Tuberous sclerosis complex (TSC) is an autosomal dominant

Transcription

1 Winter/Spring 2018 A Look at the Genetics of TSC: How Important Is Genetic Testing to Patients and Their Physicians? About TSC Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that can cause noncancerous tumors, or hamartomas, in multiple organs particularly the brain, kidneys, lungs, eyes, skin, and heart over a patient s lifetime. 1,2 Clinical manifestations vary widely, but neurologic and dermatologic manifestations are the most common presenting features that lead to initial consultation. 2 Clinical manifestations of TSC Age at which the various manifestations develop 2-9 Prenatal < 1 yr 1-5 yr >5-18 yr > 18 yr In This Edition»» A Look at the Genetics of TSC: Is Genetic Testing of Value to Patients and Their Physicians? {page 1} Abdominal Pain and Hypertension in a 24-Year-Old Woman: a Case Report {page 6} Empowering Patients to Be Proactive {page 8} What We Can Learn From a Large- Scale Study in Patients With TSC {page 10} A Focus on TAND {page 12} Nursing Matters {page 14}» TSC Support {page 22}»» Latest News & Events {page 18}» Upcoming TSC Events {page 24} Cortical tubers SENs Renal angiomyolipomas SEGAs This newsletter is brought to you by the Tuberous Sclerosis Alliance, Child Neurology Foundation, and Novartis Pharmaceuticals Corporation. Dermatologic manifestations Cardiac rhabdomyomas Retinal hamartomas LAM LAM, lymphangioleiomyomatosis (lung); SEGAs, subependymal giant cell astrocytomas; SENs, subependymal nodules. [continued on page 2] TSC Newsletter #2 Update DR.indd 1 2/5/18 12:26 PM

2 A Look at the Genetics of TSC The role of genetics in TSC Structure of hamartin (TSC1) and tuberin (TSC2) 2,10 Tuberin interaction Predicted coiled-coil TSC Activating event sites TSC Coiled-coil hamartin interaction Inhibitory event sites GAP-related domain 1807 Inhibitory event sites Activating event sites The structure of TSC1 and TSC2 genes and the main domains of hamartin and tuberin. These proteins bind each other via their respective coiled-coil domains to form an intracellular complex that integrates signals to control cellular homeostasis, oxygen levels, presence of nutrients, energy pool, and stimulation by growth factors. 10 TSC1 interacts with tuberin in the region of amino acids 302 through 430. TSC2 interacts with hamartin in the region of amino acids 1 through The activity of TSC1 and TSC2 is regulated by both inhibitory and activating phosphorylation events at locations (indicated by or, respectively). GAP, GTPase-activating protein. 2 TSC is caused by mutations in 1 of 2 tumor suppressor genes: TSC1 or TSC TSC1 is located on chromosome 9q34. 2 It spans approximately 53kb to 55kb of DNA and encodes hamartin, a hydrophilic protein with 1164 amino acids and a mass of 130 kda. This protein plays an important role in the adhesion of cells and is expressed in several adult tissues 2,10 TSC2 is located on chromosome 16p13. 2 It reaches about 43kb of DNA and encodes tuberin, an 1807-amino acid protein with mass of 198 kda. Tuberin regulates the GTP binding and hydrolyzing activity of the Ras superfamily of proteins and helps to regulate cell growth, proliferation, and differentiation 10 Both TSC1 and TSC2 are expressed in cells within multiple organs, including the kidney, brain, and lungs. 2 GTP, guanosine-5 -triphosphate. Navigating the mtor pathway Hamartin and tuberin bind to each other to regulate the mtor (mammalian target of rapamycin) pathway, an intracellular complex that controls cell growth and proliferation through the regulation of ribosome biosynthesis and protein translation. 2 A mutation in either TSC1 or TSC2 can lead to dysregulation of the mtor pathway, which, in turn, can lead to the formation of tumors in multiple organs. 2,13,14 mtor Activation in TSC Photo on cover is from megaflopp / Shutterstock.com TSC In Depth - Winter/Spring 2018 { 2 } TSC Newsletter #2 Update DR.indd 2 2/5/18 12:26 PM

3 TSC1 and TSC2 gene mutations: What s the difference? Crystal Light / Shutterstock.com Generally, patients diagnosed with TSC who have no identifiable mutations show milder clinical disease and have a lower incidence of cognitive dysfunction, seizures, and dermatologic signs than those with an identifiable mutation.2 Although approximately 15% of patients have no detectable mutation, a mutation in TSC1 or TSC2 can be detected in approximately 85% of patients with the clinical features of TSC.10,15,16 TSC2 mutations occur at a much higher frequency than TSC1 mutations. In fact, 70% to 90% of families identified with TSC had TSC2 mutations. There is also a much higher incidence of TSC2 mutations in sporadic cases.10,15 Patients with TSC2 gene mutations (vs TSC1 mutations) are more likely to experience the following10,15: Renal angiomyolipomas and renal cysts SENs Skin lesions Higher than average tuber count More LAM cysts Higher incidence of TAND (TSC-associated neuropsychiatric disorders) Seizures Kidney disease Retinal complications Interestingly, the type and location of TSC1 and TSC2 mutations have an influence on the phenotype. Only one TSC2 mutation, R905Q, has been shown to be associated with milder TSC. This mutation was discovered in 25 members of the same family, all of whom had TSC but no major skin lesions, intractable epilepsy, cognitive dysfunction, or severe organ manifestations.10 [continued on page 4] {3} TSC Newsletter #2 Update DR.indd 3 2/5/18 12:26 PM

