0.3 g/day, with normalization of albuminemia. Partial response (PR) was defined as halving proteinuria into a sub-nephrotic range and increasing albuminemia up to 3.5 g/dL. Absent response was defined as a persisting nephrotic range proteinuria. Results In the study period, 33 patients receiving a histologic diagnosis of FSGS with EM examination underwent NGS testing. Of these, 25 had available genetic results and were included. Ten patients (40%) were females, 15 (60%) were males; mean age was 40.8 years (SD ±14.5); 20 (80%) were Caucasian, 4 (16%) Black, 1 (4%) Asian. Based on EM, 11 (44%) were classified as primary forms, 14 (56%) as secondary forms. Twelve (48%) patients presented with nephrotic syndrome. Of these, 10 had a primary form. Seven (28%) had nephrotic-range proteinuria without hypoalbuminemia, 6 (24%) had subnephrotic range proteinuria. Six (54.5%) of the primary forms and 8 (57.1%) of the secondary forms had a positive genetic testing (p = 0.78). Among secondary forms, through GT, one diagnosis of Fabry disease and one of Tuberous Sclerosis were made in patients without clear systemic symptoms. Fabry disease was confirmed by presence of zebra bodies at EM. All primary forms received immunosuppressive therapies, all being rituximab-based regimens; all secondary forms received support therapy. Nine (81.1%) primary forms and 9 (64.3%) secondary forms had at least a PR to treatment (4 CR in primary group and 1 CR in secondary group) (p = 0.33). Among primary forms, 5 of 6 patients (83%) with a positive GT had at least a PR with a strong immunosuppressive therapy. In secondary forms group 4 of 8 patients (50%) had at least PR with offered support therapy. Fabry and Tuberous Sclerosis were offered specific treatments with benefit. Conclusion Percentage of positive GT did not differ in primary and secondary forms of FSGS as defined by Mayo Clinic classification. Thus a positive GT should not be considered a unique feature of secondary forms. GT was critical for an unexpected diagnosis of systemic hereditary diseases, thus enabling adequate target therapies. We believe GT should be offered to all patients with FSGS. In primary FSGS, defined according to EM, more than 80% of patients had at least a PR following immunosuppressive therapy, even in patients with positive GT. In conclusion, as clinical presentation and light microscopy are not sufficient for an accurate diagnosis, combining EM and GT is of utmost importance in proper classification and management of FSGS.

Rescue of impaired blood-brain barrier in tuberous sclerosis complex patient derived neurovascular unit

BackgroundTuberous sclerosis complex (TSC) is a multi-system genetic disease that causes benign tumors in the brain and other vital organs. The most debilitating symptoms result from involvement of the central nervous system and lead to a multitude of severe symptoms including seizures, intellectual disability, autism, and behavioral problems. TSC is caused by heterozygous mutations of either the TSC1 or TSC2 gene and dysregulation of mTOR kinase with its multifaceted downstream signaling alterations is central to disease pathogenesis. Although the neurological sequelae of the disease are well established, little is known about how these mutations might affect cellular components and the function of the blood–brain barrier (BBB).MethodsWe generated TSC disease-specific cell models of the BBB by leveraging human induced pluripotent stem cell and microfluidic cell culture technologies.ResultsUsing microphysiological systems, we demonstrate that a BBB generated from TSC2 heterozygous mutant cells shows increased permeability. This can be rescued by wild type astrocytes or by treatment with rapamycin, an mTOR kinase inhibitor.ConclusionOur results demonstrate the utility of microphysiological systems to study human neurological disorders and advance our knowledge of cell lineages contributing to TSC pathogenesis and informs future therapeutics.

Myocardial fatty foci on cardiac MRI in an adult with tuberous sclerosis complex.

We report cardiac MRI findings in a 38-year-old female Tuberous sclerosis complex (TSC) patient with regressed rhabdomyomas. Presence of myocardial fatty foci are associated with multiorgan involvement, although they are not a part of the current TSC diagnostic criteria. Presence of abnormal first pass perfusion and late Gadolinium enhancement in TSC patients should be carefully interpreted to avoid misdiagnosis.

Novel Stop-Gain TSC2 Gene Mutation in an Indian Child of Tuberous Sclerosis Complex

Novel Stop-Gain TSC2 Gene Mutation in an Indian Child of Tuberous Sclerosis Complex

Imaging of Phacomatosis: A Retrospective Study of 24 Patients

Our study delves into the radiological characteristics of phacomatoses, leveraging advanced imaging techniques like MRI and CT to differentiate and diagnose various neurocutaneous syndromes, including Sturge-Weber syndrome, neurofibromatosis types 1 and 2, tuberous sclerosis complex, and Von Hippel-Lindau disease. Conducted as a retrospective analysis at the CHU Mohammed VI's Mother and Child Hospital, our research spans over four years and eight months, examining imaging findings from 24 patients. We highlight specific radiological signatures that aid in the identification and management of these complex conditions. Our findings not only corroborate established radiological markers but also introduce new insights into the diverse manifestations of phacomatoses. This study emphasizes the critical role of imaging in enhancing diagnostic accuracy, informing therapeutic decisions, and monitoring disease progression, thereby contributing to improved patient outcomes in managing these genetic disorders.

Abnormality of Early White Matter Development in Tuberous Sclerosis Complex and Autism Spectrum Disorder: Longitudinal Analysis of Diffusion Tensor Imaging Measures.

