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Darcy A Krueger - One of the best experts on this subject based on the ideXlab platform.
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improvement in renal cystic disease of Tuberous Sclerosis complex after treatment with mammalian target of rapamycin inhibitor
The Journal of Pediatrics, 2017Co-Authors: Brian J Siroky, Alexander J Towbin, Andrew T Trout, Hannah Schafer, Anna R Thamann, Karen Agricola, Cynthia Tudor, Jamie K Capal, Bradley P Dixon, Darcy A KruegerAbstract:Renal cysts occur in approximately 50% of patients with Tuberous Sclerosis complex, but their clinical significance and response to treatment are unknown. Abdominal imaging of 15 patients with Tuberous Sclerosis complex-associated renal cystic disease who had received mammalian target of rapamycin inhibitor therapy for other Tuberous Sclerosis complex-related indications was evaluated. Reductions in cyst number, sum diameter, and volume were observed.
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Tuberous Sclerosis complex diagnostic criteria update recommendations of the 2012 international Tuberous Sclerosis complex consensus conference
Pediatric Neurology, 2013Co-Authors: Hope Northrup, Darcy A KruegerAbstract:BACKGROUND: Tuberous Sclerosis complex is highly variable in clinical presentation and findings. Disease manifestations continue to develop over the lifetime of an affected individual. Accurate diagnosis is fundamental to implementation of appropriate medical surveillance and treatment. Although significant advances have been made in the past 15 years in the understanding and treatment of Tuberous Sclerosis complex, current clinical diagnostic criteria have not been critically evaluated or updated since the last clinical consensus conference in 1998. METHODS: The 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 subcommittees, each led by a clinician with advanced expertise in Tuberous Sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important diagnostic implications and was charged with reviewing prevalence and specificity of diseaseassociated clinical findings and their impact on suspecting and confirming the diagnosis of Tuberous Sclerosis complex. RESULTS: Clinical features of Tuberous Sclerosis complex continue to be a principal means of diagnosis. Key changes compared with 1998 criteria are the new inclusion of genetic testing results and reducing diagnostic classes from three (possible, probable, and definite) to two (possible, definite). Additional minor changes to specific criterion were made for additional clarification and simplification. CONCLUSIONS: The 2012 International Tuberous Sclerosis Complex Diagnostic Criteria provide current, updated means using best available evidence to establish diagnosis of Tuberous Sclerosis complex in affected individuals.
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Tuberous Sclerosis complex surveillance and management recommendations of the 2012 international Tuberous Sclerosis complex consensus conference
Pediatric Neurology, 2013Co-Authors: Darcy A Krueger, Hope NorthrupAbstract:BACKGROUND: Tuberous Sclerosis complex is a genetic disorder affecting every organ system, but disease manifestations vary significantly among affected individuals. The diverse and varied presentations and progression can be life-threateningwithsignificantimpactoncostandqualityoflife.Currentsurveillanceandmanagementpracticesare highly variable among region and country, reflective of the fact that last consensus recommendations occurred in 1998 and an updated, comprehensive standard is lacking that incorporates the latest scientific evidence and current best clinical practices. METHODS: The 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 separate subcommittees, each led by a clinician with advanced expertise in Tuberous Sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important clinical management implications and was charged with formulating key clinical questions to address within its focus area, reviewing relevant literature, evaluating the strength of data, and providing a recommendation accordingly. RESULTS: The updated consensus recommendations for clinical surveillance and management in Tuberous Sclerosis complex are summarized here. The recommendations are relevant to the entire lifespan of the patient, from infancy to adulthood, including both individuals where the diagnosis is newly made as well as individuals where the diagnosis already is established. CONCLUSIONS: The 2012 International Tuberous Sclerosis Complex Consensus Recommendations provide an evidence-based, standardized approach for optimal clinical care provided for individuals with Tuberous Sclerosis complex.
Hope Northrup - One of the best experts on this subject based on the ideXlab platform.