4 A Look at the Genetics of TSC The importance of genetic testing The latest consensus guidelines for TSC (developed at the 2012 International Tuberous Sclerosis Complex Consensus Conference) state that the identification of a TSC1 or TSC2 pathogenic mutation is sufficient to make a definite diagnosis of TSC. 16 Future implications It has been recently suggested that in patients with TSC, determining the exact genotype-phenotype correlations might help establish individualized treatment for TSC patients and thereby possibly improve their quality of life. 10 The guidelines define a pathogenic mutation as one that clearly: Inactivates the function of the TSC1 or TSC2 protein (eg, out-of-frame indel or nonsense mutation) Prevents protein synthesis (eg, a large genomic deletion) or Is a missense mutation whose effect on protein function has been established by functional assessment If there are other TSC1 or TSC2 variants whose effect on function is less certain, they do not meet these criteria and are not sufficient to make a definite diagnosis of TSC. 16 the identification of a TSC1 or TSC2 pathogenic mutation is sufficient to make a definite diagnosis of TSC. References: 1. Yates JRW. Tuberous sclerosis. Eur J Hum Genet. 2006;14: Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006;355(13): Borkowska J, Schwartz RA, Kotulska K, Josiah S. Tuberous sclerosis complex: tumors and tumorigenesis. Int J Dermatol. 2011;50(1): Richardson EP Jr. Pathology of tuberous sclerosis: neuropathologic aspects. Ann NY Acad Sci. 1991;615: Haque A, Sharmi LS, Ekram A, Islam S. Tuberous sclerosis complex in a family. J Med. 2010;11(1): Sweeney SM. Pediatric dermatologic surgery: a surgical approach to the cutaneous features of tuberous sclerosis complex. Adv Dermatol. 2004;20: Rowley SA, O Callaghan FJ, Osborne JP. Ophthalmic manifestations of tuberous sclerosis: a population based study. Br J Ophthalmol. 2001;85(4): Franz DN. Non-neurologic manifestations of tuberous sclerosis complex. J Child Neurol. 2004;19(9): Johnson SR. Lymphangioleiomyomatosis. Eur Respir J. 2006;27(5): Rosset C, Brinckmann ON, Ashton-Prolla P. TSC1 and TSC2 gene mutations and their implications for treatment in Tuberous Sclerosis Complex: a review. Genetics and Molecular Biol. 2017;40(1): Maheshwar MM, Cheadle JP, Jones AC, et al. The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis. Hum Mol Genet. 1997;6(11): Kwiatkowska J, Jozwiak S, Hall F, et al. Comprehensive mutational analysis of the TSC1 gene: observations on frequency of mutation, associated features, and nonpenetrance. Ann Hum Genet. 1998;62: Chan JA, Zhang H, Roberts PS, et al. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mtor activation. J Neuropathol Exp Neurol. 2004;63(12): Inoki K, Corradetti MN, Guan K-L. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet. 2005;37(1): Dabora SL, Jozwiak S, Franz DN, et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1 disease in multiple organs. Am J Hum Genet. 2001;68(1): Northrup H, Krueger DA, on behalf of the International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49(4): TSC In Depth - Winter/Spring 2018 { 4 } TSC Newsletter #2 Update DR.indd 4 2/5/18 12:26 PM

5 { 5 } Crystal Light / Shutterstock.com TSC Newsletter #2 Update DR.indd 5 2/5/18 12:26 PM

6 Not an actual patient. TSC In Depth - Winter/Spring TSC Newsletter #2 Update DR.indd 6 Martin Novak / Shutterstock.com {6} 2/5/18 12:26 PM

7 Abdominal Pain and Hypertension in a 24-Year-Old Woman: a Case Report * A 24-year-old woman with abdominal pain and hypertension visited her primary care physician 3 times over the course of 2 months. An abdominal ultrasound revealed multiple bilateral renal angiomyolipomas. Her physician referred her to a nephrologist for further evaluation and treatment. Because the woman had multiple renal angiomyolipomas, the nephrologist suspected tuberous sclerosis complex (TSC) even though the patient reported no history of neurologic or psychiatric issues. The physical examination revealed signs of TSC that included confetti skin lesions and dental enamel pits on several teeth. The nephrologist definitively diagnosed the patient with TSC based on the latest consensus guidelines stating that 1 major manifestation (the renal angiomyolipomas) plus 2 or more minor manifestations (the confetti skin lesions and dental enamel pits) are sufficient for a definitive TSC diagnosis. 1 The nephrologist then ordered a brain MRI and a pulmonary ultrasound to determine whether other manifestations might be present. The MRI showed additional major manifestations: 1 subependymal nodule and 2 cortical tubers; the lung scan was clear. The nephrologist shared the findings with the patient s primary care physician. He also prescribed an angiotensin-converting enzyme inhibitor for her hypertension and sent the patient and the results of the MRI to a neurologist for a full neurologic work-up and ongoing surveillance. One year later, she continues to see her nephrologist and neurologist regularly and has also had a dermatologic exam. Her hypertension is controlled and she actively monitors her health by ensuring that each specialist is aware of every TSC manifestation with which she is affected. Discussion: Was it appropriate for the nephrologist to order a brain MRI and a pulmonary ultrasound? Who should be the patient-care point person in this scenario to ensure that the patient is keeping up with regular monitoring of various manifestations? What new challenges might the patient face as she grows older? Reference: 1. Northrup H, Krueger DA, for the International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49(4): MRI, magnetic resonance imaging. *Not an actual patient; for illustrative purposes only. { 7 } TSC Newsletter #2 Update DR.indd 7 2/5/18 12:26 PM