Background: Abnormalities in white matter development may influence development of autism spectrum disorder in tuberous sclerosis complex (TSC). Our goals for this study were as follows: (1) use data from a longitudinal neuroimaging study of tuberous sclerosis complex (TACERN) to develop optimized linear mixed effects models for analyzing longitudinal, repeated diffusion tensor imaging metrics (fractional anisotropy, mean diffusivity) pertaining to select white matter tracts, in relation to positive Autism Diagnostic Observation Schedule-Second Edition classification at 36 months, and (2) perform an exploratory analysis using optimized models applied to all white matter tracts from these data. Methods: Eligible participants (3-12 months) underwent brain magnetic resonance imaging (MRI) at repeated time points from ages 3 to 36 months. Positive Autism Diagnostic Observation Schedule-Second Edition classification at 36 months was used. Linear mixed effects models were fine-tuned separately for fractional anisotropy values (using fractional anisotropy corpus callosum as test outcome) and mean diffusivity values (using mean diffusivity right posterior limb internal capsule as test outcome). Fixed effects included participant age, within-participant longitudinal age, and autism spectrum disorder diagnosis. Results: Analysis included data from n = 78. After selecting separate optimal models for fractional anisotropy and mean diffusivity values, we applied these models to fractional anisotropy and mean diffusivity of all 27 white matter tracts. Fractional anisotropy corpus callosum was related to positive Autism Diagnostic Observation Schedule-Second Edition classification (coefficient = 0.0093, P = .0612), and mean diffusivity right inferior cerebellar peduncle was related to positive Autism Diagnostic Observation Schedule-Second Edition classification (coefficient = -0.00002071, P = .0445), though these findings were not statistically significant after multiple comparisons correction. Conclusion: These optimized linear mixed effects models possibly implicate corpus callosum and cerebellar pathology in development of autism spectrum disorder in tuberous sclerosis complex, but future studies are needed to replicate these findings and explore contributors of heterogeneity in these models.

Prevalence of Liver Steatosis in Tuberous Sclerosis Complex Patients: A Retrospective Cross-Sectional Study.

Introduction: Tuberous sclerosis complex (TSC) is a genetic disease caused by pathogenetic variants in either the TSC1 or TSC2 genes. Consequently, the mechanistic target of the rapamycin complex 1 (mTORC1) pathway, a regulator of cell growth, metabolism, and survival, becomes inappropriately activated, leading to the development of benign tumors in multiple organs. The role of mTORC1 in lipid metabolism and liver steatosis in TSC patients has not been well-studied, and clinical data on liver involvement in this population are scarce. Methods: We conducted a retrospective, cross-sectional study to compare liver steatosis in TSC patients with age-, sex-, BMI-, and diabetes status-matched controls. Participants with a definite diagnosis of TSC were recruited from the TSC clinic at UZ Brussel. Liver steatosis was quantified using the fat signal fraction from in-phase and out-of-phase MRI, with a threshold of ≥5% defining the presence of steatosis. We also evaluated the prevalence of liver angiomyolipomata in the TSC group and analyzed risk factors for both liver steatosis and angiomyolipomata. Results: The study included 59 TSC patients and 59 matched controls. The mean fat signal fraction was 4.0% in the TSC group and 3.9% in the controls, showing no significant difference (two-tailed Wilcoxon signed ranks test, p = 0.950). Liver steatosis was observed in 15.3% of TSC patients compared to 23.7% of the controls, which was not statistically significant (two-tailed McNemar test, p = 0.267). Liver angiomyolipomata were identified in 13.6% of the TSC cohort. Conclusions: Our study, describing in detail the liver phenotype of TSC patients, did not reveal a significant difference in the prevalence of MRI-assessed liver steatosis in a large cohort of TSC patients compared to a closely matched control group.

Introduction: A Practical Guide to Central Nervous System Malformations—From Genetics, to Diagnosis and Treatment

AbstractCentral nervous system (CNS) malformations encompass diverse congenital anomalies impacting brain and spinal cord development, profoundly affecting neurological function. They arise from disruptions in embryonic neural tube formation, neuronal migration, and cortical organization. This abstract provides a comprehensive overview of CNS malformations, covering classification, etiology, clinical manifestations, and diagnostic challenges. CNS malformations fall into distinct groups: neural tube defects (e.g., anencephaly, spina bifida), resulting from incomplete neural tube closure; malformations of cortical development (e.g., lissencephaly, polymicrogyria), featuring irregularities in cortical folding; and anomalies affecting structures like the corpus callosum, cerebellum, and CNS vasculature, alongside conditions such as hydrocephalus and Chiari malformations. Genetic factors, including mutations in LIS1, DCX, and RELN, contribute significantly, while environmental factors like maternal folic acid deficiency also play a role. Some malformations occur in genetic syndromes (e.g., tuberous sclerosis, neurofibromatosis). Clinical presentations vary, with neural tube defects typically presenting severe deficits at birth, while cortical malformations manifest as intellectual disabilities, seizures, and motor deficits. Hydrocephalus elevates intracranial pressure, and Chiari malformations cause headaches and neurological symptoms. Diagnosis necessitates a multidisciplinary approach involving clinical evaluation, neuroimaging, genetic testing, and histopathological analysis. Prenatal diagnosis via ultrasound and magnetic resonance imaging is crucial for planning interventions, while postnatal diagnosis relies on clinical and imaging findings.Understanding CNS malformations is vital for early detection, intervention, and comprehensive care provision. Advances in genetics and neuroimaging offer hope for improved outcomes and better quality of life for affected individuals.