Tuberous sclerosis complex is an autosomal-dominant, neurocutaneous, multisystem disorder characterized by cellular hyperplasia and tissue dysplasia. The genetic cause is mutations in the TSC1 gene , found on chromosome 9q34, and TSC2 gene , found on chromosome 16p13. The clinical phenotypes resulting from mutations in either of the 2 genes are variable in each individual. Herein, advances in the understanding of molecular mechanisms in tuberous sclerosis complex are reviewed, and current guidelines for diagnosis, treatment, follow-up, and management are summarized.
Key points
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Hypopigmented macules in the skin coupled with either epilepsy or autism are important diagnostic findings.
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Prenatal identification of a cardiac rhabdomyoma is a common early presenting manifestation.
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Hyperactivity of the mechanistic target of rapamycin complex 1 (mTORC1) constitutes the molecular basis of tuberous sclerosis complex (TSC).
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Symptomatic treatments as well as molecular-targeted therapy with current mTORC1 inhibitors are treatment options.
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The mTORC1 inhibitor, everolimus, is approved by the US Food and Drug Administration for the treatment of renal angiomyolipomas that do not require immediate surgery in adults with TSC and subependymal giant cell astrocytomas that cannot be surgically resected in adults or children with TSC.
Introduction
Tuberous sclerosis complex (TSC) is an autosomal-dominant, neurocutaneous, multisystem disorder characterized by cellular hyperplasia and tissue dysplasia. The disease has 2 known genetic loci: TSC1 , found on chromosome 9q34; and TSC2 , found on chromosome 16p13. Clinical phenotypes resulting from mutations in either of these genes are variable.
Introduction
Tuberous sclerosis complex (TSC) is an autosomal-dominant, neurocutaneous, multisystem disorder characterized by cellular hyperplasia and tissue dysplasia. The disease has 2 known genetic loci: TSC1 , found on chromosome 9q34; and TSC2 , found on chromosome 16p13. Clinical phenotypes resulting from mutations in either of these genes are variable.
Epidemiology
TSC can be identified in all ethnic groups and is equally identified in both sexes. Population studies have estimated a prevalence of 1 in 6000 to 9000 people. Although TSC is an autosomal-dominant inherited disorder, up to 65% to 75% of people affected with TSC have had spontaneous mutations. An estimated 40,000 Americans and at least 2 million people worldwide are affected with TSC.
Cause
TSC can be caused by mutations in 2 different genes: the TSC1 gene, found on chromosome 9q34; and the TSC2 gene, found on 16p13. The TSC2 gene accounts for as many as 90% of the clinical cases; however, mutations in both TSC1 and TSC2 may produce the same phenotype, varying from individual to individual. This genetic heterogeneity is made more complex by variable clinical expression even with the same genetic mutation within a given family ( Figs. 1–12 ).
The Tuberous Sclerosis Complex Variation Database ( http://chromium.liacs.nl/LOVD2/TSC/home ) of small mutations, small and large deletions, and rearrangements for both genes has compiled more than 500 different mutations. The TSC1 gene incorporates mainly small mutations that result in nonsense or frameshifts, which lead to protein truncation, whereas most TSC2 mutations involve missense mutations (25% to 32%) and large deletions or rearrangements (12% to 17%). TSC2 gene mutations are more common whether in familial patients (about 65%) or in sporadic patients (about 75%), accounting for a ratio of TSC2:TSC1 of almost 2:1 in familial patients and 3.5:1 in sporadic cases.
Clinical differences between individuals who harbor the TSC2 versus the TSC1 mutation indicate that more severe clinical manifestations often occur in those with TSC2 mutations. These individuals tend to have more hypomelanotic macules and learning disabilities, with more frequent neurologic and ophthalmologic signs, renal cysts, and ungual fibromas in male individuals.
Pathophysiology
The pathologic condition of TSC is characterized by cellular hyperplasia and tissue dysplasia affecting multiple organs. Following the discovery of the TSC1 and TSC2 genes and their respective protein product (hamartin and tuberin), subsequent genetic and functional studies have identified several downstream targets and signaling cascades ( Fig. 1 ). Tsc1 and Tsc2, together with a third protein, TBC1D7, form the TSC protein complex, which regulates multiple cellular processes and importantly acts as a critical negative regulator of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a serine/threonine kinase that is central to many cell functions including cell growth and proliferation. Rheb (Ras homolog enriched in brain) is a specific GTPase downstream of the TSC protein complex that functionally links TSC1/TSC2 to mTORC1 (see Fig. 1 ). The TSC1/TSC2 complex functions as a GTPase-activating protein (GAP) for Rheb and stimulates the conversion of Rheb-GTP to a GDP-bound state, thereby inactivating Rheb signaling and thus removing its stimulatory effect on mTORC1. Conversely, loss-of-function mutations in either TSC1 or TSC2 lead to enhanced Rheb-GTP signaling and mTORC1 activation (see Fig. 1 ). Constitutively active mTORC1 signaling thus constitutes the molecular basis of TSC.
mTORC1 has emerged as a central regulator of cell growth and metabolism. Not surprisingly, derangement in the mTOR pathway has been linked to the process of aging and a myriad of human diseases, including neurodegenerative, neurodevelopmental, and psychiatric diseases, epilepsy, cancer, obesity, type 2 diabetes, and others. When in its active state, mTORC1 phosphorylates the translational regulators 4E-BP1 (eukaryotic translation initiation factor 4E-binding protein 1) and S6K1 (S6 kinase 1), which, in turn, stimulate protein synthesis. Through other direct and secondary downstream targets, mTORC1 critically regulates anabolic pathways that enable an adaptation to various external stimuli and lead to an increase in cell size and growth. Active mTORC1 stimulates the biosynthesis of ribosomes, lipid biogenesis, glucose metabolism, nucleotide synthesis, mitochondrial and lysosomal biogenesis, ATP, and amino acid production (see Fig. 1 ). mTORC1 also functions as a negative regulator for autophagy, another key cellular pathway that has been implicated in many diseases including neurodegenerative and neurodevelopmental diseases (see Fig. 1 ).