8 Empowering Patients to Be Proactive A new patient campaign was launched in April that empowers patients and their caregivers to be proactive in managing their tuberous sclerosis complex (TSC) by actively monitoring all possible manifestations, including renal, dermatologic, pulmonary, cardiovascular, and neurologic. The campaign invites patients to know more about their TSC-related renal angiomyolipomas, including the Quantity of renal lesions Size of the largest lesion (and the risks associated with those ~4 cm or more in diameter) 1,2 Rate of growth (and the risks associated with rapidly growing tumors) 1-5 Importance of regular physician visits and scans (MRIs preferred) 3 TSC In Depth - Winter/Spring 2018 { 8 } TSC Newsletter #2 Update DR.indd 8 2/5/18 12:27 PM

9 Patients have several 4KnowMore resources to use, including the following: 4KnowMore Patient Website: Motivates patients to be proactive and informs them about TSC kidney care; visit for more information TSC kidney health begins with you Thanks to advances in medical research, we know more about tuberous sclerosis complex (TSC) and its kidney tumors than ever before. And we know that it s critical that you and your doctor stay on top of your kidney health visits and screenings.» Inside are 4 things to know to take control TSC Symptom Tracker A change in any tuberous sclerosis complex (TSC) symptom is always important to discuss with your health care provider. This checklist can help your kidney specialist understand what TSC symptoms you have had since your last visit. Date of kidney checkup: Month/Day/Year If you have not had any of the symptoms listed in a particular section, just leave the area blank. Have a healthy discussion Make the conversation count. Next visit: Month/Day/Year Things to tell your doctor Since my last visit: Keep this sheet to compare to next year s visit. 1. I have had symptoms that might be related to my kidneys: (Circle all that apply.) Blood in the urine Back or side pain 2. I have had new or worsening signs and symptoms such as: (Circle all that apply.) SKIN ISSUES Bumps on my face Light-colored spots Skin tags Bumps on my lower back Bumps around my nails Other LUNG CONCERNS Shortness of breath Chest aches NEUROLOGIC PROBLEMS Sleep problems Headaches Frequent cough Wheezing Other EYE LESIONS OR VISION ISSUES DENTAL ISSUES Bumps (growths) over a tooth or gum Pitting (dents) in teeth Do you have other concerns that you would like to discuss with your doctor? Write them down in the space below. Remember, symptoms are not the only clues to your TSC kidney health. In fact, sometimes TSC kidney tumors cause no symptoms. So, along with tracking your signs and symptoms of TSC, it is very important to also have regular MRIs to scan your kidneys. This way, you and your doctor can keep track of new or growing TSC kidney tumors so they do not lead to other health problems over time. MRI, magnetic resonance imaging. Novartis Pharmaceuticals Corporation East Hanover, New Jersey TSC Doctor Discussion Guide Use this tool to tell your doctor about changes to your health To learn more, visit today! 2017 Novartis 4/17 Symptom Tracker: Helps patients keep track of TSC symptoms (especially those possibly related to kidney issues); a printable form is available at Have a healthy discussion Questions to ask your doctor Use this tool to help you talk with your doctor Having a lifelong condition like tuberous sclerosis complex (TSC) can be stressful. In fact, it is normal to feel anxious before and during your doctor s appointment. But remember, the more comfortable you are sharing your health concerns, the better your well-being. This discussion guide will help you discuss TSC with your doctor, so you can become partners in managing it. Review it before you go, and bring it with you to your appointment. Ask a close friend or family member who understands your medical needs to go with you and take notes during the appointment. Otherwise, take notes yourself. Your doctor visit is a chance to learn more about your health. Date: Remember: The better prepared you are, the more you will get out of the doctor visit. Asking your doctor these questions will help you stay informed and involved in your treatment plan. Based on my most recent medical tests 1. What is my kidney (renal) function? Has it changed since my last visit? If so, do you recommend any changes to my care? 2. What is my blood pressure? Has it changed since my last visit? If so, do you recommend any changes to my care? 3. How many TSC kidney tumors (renal angiomyolipomas) do I have? Do I have more than at my last visit? Are they in both kidneys or just one? 4. How big is my largest tumor? Do I have any tumors over 4 cm in diameter? If your doctor says yes, you might want to say: I understand that renal angiomyolipomas are more likely to rupture when they are about 4 cm or larger. Can we discuss a plan of action? 5. The TSC guidelines recommend a scan of your kidneys every 1 to 3 years. If you are not getting scans this frequently, ask: Should I get a scan every 1 to 3 years? 4KnowMore Brochure: Educates and encourages patients to take charge of their TSC and its kidney issues; it is available at TSC community events, TSC centers, and in offices like yours; this brochure is available from your Novartis sales representative Health Care Provider Discussion Guide: Empowers patients to get the most out of their annual visit with you; a printable form is available at Continued on next page AGM Additionally, there is a webcast available for viewing on demand, led by Dr Joshua Samuels, a nephrologist at the University of Texas-Memorial Hermann TSC Center of Excellence in Houston. This presentation followed by a question-and-answer session is a comprehensive look at TSC-related renal angiomyolipomas and is suitable for patients and caregivers alike. To view, visit The webcast is sponsored by Novartis. Join in the 4KnowMore effort By using and disseminating 4KnowMore materials, you can empower your patients and raise awareness of the importance of regular monitoring. For more information about patient resources, visit References: 1. Kapoor A, Girard L, Lattouf J-B, et al. Evolving strategies in the treatment of tuberous sclerosis complex-associated angiomyolipomas (TSCAML). Urology. 2016; 89: Yamakado K, Tanaka N, Nakagawa T, Kobayashi S, Yanagawa M, Takeda K. Renal angiomyolipoma: relationships between tumor size, aneurysm formation, and rupture. Radiology. 2002;225: Krueger DA, Northrup H; for the International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49(4): Siroky BJ, Yin H, Bissler JJ. Clinical and molecular insights into tuberous sclerosis complex renal disease. Pediatr Nephrol. 2011;26(6): Seyam RM, Bissada NK, Kattan SA, et al. Changing trends in presentation, diagnosis and management of renal angiomyolipoma: comparison of sporadic and tuberous sclerosis complex-associated forms. Urology. 2008;72: {9} TSC Newsletter #2 Update DR.indd 9 2/5/18 12:27 PM