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Tuberous Sclerosis complex surveillance and management recommendations of the 2012 international Tuberous Sclerosis complex consensus conference
Pediatric Neurology, 2013Co-Authors: Darcy A Krueger, Hope NorthrupAbstract:BACKGROUND: Tuberous Sclerosis complex is a genetic disorder affecting every organ system, but disease manifestations vary significantly among affected individuals. The diverse and varied presentations and progression can be life-threateningwithsignificantimpactoncostandqualityoflife.Currentsurveillanceandmanagementpracticesare highly variable among region and country, reflective of the fact that last consensus recommendations occurred in 1998 and an updated, comprehensive standard is lacking that incorporates the latest scientific evidence and current best clinical practices. METHODS: The 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 separate subcommittees, each led by a clinician with advanced expertise in Tuberous Sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important clinical management implications and was charged with formulating key clinical questions to address within its focus area, reviewing relevant literature, evaluating the strength of data, and providing a recommendation accordingly. RESULTS: The updated consensus recommendations for clinical surveillance and management in Tuberous Sclerosis complex are summarized here. The recommendations are relevant to the entire lifespan of the patient, from infancy to adulthood, including both individuals where the diagnosis is newly made as well as individuals where the diagnosis already is established. CONCLUSIONS: The 2012 International Tuberous Sclerosis Complex Consensus Recommendations provide an evidence-based, standardized approach for optimal clinical care provided for individuals with Tuberous Sclerosis complex.
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Tuberous Sclerosis complex diagnostic criteria update recommendations of the 2012 international Tuberous Sclerosis complex consensus conference
Pediatric Neurology, 2013Co-Authors: Hope Northrup, Darcy A KruegerAbstract:BACKGROUND: Tuberous Sclerosis complex is highly variable in clinical presentation and findings. Disease manifestations continue to develop over the lifetime of an affected individual. Accurate diagnosis is fundamental to implementation of appropriate medical surveillance and treatment. Although significant advances have been made in the past 15 years in the understanding and treatment of Tuberous Sclerosis complex, current clinical diagnostic criteria have not been critically evaluated or updated since the last clinical consensus conference in 1998. METHODS: The 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 subcommittees, each led by a clinician with advanced expertise in Tuberous Sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important diagnostic implications and was charged with reviewing prevalence and specificity of diseaseassociated clinical findings and their impact on suspecting and confirming the diagnosis of Tuberous Sclerosis complex. RESULTS: Clinical features of Tuberous Sclerosis complex continue to be a principal means of diagnosis. Key changes compared with 1998 criteria are the new inclusion of genetic testing results and reducing diagnostic classes from three (possible, probable, and definite) to two (possible, definite). Additional minor changes to specific criterion were made for additional clarification and simplification. CONCLUSIONS: The 2012 International Tuberous Sclerosis Complex Diagnostic Criteria provide current, updated means using best available evidence to establish diagnosis of Tuberous Sclerosis complex in affected individuals.
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Tuberous Sclerosis complex consensus conference revised clinical diagnostic criteria
Journal of Child Neurology, 1998Co-Authors: E S Roach, Manuel Gomez, Hope NorthrupAbstract:At the recent Tuberous Sclerosis complex consensus conference, the clinical diagnostic criteria for Tuberous Sclerosis complex were simplified and revised to reflect both new clinical information about Tuberous Sclerosis complex and an improved understanding of the disorder derived from molecular genetic studies. Based on this new information, some clinical signs once regarded as pathognomonic for Tuberous Sclerosis complex are now known to be less specific. No single sign is present in all affected patients, and there is no proof that any single clinical or radiographic sign is absolutely specific for Tuberous Sclerosis complex. Accordingly, the clinical and radiographic features of Tuberous Sclerosis complex have now been divided into major and minor categories based on the apparent degree of specificity for Tuberous Sclerosis complex of each feature. A definitive diagnosis of Tuberous Sclerosis complex now requires two or more distinct types of lesions, rather than multiple lesions of the same type in ...