Important to clinical practice, the activity of mTORC1 is very sensitive to the macrolide antibiotic rapamycin and related compounds. When bound to the adapter protein FKBP12, rapamycin physically binds and blocks mTOC1 kinase activity. The pivotal role of deregulated mTORC1 signaling in the pathogenesis of TSC and associated conditions with hyperactive mTORC1 has provided a strong molecular basis for the use of mTORC1 inhibitors, such as rapamycin, as a targeted therapy. Indeed, derivatives of rapamycin have successfully entered the clinic as discussed later. By bridging decades of basic research into the molecular basis of TSC to a successful clinical application, the development of mTORC1 inhibitors can be viewed as a model for the bench-to-beside paradigm of translation research.
Diagnostic Approach
Box 1 describes the clinical features of each diagnostic approach.
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Definite diagnosis: 2 major features or 1 major feature with greater than 2 minor features or the presence of a TSC1 or TSC2 mutation of confirmed pathogenicity a
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Possible diagnosis: Either 1 major feature or greater than 2 minor features
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Major criteria:
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Skin/oral cavity
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Hypomelanotic macules (n>3, at least 5 mm diameter)
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Angiofibromas (n>3) or fibrous cephalic plaque
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Ungual fibromas (n>2)
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Shagreen patch
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Central nervous system
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Cortical dysplasias (includes tubers and cerebral white matter radial migration lines)
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Subependymal nodules
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Subependymal giant cell astrocytoma
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Heart
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Cardiac rhabdomyoma
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Lungs
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Lymphangioleiomyomatosis b
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Kidney
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Angiomyolipomas (n>2) b
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Eyes
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Multiple retinal hamartomas
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Minor criteria:
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Skin/oral cavity
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“Confetti” skin lesions
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Dental enamel pits (n>3)
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Intraoral fibromas (n>2)
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Kidney
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Multiple renal cysts
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Eyes
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Retinal achromic patch
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Other organs
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Nonrenal hamartomas
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Genetics: identification of either a TSC1 or a TSC2 pathogenic a mutation in DNA from normal tissue is sufficient to make a definite diagnosis
a A pathogenic mutation is defined as a mutation that clearly inactivates the function of the TSC1 or TSC2 proteins, prevents protein synthesis, or is a missense mutation whose effect on protein function has been established by functional assessment ( www.lovd.nl/TSC1 , www.lovd/TSC2 )
b A combination of the 2 major clinical features (lymphangioleiomyomatosis and angiomyolipomas) without other features does not meet criteria for a definite diagnosis.
The diagnosis of TSC is made by careful clinical examination and is supported by selective organ imaging and laboratory testing, including genetic evaluation. Additional investigations are used primarily to confirm the diagnosis, determine the extent of disease by identifying which organs are involved, and clarify parental recurrence risks.
There are no symptoms that are specific for TSC. However, there are several common presentations that should prompt consideration of TSC and further investigation. First and foremost is the identification of a family member with TSC. If the family member is a first-degree relative (ie, a parent or siblings), there is an up to 50% chance for the patient under evaluation to have the disorder. This 50% risk remains when multiple siblings are affected and may even occur when the affected parent is unaware of his or her diagnostic status. A gonadal mosaicism in a clinically unaffected parent is an additional, albeit rare, cause. TSC is a condition whereby the only organ affected with the TSC mutation is the gonads and their affected gametes, thus allowing the potential for multiple affected children from an otherwise unaffected parent. This risk is estimated to be less than 2% for all parents with an affected child.
The recognition of diagnostic hallmarks should prompt further consideration of an underlying diagnosis of TSC (see Box 1 ). Patients commonly come to medical attention through one of several ways: prenatal identification of cardiac rhabdomyomas, postnatal identification of hypopigmented macules on the skin, or the development of seizures, especially with infantile spasms and during an evaluation for autism with or without cognitive impairment. Under these specific clinical scenarios, a heightened suspicion for underlying diagnosis of TSC is warranted.
Among infants with multiple cardiac rhabdomyomas, 80% or more are ultimately diagnosed with TSC. These lesions may be identified at 22 weeks of gestation. Most patients have an average of 3 lesions, 3 to 25 mm in size, but isolated lesions are also of diagnostic significance. Cardiac rhabdomyomas are most commonly located within the ventricles along the septum rather than within the walls or atria.
Hypopigmented macules spots are identifiable in the vast majority of patients and approaches 90% to 95%. The classic ash leaf spot, while not diagnostic, characteristically has a pyramidal shape with a rounded bottom and pointed end. Most macules can be seen under ambient light but visualization can be enhanced with the use of a Wood lamp.
Up to 90% of patients with TSC will experience epilepsy in their lifetime. All seizure types may develop, with the possible exception of pure absence epilepsy. Seizures are most often manifest in childhood with infantile spasms as the presenting feature in one-third of patients.
Autism spectrum disorders (ASD) among other behavioral problems can be identified in 40% to 50% of patients with TSC. Patients affected with ASD have a 75% prevalence of coexisting cognitive impairment and an additional 75% to 100% prevalence of concurrent epilepsy.
Practical Management, Follow-up, and Surveillance
Box 2 provides resources for TSC patients and caregivers.
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