10 What We Can Learn From a Large-Scale Study in Patients With TSC Baseline data from the largest clinical case series of tuberous sclerosis complex (TSC) to date were recently published in Orphanet Journal of Rare Diseases. These data are from the TuberOus SClerosis registry to increase disease Awareness (TOSCA), an international disease registry designed to address knowledge gaps in the natural history and management of TSC. In this paper, Kingswood et al present information on the prevalence of each manifestation of TSC in this specialist clinical population. Patients in the registry will be followed for up to 5 years and annual interim analyses will be conducted. TOSCA contains baseline core data from 2093 patients enrolled at 170 sites across 31 countries. The median age of patients at enrollment was 13 years TSC In Depth - Winter/Spring 2018 { 10 } Guschenkova / Shutterstock.com (range, 0-71) and the median age at diagnosis of TSC was 1 year (range, 0-69). The registry will provide a detailed description of the severity of various TSC manifestations over time. TOSCA investigators believe the data will be helpful in developing comprehensive management and surveillance strategies that lead to more proactive, pre-emptive disease management and better outcomes in the future. Although TOSCA is a large clinical case series, it should be noted that patients were recruited through clinical centers with expertise in TSC and milder cases may not always be seen at these centers. Therefore, study design includes potential limitations inherent to clinical case series. TOSCA: Occurrence rates of key manifestations of TSC at baseline (in order of prevalence) Cortical tubers (82.2%)»»»»»» Subependymal nodules (78.2%)» At least 3 hypomelanotic macules (66.8%)» Facial angiofibromas (57.3%)» Mild to profound intellectual disability (54.9%)» Renal angiomyolipomas (47.2%) Cardiac rhabdomyomas (34.3%) Shagreen patches (27.4%)» Forehead plaque (14.1%)»» Subependymal giant cell astrocytomas (24.4%)» Lymphangioleiomyomatosis (6.9%) Note: TSC-associated neuropsychiatric disorders (TAND) were diagnosed late, and not evaluated in 30% to 50% of patients TSC Newsletter #2 Update DR.indd 10 2/5/18 12:27 PM

11 Renal manifestations in the TOSCA registry In the TOSCA registry, renal angiomyolipomas were reported in 47.2% of patients (n=987). Women were more likely to have this manifestation than men (57.5% vs 42.5%, respectively). Most renal angiomyolipomas (95.8%) were diagnosed prior to recruitment; at the baseline assessment, 83.7% of them were without any signs and symptoms. In medical histories, the most commonly reported signs and symptoms included pain (n=51 [5.4%]), elevated blood pressure (n=48 [5.1%]), impaired renal function (n=36 [3.8%]), hemorrhage (n=47 [5%]), and microscopic hematuria (n=35 [3.7%]). In patients with ongoing renal lesions: 87.6% (n=829) had multiple lesions 83.8% (n=793) had bilateral angiomyolipomas 34.8% (n=329) had renal angiomyolipomas >3 cm in diameter 41.9% (n=396) had both multiple and bilateral renal angiomyolipomas Regarding other renal manifestations, multiple renal cysts were found in 22.8% of patients. Infrequently noted were polycystic kidneys (3.5%), impaired renal function unrelated to angiomyolipoma (2.1%), and renal malignancy (1.1%). Data from TOSCA also show a pattern to the emergence and prevalence of TSC manifestations. TSC manifestations by age: TOSCA registry results Age range 2 >2-5 >5-9 >9-14 >14-18 >18-20 > Patients, % a SEGA (n=510) SEN (n=1636) Cortical tuber (n=1721) Renal angiomyolipoma (n=987) LAM (n=144) Facial angiofibroma (n=1199) 100 Patients, % a Shagreen patch (n=573) Forehead plaque (n=295) 3 hypomelanotic macules (n=1399) Ungual or periungual fibromas (n=350) Retinal hamartoma (n=294) Cardiac rhabdomyoma (n=717) LAM, lymphangioleiomyomatosis; SEGA, subependymal giant cell astrocytoma; SEN, subependymal nodules. Major manifestations of TSC categorized by age range in TOSCA participants (N=2093). a Percentage of patients with the manifestation in each age category was calculated based on the total number of patients under the respective age group. Reference: Kingswood JC, d Augeres GB, Belousova E, et al. TuberOus SClerosis registry to increase disease Awareness (TOSCA) baseline data on 2093 patients. Orphanet J Rare Dis. 2017;12(1):2. Doi: /s { 11 } TSC Newsletter #2 Update DR.indd 11 2/5/18 12:27 PM