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Tuberous Sclerosis complex consensus conference revised clinical diagnostic criteria
Journal of Child Neurology, 1998Co-Authors: E S Roach, Manuel Gomez, Hope NorthrupAbstract:At the recent Tuberous Sclerosis complex consensus conference, the clinical diagnostic criteria for Tuberous Sclerosis complex were simplified and revised to reflect both new clinical information about Tuberous Sclerosis complex and an improved understanding of the disorder derived from molecular genetic studies. Based on this new information, some clinical signs once regarded as pathognomonic for Tuberous Sclerosis complex are now known to be less specific. No single sign is present in all affected patients, and there is no proof that any single clinical or radiographic sign is absolutely specific for Tuberous Sclerosis complex. Accordingly, the clinical and radiographic features of Tuberous Sclerosis complex have now been divided into major and minor categories based on the apparent degree of specificity for Tuberous Sclerosis complex of each feature. A definitive diagnosis of Tuberous Sclerosis complex now requires two or more distinct types of lesions, rather than multiple lesions of the same type in the same organ system. Although diagnosis on purely clinical grounds can continue to be difficult in a few patients, there should be little doubt about the diagnosis for those individuals who fulfill these strict criteria. Couples with more than one child with Tuberous Sclerosis complex, no extended family history, and no clinical features of Tuberous Sclerosis complex are more likely to have germline mosaicism for Tuberous Sclerosis than nonexpression of the mutation. Germline mosaicism, while fortunately rare, will not be suspected from either diagnostic criteria or molecular testing until a couple has multiple affected children. Genetic counseling for families with one affected child should include a small (1% to 2%) possibility of recurrence, even for parents who have no evidence of Tuberous Sclerosis complex after a thorough diagnostic evaluation.
Steve E Roach - One of the best experts on this subject based on the ideXlab platform.
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subependymal giant cell astrocytoma diagnosis screening and treatment recommendations from the international Tuberous Sclerosis complex consensus conference 2012
Pediatric Neurology, 2013Co-Authors: Jonathan Roth, David Neal Franz, Steve E Roach, Mary Kay Koenig, Sergiusz Joźwiak, Ute Bartels, Howard L Weiner, Henry Z WangAbstract:BACKGROUND: Tuberous Sclerosis complex is an autosomal dominant disorder predisposing to the development of benign lesions in different body organs, mainly in the brain, kidney, liver, skin, heart, and lung. Subependymal giant cell astrocytomas are characteristic brain tumors that occur in 10% to 20% of Tuberous Sclerosis complex patients and are almost exclusively related to Tuberous Sclerosis complex. Subependymal giant cell astrocytomas usually grow slowly, but their progression ultimately leads to the occlusion of the foramen of Monro, with subsequent increased intracranial pressure and hydrocephalus, thus necessitating intervention. During recent years, secondary to improved understanding in the biological and genetic basis of Tuberous Sclerosis complex, mammalian target of rapamycin inhibitors have been shown to be effective in the treatment of subependymal giant cell astrocytomas, becoming an alternative therapeutic option to surgery. METHODS: In June 2012, an International Tuberous Sclerosis Complex Consensus Conference was convened, during which an expert panel revised the diagnostic criteria and considered treatment options for subependymal giant cell astrocytomas. This article summarizes the subpanel’s recommendations regarding subependymal giant cell astrocytomas. CONCLUSIONS: Mammalian target of rapamycin inhibitors have been shown to be an effective treatment of various aspects of Tuberous Sclerosis complex, including subependymalgiantcellastrocytomas.Bothmammaliantargetofrapamycininhibitorsandsurgeryhavearoleinthe
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diagnosis of Tuberous Sclerosis complex
Journal of Child Neurology, 2004Co-Authors: Steve E Roach, Steven SparaganaAbstract:Tuberous Sclerosis complex is a dominantly inherited disorder affecting multiple organs; because of its phenotypic variability, the diagnosis of Tuberous Sclerosis complex can be difficult in the young or in individuals with subtle findings. Recently revised consensus diagnostic criteria for Tuberous Sclerosis complex reflect an improved understanding of its clinical manifestations and its genetic and molecular mechanisms. The diagnostic criteria are based on the premise that there are probably no truly pathognomonic clinical signs for Tuberous Sclerosis complex; signs that were once regarded as specific occur as isolated findings in individuals with no other clinical or genetic evidence of Tuberous Sclerosis complex. Consequently, the revised criteria require Tuberous Sclerosis complex-associated lesions of two or more organ systems or at least two dissimilar lesions of the same organ to confirm the diagnosis. The addition of DNA testing complements clinical diagnosis and allows more precise genetic counseling and, in some individuals, prenatal diagnosis. Nevertheless, the 15% false-negative rate for DNA testing and the occurrence of germline mosaicism in about 2% of individuals with Tuberous Sclerosis complex make it difficult to exclude the diagnosis of Tuberous Sclerosis complex in family members.
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renal lesion growth in children with Tuberous Sclerosis complex
The Journal of Urology, 1998Co-Authors: David H Ewalt, Steven Sparagana, Eugene Sheffield, Mauricio R Delgado, Steve E RoachAbstract:AbstractPurpose: Renal lesions, including angiomyolipoma, renal cysts (simple and polycystic kidney disease) and renal cell carcinoma, develop in patients with Tuberous Sclerosis complex. While the...