12 TSC-Associated Pediatric Neurologic Concerns A Focus on TAND It is now commonly recognized that more than 90% of patients with tuberous sclerosis complex (TSC) may not only have physical manifestations, but also be affected by a wide array of behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties that can have an enormously negative impact on the quality of life for those with TSC and their caregivers. 1,2 In scientific literature and in clinical practice, these varying manifestations have been categorized by several different terms, including neurocognitive issues, neurobehavioral difficulties, learning issues, mental health issues, neuropsychiatric disorders, and cognitive and behavioral difficulties. 1 To simplify diagnosis and understanding of these manifestations, the term TAND (TSC- Associated Neuropsychiatric Disorders) was introduced in 2012 as an umbrella term for the vast range of these TSC-associated disorders. 1,2 The idea for this comprehensive term was developed at meetings of the Neuropsychiatry Panel at the 2012 International Consensus Conference on TSC. There, members drew a parallel between the treatment gaps that are sometimes seen in TSC and those once seen in patients with human immunodeficiency virus (HIV), when a focus on the physical treatment of HIV-positive patients overshadowed the attention paid to the major neuropsychiatric features of HIV. The HIV community introduced the term HAND (HIV-associated neurocognitive disorders) to draw attention to these concerns. 1 Motivated by the HIV analogy, the 2012 TSC Neuropsychiatry Panel introduced the term TAND and also recommended that everyone with TSC should be screened for TAND at least annually. To encourage the process, a TAND Checklist was developed and validated. 1,2 TSC In Depth - Winter/Spring 2018 { 12 } Adapted from pimchawee / Shutterstock.com TSC Newsletter #2 Update DR.indd 12 2/5/18 12:27 PM

13 more than 90% of patients with tuberous sclerosis complex (TSC) may not only have physical manifestations, but also be affected by a wide array of behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties Understanding the neuropsychiatric issues experienced by someone with TSC is especially important because there is so much variation among different people with TSC. TAND may also develop later in life after many years of relatively normal functioning. By understanding the individual s strengths and difficulties, the best treatment options can be determined. Based on the results of individual assessment, a management plan should be developed with the patient, caregivers, and team of health care professionals. 1 TAND includes a range of difficulties at a number of different levels 3 Academic level Reading, writing, spelling, mathematics Behavioral level Aggression, temper tantrums, anxiety, depressed mood, self-injury, inattention, hyperactivity, impulsivity, language delay, poor eye contact, repetitive behaviors, sleep problems Intellectual level Intellectual disability, uneven intellectual profiles Neuropsychological level Sustained attention, dual-tasking, attention switching, memory recall, spatial working memory, cognitive flexibility Autism spectrum disorder (ASD), attention-deficit hyperactivity disorder Psychiatric level (ADHD), anxiety disorder, depressive disorder Psychosocial level Self-esteem, self-efficacy, parental stress, relationship difficulties References: 1. de Vries PJ, Whittemore VH, Leclezio L, et al. Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND Checklist. Pediatr Neurol. 2015; 52(1): Leclezio L, de Vries J. Towards an improved understanding of TSC-Associated Neuropsychiatric Disroders (TAND). Adv Austism. 2016;2(2): Curatolo P, Moavero R, devries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet. 2015;14: { 13 } TSC Newsletter #2 Update DR.indd 13 2/5/18 12:27 PM

14 Nursing Matters The Role of Nurses in Transitioning Pediatric Patients With TSC to the Adult Setting Q&A With Rebecca J. Schultz, PhD, RN, CPNP Rebecca Schultz is a registered nurse and a certified pediatric nurse practitioner. She has a PhD in nursing science, a master of science in nursing, and a bachelor of science in nursing. For the past 29 years she has worked at Texas Children s Hospital/Baylor College of Medicine in Houston, Texas, where she is an assistant professor in the pediatrics and neurology department and a nurse practitioner in the Comprehensive Epilepsy Program and the Blue Bird Circle Rett Center. In total, she has 42 years experience in the nursing field 13 years as a nurse and 29 years as an advanced practice nurse. QQ In general, what is your experience in transitioning patients from pediatric to adult care? AA My interest in transitioning patients with neurologic disorders, specifically those with epilepsy, started about 10 years ago when I began trying to find adult providers to accept the care of my 18 to 21 year old patients, many of whom had some degree of intellectual disability and epilepsy. I soon realized this was a big problem: there was no one to accept these patients. Transition is a difficult process for most patients with neurologic disorders. Many have been treated by the same provider for many years, some since birth. Parents, as well as the teens, have developed a trusting relationship. Just the thought of moving on to a new provider is scary for the family. My clinical experience in transitioning patients involves youths with epilepsy, most of whom have complex medical and/ or genetic conditions and some degree of intellectual disability. This process is time-consuming and requires careful planning, teaching/learning self-management skills, identifying community resources, determining decision-making capacity, and identifying adult providers who are knowledgeable of the specific neurologic condition and accept the family s insurance. Starting early is essential! Transition takes time, self-advocacy skills, and tenacity. QQ Share your experience in advising patients specifically with tuberous sclerosis complex (TSC). AA In my opinion, TSC is one of the most complex conditions to transition. Specific needs vary from one youth and family to another; each requires an individualized plan. There is no one-size-fits-all solution. Most see multiple subspecialists; finding and coordinating adult subspecialists can be very difficult and time consuming. Setting the expectation that the teen will move on to the adult health care system is the first step. This fact is often quite surprising to parents. They just haven t thought that far in the future. It s scary to think about moving from a provider with whom you ve established a trusting relationship, since infancy for some that s 18 or more years of seeing the same provider. Discussing the youth s plans and/or the parents plan for the future is essential. This discussion should start early so there is ample time to prepare. Some teens will move on to college, others to vocation training and a job, and some will require lifelong assistance and care. The spectrum of needs is quite broad. Teens who are moving away to college must know about their condition, their medications, how to get medication refills ie, self-management and selfadvocacy skills. They should have an emergency plan in place, eg, find the college campus health center and share medical needs. They need to decide whether they need a provider close to home or one close to college. If they are not able to drive, what mode of transportation is available? The needs of teens who have significant intellectual disabilities are quite different. Legal competency and decision-making capacity must be assessed, as well as where he/she will live home, group home, residential facility and respite care for parents. QA & TSC In Depth - Winter/Spring 2018 { 14 } TSC Newsletter #2 Update DR.indd 14 2/5/18 12:27 PM

15 Micolas / Shutterstock.com QQ Is transitioning patients with TSC more challenging AA QQ How helpful do you believe the Child Neurology Foundation than transitioning patients with non-tsc related neurologic issues? In my experience, the fundamentals of transitioning youths with TSC are similar to the challenges of transitioning other youth with complex neurologic conditions. Locating and coordinating the multiple medical subspecialists is the most challenging. For those youths who have intellectual disabilities, locating an adult provider who feels comfortable managing their care adds to the challenge. The needs of teens with intellectual disabilities and the needs of their family are different. Decision-making capacity must be addressed, as well as where he/she will live at home, in a group home or a residential facility. As the teen is approaching adulthood, parents may need to re-evaluate their expectations for the future and make more realistic plans. These are not easy things to think about. AA (CNF) guidelines* have been/will be to the nursing community? In your personal/professional opinion, how much of a need is there for better transitioning throughout the United States? I believe the CNF guidelines will be very helpful to the nursing community as well as other disciplines. In my opinion, one of the major strengths of these guidelines is the team approach; no one discipline or provider is responsible for the entire process. The guidelines provide a clear framework for developing a nursing care plan for transition of care beginning with identification of the patient, then developing a tracking method, teaching the teen about his/her condition and self-management skills, teaching about the risks of driving, alcohol and substance abuse, promoting independence, etc. [continued on page 16] * Brown LW, Camfield P, Capers M, et al. The neurologist s role in supporting transition to adult health care: a consensus statement. Neurology. 2016;87(8): { 15 } TSC Newsletter #2 Update DR.indd 15 2/5/18 12:27 PM

16 There is a critical need for better transition of care from pediatrics to the adult health care system. We must prepare youths to become independent and competent in managing their health condition. What medication do they take and why? How do they get a refill? How will they pay for medication and office visits? A successful transition can prevent gaps in care that may result in medical crises and increased health care costs, and improve overall health and well-being. QQ From the CNF guidelines, are any of the 8 principles more critical than the others? Are there any principles that are easier/more difficult for the team to manage? AA While all 8 principles are important and, we believe, will lead to improved transition outcomes, there are 5 principles that I believe are critical. They are: #1) starting the discussion early this allows all members of the team (including parents and teens) time to prepare and complete the process; #2 and #3) assessing transition readiness and teaching/ learning self-management and self-advocacy skills; #4) determining legal competency by age 14; this is essential, particulary for those who have significant intellectual disabilities it takes times and may be expensive; and #7) identifying an appropriate adult provider(s). QQ What is your perspective on some common pitfalls in transitioning? Do patients and their caregivers ever feel abandoned when told they should begin preparing for transition? AA Feelings of fear, rejection, and uncertainty were common themes I found in my research (Parental experiences transitioning their adolescent with This can be a very emotional time for parents/caregivers, particularly when they begin trying to navigate the health care system. epilepsy and cognitive impairments to adult health care. J Pediatr Health Care. 2013;27(5):359-66). I also hear similar comments in my clinical practice. You are kicking me to the curb or Changes are scary are common feelings expressed by nearly everyone when I mention the need to transition. There is often uncertainty of where they will receive health care or the source of insurance coverage. QQ Can this become an emotional exercise? A A This can be a very emotional time for parents/ caregivers, particularly when they begin trying to navigate the health care system. It s frustrating they get multiple different answers from various agencies and often feel they are transferred from one to the next and that no one really knows what is going on. Adapted from Wikrom Kitsamritchai / Shutterstock.com TSC In Depth - Winter/Spring 2018 { 16 } TSC Newsletter #2 Update DR.indd 16 2/5/18 12:27 PM