Sergiusz Joźwiak - One of the best experts on this subject based on the ideXlab platform.
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subependymal giant cell astrocytoma diagnosis screening and treatment recommendations from the international Tuberous Sclerosis complex consensus conference 2012
Pediatric Neurology, 2013Co-Authors: Jonathan Roth, David Neal Franz, Steve E Roach, Mary Kay Koenig, Sergiusz Joźwiak, Ute Bartels, Howard L Weiner, Henry Z WangAbstract:BACKGROUND: Tuberous Sclerosis complex is an autosomal dominant disorder predisposing to the development of benign lesions in different body organs, mainly in the brain, kidney, liver, skin, heart, and lung. Subependymal giant cell astrocytomas are characteristic brain tumors that occur in 10% to 20% of Tuberous Sclerosis complex patients and are almost exclusively related to Tuberous Sclerosis complex. Subependymal giant cell astrocytomas usually grow slowly, but their progression ultimately leads to the occlusion of the foramen of Monro, with subsequent increased intracranial pressure and hydrocephalus, thus necessitating intervention. During recent years, secondary to improved understanding in the biological and genetic basis of Tuberous Sclerosis complex, mammalian target of rapamycin inhibitors have been shown to be effective in the treatment of subependymal giant cell astrocytomas, becoming an alternative therapeutic option to surgery. METHODS: In June 2012, an International Tuberous Sclerosis Complex Consensus Conference was convened, during which an expert panel revised the diagnostic criteria and considered treatment options for subependymal giant cell astrocytomas. This article summarizes the subpanel’s recommendations regarding subependymal giant cell astrocytomas. CONCLUSIONS: Mammalian target of rapamycin inhibitors have been shown to be an effective treatment of various aspects of Tuberous Sclerosis complex, including subependymalgiantcellastrocytomas.Bothmammaliantargetofrapamycininhibitorsandsurgeryhavearoleinthe
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Tuberous Sclerosis complex advances in diagnosis genetics and management
Journal of The American Academy of Dermatology, 2007Co-Authors: Robert A Schwartz, Katarzyna Kotulska, Geover Fernandez, Sergiusz JoźwiakAbstract:Tuberous Sclerosis complex (TSC) is an autosomal dominant multisystem neurocutaneous syndrome characterized by the development of multiple hamartomas distributed throughout the body, skin, brain, heart, kidneys, liver, and lungs. Two-thirds of patients represent sporadic mutations. The classic triad is seizures, mental retardation, and cutaneous angiofibromas. However, the full triad occurs in only 29% of patients; 6% of them lack all three of them. Two tumor suppressor genes responsible for TSC have been identified: TSC1 gene on chromosome 9 and TSC2 on chromosome 16. This article highlights the most recent significant advances in the diagnosis and genetics of TSC, along with a discussion on the limitations and the usefulness of the revised 1998 clinical criteria for the Tuberous Sclerosis complex. The "ash leaf" macule often comes in other shapes, such as round; most are polygonal, usually 0.5 cm to 2.0 cm in diameter, resembling a thumbprint. Since the death of its describer, Thomas Fitzpatrick, we call each a "Fitzpatrick patch." Special attention is paid in this work to TSC treatment options, including therapeutic trials with rapamycin, also known as sirolimus. Learning objective After completing this learning activity, participants should familiar with Tuberous Sclerosis complex, its cutaneous signs and systemic findings stratified by patient age, its genetics, and the potential for meaningful therapeutic intervention.
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clinical and genotype studies of cardiac tumors in 154 patients with Tuberous Sclerosis complex
Pediatrics, 2006Co-Authors: Sergiusz Joźwiak, Katarzyna Kotulska, Dorota Domanskapakiela, Jolanta Kasprzykobara, Malgorzata Tomyndrabik, Penelope S Roberts, David J KwiatkowskiAbstract:OBJECTIVE. Tuberous Sclerosis complex is an autosomal dominant disorder in which hamartomas occur in several organs. Cardiac rhabdomyomas, the most common heart tumors of childhood, are well known to be associated with Tuberous Sclerosis complex. Our aim for this study was to characterize the incidence, progression, and clinical consequences of Tuberous Sclerosis complex–associated rhabdomyomas in a large cohort of patients with TSC1 and TSC2 genotypes. PATIENTS AND METHODS. Patients (154) with Tuberous Sclerosis complex were evaluated, including clinical assessment, electrocardiography, and echocardiography. Mutations in TSC1 or TSC2 genes were identified in 127 patients. RESULTS. Cardiac rhabdomyomas were found in 74 (48%) patients. Tumors were most frequent in children younger than 2 years (65%). Tumor regression or disappearance was observed in 37 (68%) of 55 children. However, in 6 (3.9%) of them (aged 10-15 years), cardiac rhabdomyomas were noted to either grow (3 cases) or appear de novo (3 cases), such that the frequency of cardiac rhabdomyomas in adolescents was 6 (54%) of 11. Most (61%) tumors were clinically silent. Clinical manifestations included heart failure (5.4%), arrhythmias (23%), and murmurs (14.9%). One child died as a result of cardiac insufficiency. Cardiac rhabdomyomas were more frequent in theTSC2 (54%) than TSC1 (20%) groups. CONCLUSIONS. Cardiac rhabdomyomas are seen in the majority of young children with Tuberous Sclerosis complex. Most produce no clinical consequences and will spontaneously regress. However, during puberty, cardiac rhabdomyomas may enlarge or appear de novo; thus, attention should be paid to potential clinical signs and monitoring by echocardiography should be performed. Cardiac rhabdomyomas were observed more often in the TSC2 group.
David J Kwiatkowski - One of the best experts on this subject based on the ideXlab platform.
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advances and future directions for Tuberous Sclerosis complex research recommendations from the 2015 strategic planning conference
Pediatric Neurology, 2016Co-Authors: Mustafa Sahin, Elizabeth P Henske, Alcino J. Silva, John J. Bissler, David J Kwiatkowski, Brendan D Manning, Kevin C Ess, Eric Klann, Steven L Roberds, Coryse St HillaireclarkeAbstract:On March 10 to March 12, 2015, the National Institute of Neurological Disorders and Stroke and the Tuberous Sclerosis Alliance sponsored a workshop in Bethesda, Maryland, to assess progress and new opportunities for research in Tuberous Sclerosis complex with the goal of updating the 2003 Research Plan for Tuberous Sclerosis (http://www.ninds.nih.gov/about_ninds/plans/tscler_research_plan.htm). In addition to the National Institute of Neurological Disorders and Stroke and Tuberous Sclerosis Alliance, participants in the strategic planning effort and workshop included representatives from six other Institutes of the National Institutes of Health, the Department of Defense Tuberous Sclerosis Complex Research Program, and a broad cross-section of basic scientists and clinicians with expertise in Tuberous Sclerosis complex along with representatives from the pharmaceutical industry. Here we summarize the outcomes from the extensive premeeting deliberations and final workshop recommendations, including (1) progress in the field since publication of the initial 2003 research plan for Tuberous Sclerosis complex, (2) the key gaps, needs, and challenges that hinder progress in Tuberous Sclerosis complex research, and (3) a new set of research priorities along with specific recommendations for addressing the major challenges in each priority area. The new research plan is organized around both short-term and long-term goals with the expectation that progress toward specific objectives can be achieved within a five to ten year time frame.
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reversal of learning deficits in a tsc2 mouse model of Tuberous Sclerosis
Nature Medicine, 2008Co-Authors: Dan Ehninger, Vijaya Ramesh, Sangyeul Han, Carrie Shilyansky, Yu Zhou, David J Kwiatkowski, Alcino J. SilvaAbstract:Tuberous Sclerosis is a single-gene disorder caused by heterozygous mutations in the TSC1 (9q34) or TSC2 (16p13.3) gene and is frequently associated with mental retardation, autism and epilepsy. Even individuals with Tuberous Sclerosis and a normal intelligence quotient (approximately 50%) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits. Here we report that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2(+/-) mice) show deficits in learning and memory. Cognitive deficits in Tsc2(+/-) mice emerged in the absence of neuropathology and seizures, demonstrating that other disease mechanisms are involved. We show that hyperactive hippocampal mammalian target of rapamycin (mTOR) signaling led to abnormal long-term potentiation in the CA1 region of the hippocampus and consequently to deficits in hippocampal-dependent learning. These deficits included impairments in two spatial learning tasks and in contextual discrimination. Notably, we show that a brief treatment with the mTOR inhibitor rapamycin in adult mice rescues not only the synaptic plasticity, but also the behavioral deficits in this animal model of Tuberous Sclerosis. The results presented here reveal a biological basis for some of the cognitive deficits associated with Tuberous Sclerosis, and they show that treatment with mTOR antagonists ameliorates cognitive dysfunction in a mouse model of this disorder.