17 QQ Are there ways to address/avoid emotional complications? AA Are there ways to mitigate emotional stress? Talk about it. Reach out to other families. Parents tell me the most helpful resources for information about community resources, insurance, school, etc, are other families, family support groups like Tuberous Sclerosis Alliance, and the clinic social worker. I find parents have a wealth of information about what agencies to call and how to navigate the system. I learn from them and keep a list of those resources so I can share them with other parents. QQ Do you ever find there is not an appropriate adult provider nearby and/or the adult provider is not receptive to ensuring a healthy transition? AA Absolutely! It s very common. Sometimes adult providers are not receptive because they do not feel comfortable with the complexity of the case. With some education and assurance that the child neurologist will be available for consultation as needed, an adult provider may be receptive to accepting the case. This highlights the importance of CNF principles 7 and 8 identifying and communicating with the accepting adult provider. This communication could be via phone, a joint telemedicine visit with the child neurologist and accepting provider, or joint visit with the child neurologist and adult provider at the last planned clinic visit in the child neurologist s office. QQ How important are nurses to a proper transition? A A Nurses are essential in promoting a successful transition. I am aware that not all neurology providers have a nurse to assist in this process. However, in my opinion, nurses can take ownership and lead this process. The guidelines provide a clear framework for developing a nursing care plan for transition of care, beginning with identifying the patient and informing the family and teen of the expectation of future transition to an adult provider, then developing a tracking method; teaching the teen about his/her condition and self-management skills; teaching about the risks of driving, alcohol and substance abuse; promoting independence; assisting in identifying adult providers; and confirming the transfer has been completed. When nurses assume these responsibilities, the health care provider (physician, advanced practice nurse, physician assistant) can focus on ensuring the medical summary is complete and communicating with the receiving adult provider. QQ Should nurses play a role in coordinating care among various educational, vocational, and community services providers? AA Nurses play a key role in coordinating care among specialists, the school, and community service providers. In my opinion, this is a natural role for nurses because of the holistic approach of nursing practice. The focus is on the youth and family and their interactions with the community. The social determinants of health are extremely important. At times, it is the social determinants lack of resources to pay for services, lack of transportation, etc that lead to poor health outcomes. During this transition phase, patients become more vulnerable to interruptions in their support systems. Nurses can assess the social situation and act accordingly. QQ Should pediatric neurology nurses play a role in transitioning patients with TSC to other adult specialists, such as dermatologists, kidney specialists (nephrologists or urologists) and/or pulmonologists? AA Yes, pediatric neurology nurses can play a key role in transitioning patients with TSC to all adult subspecialists. Communicating with nurses in the adult providers offices can help in connecting the providers, determining whether the adult provider accepts the patient s insurance, and ensuring receipt of medical records. By doing so, the pediatric nurse has a name to share with the family; having a specific name of a person to talk to helps make the family feel more connected. A name provides the initial step in establishing a relationship. Building relationships is key to a successful transition. We thank Rebecca J. Schultz, PhD, RN, CPNP for sharing with us her perspective on transition of care for TSC patients. Above image adapted from Wikrom Kitsamritchai / Shutterstock.com { 17 } TSC Newsletter #2 Update DR.indd 17 2/5/18 12:27 PM

18 Latest News & Events From TS Alliance and Child Neurology Foundation Spotlight on research, collaborations, and new initiatives The Child Neurology Foundation (CNF) announces a new Family Support and Empowerment Program (FSEP) for your patients and their families. This service offers families a free, direct connection with an experienced, compassionate Peer Support Specialist to help navigate the journey of disease diagnosis, treatment, and management for a child living with a neurologic condition. Besides drawing from their own life experiences, Peer Support Specialists have received comprehensive training on the needs of the child neurology community. Since early 2017, FSEP has reached families from 28 states and 24 countries. Contact FSEP at info@childneurologyfoundation.org to receive free FSEP notecards for your office. CNF is committed to serving as the connective center of education and support for children and families living with neurologic conditions. The 2017 program priorities include a focus on the following: Transition of Care: Helping to support youth, families, and child neurology teams in the transition from pediatric to adult health care systems Sudden Unexpected Death in Epilepsy (SUDEP): Improving communication between the child neurology team and patients/families when discussing difficult information Parent Coaches: Building a team to provide virtual support for families navigating the path of living with a neurologic condition Virtual Disease Directory: Enhancing an online portal that serves as the premier source of disease information Infantile Spasms Awareness: Coordinating a collaborative advocacy model to enhance infantile spasms awareness Respite Care Notebook: Developing a user-friendly notebook reflective of the comprehensive needs of the child neurology community Partner Connections: Developing Pathways an enewsletter featuring patient educational information, advocacy events, scholarships, and other opportunities of interest to the child neurology community Grants and Scholarships: Awarding research grants and summer scholarships focused on child neurology The Child Neurology Foundation connects partners from all areas of the child neurology community, so those navigating the journey of disease diagnosis, management, and care have the ongoing support of those dedicated to treatments and cures. Child Neurology Foundation 201 Chicago Avenue, #200 Minneapolis, MN TSC In Depth - Winter/Spring 2018 { 18 } TSC Newsletter #2 Update DR.indd 18 2/5/18 12:27 PM