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clinical and genotype studies of cardiac tumors in 154 patients with Tuberous Sclerosis complex
Pediatrics, 2006Co-Authors: Sergiusz Joźwiak, Katarzyna Kotulska, Dorota Domanskapakiela, Jolanta Kasprzykobara, Malgorzata Tomyndrabik, Penelope S Roberts, David J KwiatkowskiAbstract:OBJECTIVE. Tuberous Sclerosis complex is an autosomal dominant disorder in which hamartomas occur in several organs. Cardiac rhabdomyomas, the most common heart tumors of childhood, are well known to be associated with Tuberous Sclerosis complex. Our aim for this study was to characterize the incidence, progression, and clinical consequences of Tuberous Sclerosis complex–associated rhabdomyomas in a large cohort of patients with TSC1 and TSC2 genotypes. PATIENTS AND METHODS. Patients (154) with Tuberous Sclerosis complex were evaluated, including clinical assessment, electrocardiography, and echocardiography. Mutations in TSC1 or TSC2 genes were identified in 127 patients. RESULTS. Cardiac rhabdomyomas were found in 74 (48%) patients. Tumors were most frequent in children younger than 2 years (65%). Tumor regression or disappearance was observed in 37 (68%) of 55 children. However, in 6 (3.9%) of them (aged 10-15 years), cardiac rhabdomyomas were noted to either grow (3 cases) or appear de novo (3 cases), such that the frequency of cardiac rhabdomyomas in adolescents was 6 (54%) of 11. Most (61%) tumors were clinically silent. Clinical manifestations included heart failure (5.4%), arrhythmias (23%), and murmurs (14.9%). One child died as a result of cardiac insufficiency. Cardiac rhabdomyomas were more frequent in theTSC2 (54%) than TSC1 (20%) groups. CONCLUSIONS. Cardiac rhabdomyomas are seen in the majority of young children with Tuberous Sclerosis complex. Most produce no clinical consequences and will spontaneously regress. However, during puberty, cardiac rhabdomyomas may enlarge or appear de novo; thus, attention should be paid to potential clinical signs and monitoring by echocardiography should be performed. Cardiac rhabdomyomas were observed more often in the TSC2 group.
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Tuberous Sclerosis from tubers to mtor
Annals of Human Genetics, 2003Co-Authors: David J KwiatkowskiAbstract:Summary Tuberous Sclerosis (TSC) is an autosomal dominant hamartoma syndrome whose causative genes (TSC1 and TSC2) were identified 5 and 9 years ago respectively. Their encoded proteins are large, and apart from a strong binding interaction with each other, relatively little was known about their biochemical function. Recent studies in Drosophila have pinpointed a critical function for the Drosophila TSC1/TSC2 homologues in the regulation of cell size. Epistasis experiments and a variety of biochemical studies that followed have indicated a critical function for these proteins in the highly conserved PI-3-kinase-Akt-mTOR signalling pathway. The clinical problem Tuberous Sclerosis (TSC) is an autosomal dominant hamartoma syndrome with a prevalence of 1 in 6000 to 10000 births. Most of the hamartomas and other lesions seen in Tuberous Sclerosis are very unusual in the general population, such that the formal diagnostic criteria (Roach et al. 1998) may be condensed fairly accurately to the following simple formulation: a patient has TSC if they have two different types of classic TSC hamartoma. Most TSC patients have hamartomas in the brain, skin, kidneys, and heart (Gomez et al. 1999). Involvement of the lung, gastrointestinal tract, bones, retina, and gingiva are also often seen. A hamartoma is a group of dysplastic, disorganized cells within an organ with some growth potential. In aggregate the TSC hamartomas occurring in the brain, skin, kidneys and heart have no common histologic features, but often consist of multiple cell types. During childhood the predominant morbidity in TSC is neurologic, due to involvement of the brain by the hallmark cortical tubers. Seizures are seen in about 90% of patients, often presenting as infantile spasms, and mental retardation and a