19 Spotlight on recent TSC events from the TS Alliance: Highlights From the International Research Conference and Patient-Focused Drug Development Meeting The 2017 International Research Conference on TSC and LAM: Innovating Through Partnerships was held from June 22 to 24. Co-hosted by the TS Alliance and The LAM Foundation, the conference brought together more than 200 researchers and patient advocates from 32 countries. It was chaired by Drs Steven L. Roberds and Francis X. McCormack, and featured presentations and panel discussions regarding the impact of research on advances in TSC and LAM clinical care. The conference also highlighted exciting new initiatives at every level, from basic science to translational research, which will accelerate future breakthroughs in both diseases. On June 21, the TS Alliance hosted an externally led patient-focused drug development meeting. At this meeting, parents of children with tuberous sclerosis complex (TSC), adults with TSC, and adults with lymphangioleiomyomatosis (LAM) provided heartfelt testimony to representatives of the US Food and Drug Administration (FDA) to help them understand the aspects of TSC and LAM that most impact the daily lives of patients and their caregivers. Attendees heard the challenges faced by these individuals and families, as well as the courage they demonstrated as they shared their stories. Video recordings are available to watch at The Tuberous Sclerosis Alliance is the only national organization dedicated to finding a cure for TSC while improving the lives of those affected. It works to improve quality of life for individuals and families affected by TSC by stimulating and sponsoring research; creating programs, support services, and resource information; and developing and implementing public and professional education programs designed to heighten awareness of TSC. Tuberous Sclerosis Alliance 801 Roeder Road, Suite 750 Silver Spring, Maryland (toll free) { 19 } TSC Newsletter #2 Update DR.indd 19 2/5/18 12:27 PM

20 TRANSITIONING to adult health care An Interactive Resource for Your Neurology Practice TSC In Depth - Winter/Spring 2018 { 20 } TSC Newsletter #2 Update DR.indd 20 2/5/18 12:27 PM

21 TRANSITIONING TO ADULT HEALTH CARE An Interactive Resource for Your Neurology Practice Expectation of Transition Yearly Self-Management Assessment Annual Discussion of Medical Condition and Age-Appropriate Concerns Evaluation of Legal Competency 8 Common Principles to Assist with the Transition of Care Transitioning from the pediatric to adult health care system should be expected for all patients living with a neurologic condition. However, for some, transitioning from their child neurologist to an adult neurologist can prove challenging. To that end, Transition of Care is one of the Child Neurology Foundation s (CNF) most important and comprehensive Program Priorities described as: helping to support youth, families, and child neurology teams in the medical transition from pediatric to adult health care systems. Led by CNF, the 2016 consensus statement, The Neurologist s Role in Supporting Transition to Adult Health Care was endorsed by the American Academy of Neurology, the Child Neurology Society, the American Epilepsy Society, and the American Academy of Pediatrics. The consensus statement identifies 8 Common Principles for the neurology team to employ that will support the medical transition of youth with neurological conditions. 5 Annual Review of Transition Plan of Care 6 Child Neurology Team Responsibilities 7 Identification of Adult Provider 8 Transfer Complete To aid in successful transitions, the CNF Transition Project Advisory Committee (TPAC) developed tools to help practices implement these 8 Common Principles. CNF s new interactive resource outlines each of the 8 Common Principles and matches each Principle with free downloadable tools for use in practice. Get started at: The CNF gratefully acknowledges the work of the TPAC to develop these tools. The TPAC is supported by Eisai, Inc., Novartis Pharmaceuticals, Ipsen Biopharmaceuticals, and Upsher-Smith Laboratories. { 21 } TSC Newsletter #2 Update DR.indd 21 2/5/18 12:27 PM

22 TSC Support There are several resources available to your patients who would like more information on tuberous sclerosis complex (TSC). Tuberous Sclerosis Alliance The Tuberous Sclerosis Alliance (TS Alliance) was formed in the 1970s by 4 mothers with a desire to provide fellowship, generate awareness, pursue knowledge about TSC, and provide hope to those with the condition. These goals still drive the organization today. The alliance has a comprehensive website with information and educational materials for patients and their families about living with the disease ( It also organizes frequent fundraising activities for TSC patients, including the Step Forward to Cure Tuberous Sclerosis Complex movement, the TS Alliance s largest national event, organized in more than 30 communities across the United States. This walk program offers the opportunity to make an impact on the lives of those living with TSC as well as fund research into cures for other diseases like epilepsy, autism, and cancer. The TS Alliance s TSC Connect is an organized partnership of people whose lives have been affected by TSC. It provides the latest medical information, education, and support to anyone seeking to understand TSC and offers them words of encouragement and empowerment. Volunteers bring to the network a wealth of knowledge, awareness, and experience. They offer support and share their experiences with others who are facing the challenges of TSC. The program connects people by geographic area, manifestations, or age of the person with TSC and lets volunteers choose the issues they have personal experience with and are willing to discuss with others. Patients can join TSC Connect by visiting The TS Alliance Educator Mentor program The TS Alliance also offers support to school systems that are educating a student with TSC and need support in understanding TSC or strategies to use in the classroom. The TS Alliance Educator Mentor program includes teachers, therapists, and administrators with experience in educating children with TSC. For more information, please contact Dena Hook, vice president of outreach, at dhook@tsalliance.org or Inspire.com provides an online patient support community for 750,000 patients and 3400 TSC board peers. The organization partners with respected national patient advocacy groups to provide safe online health and wellness communities in which patients, families, friends, and caregivers connect with one another for support and information. On the website, TSC patients can join groups about health topics that are important to them, make friends who share health interests, and control what they share with extensive privacy settings. Step Forward to Cure Tuberous Sclerosis Complex is a registered trademark of Tuberous Sclerosis Alliance Corporation. TSC In Depth - Winter/Spring 2018 { 22 } TSC Newsletter #2 Update DR.indd 22 2/5/18 12:27 PM