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Costs and Benefits of Syndrome Clarification in patients with Intellectual Disability and Epilepsy BRIDGE Bristol May 13-14th, 2010 Thomas Dorn Overview • Introduction • Case Report • Genetic Counseling – Importance of exact diagnosis • Prevention of complications, avoidance of wrong treatments • Identification of treatable/modifyable diseases • Ethical aspects • Legal aspects • Financial aspects (CH) • Summary • Future developments 2 Introduction Etiology of ingtellectual disability (IQ < 70) Rauch A et al.. Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. Am J Med Genet 2006; Part A 140A: 2063–2074. 3 Case Report (f, *1978) • • Intellectual disability (one-word sentences to express her requirements, behavioural disorder) Symptomatic generalised epilepsy with (in part serial) epileptic Spasms and atypical absences 4 Case Report (f, *1978) • • Intellectual disability (one-word sentences to express her requirements, behavioural disorder) Symptomatic generalised epilepsy with (in part serial) epileptic Spasms and atypical absences 5 Case Report (f, *1978) 6 Case Report (f, *1978) 7 Case Report (f, *1978) Discussion within the family concerning genetic tests 8 Case Report (f, *1978) Bilateral frontoparietal Polymicrogyria due to homozygous mutation in G-proteine receptor 56 gene in index patient not present in a healthy brother and his healthy consanguinous wife, but present in a heterozygous manner in the (consanguinous) parents Bilateral frontoparietal polymicrogyria, Lennox-Gastaut syndrome, and GPR56 gene mutations. Parrini E, Ferrari AR, Dorn T, Walsh CA, Guerrini R. Epilepsia. 2009;50:1344-53. Epub 2008 Oct 6. 9 Genetic Counseling – Importance of exact diagnosis Bilateral periventricular nodular heterotopia From: Stefan H: Epilepsien - Diagnose und Behandlung, Geigy-Verlag 1994 10 Genetic Counseling – Importance of exact diagnosis Bilateral periventricular nodular heterotopia • Genetics/Pathogenesis: – Usually X-chromosomal (Xq28) – Gene encoding Filamin 1 (= „actin-cross-linkingphosphoprotein“) – Mainly women, male patients rare, male gene carriership usually letal (missed abortion) or with cerebellar and extracerebral malformations – Impaired migration of neuronal cells • • • • Signs and symptoms: – Refractory epilepsy – Intellectual disability – Dysmorphic signs – Ductus botalli apertus – Coagulopathy Diagnosis – MRI Therapy (symptomatic): – Antiepileptic drugs – No surgical treatment of epilepsy – (surgical) treatment of extracerebral manifestations Genetic Counseling of women with child bearing potential 11 Genetic Counseling – Importance of exact diagnosis Bilateral periventricular nodular heterotopia Patient First seizures Seizure activity GO *1954, m 15 J seizure free > 1 Jahr with VPA+LTG+TPM Comorbidities supradiaphragmatic aortal aneurysma IV Social situation Genotype Filamin 1 - gene intron 11 acceptor splice site mutation, mosaicsm* AM *1969, w 18J 1 complex partial seizure/2 years with VPA+LTG none CC *1967, w 29 J 1 seizure/ 3 months with CBZ DW * 1973, m 10 J seizure freee with PHT Hydatid mole Psychosis Hair dresser, later job in selling, no work at present no filamin-1-mutation Textile engineer Banker no filamin-1-Mutation no filamin-1-Mutation *R. Guerrini, D. Mei, S. Sisodiya, F. Sicca, B. Harding, Y. Takahashi, T. Dorn et al Neurology 2004;63:51–56. E. Parrini, D. Mei, M. Wright,T. Dorn, R. Guerrini. Neurogenetics (2004) 5:191–196 12 Prevention of Complications/Avoidance of wrong tretaments Progressive myoclonic epilepsies – Myoclonic jerks, seizures, ataxia and intellectual decline/impairment Syndrome Age of manifestation Additional symptoms Unverricht-Lundborg 6-13 y None or mild cognitive impairment Lafora Ca. 15 y Visual loss (fast progression) Psychosis Ceroidlipofuscinoses 0.5 y (Santavuori) - > 30 y (Kufs, Parry) Visual loss (Atrophy of tractus opticus, retinopathy (except Kufs, Parry, northern epilepsy) Extrapyramidal Sympoms (Kufs, SpielmeyerVogt) Sialidosen During 1. y (type 2) „cherry red macular spots“, Visual Loss, 10-20 y (type 1) cataracta, choreoathetosis (type 1, 2) dysmorphia, dysostosis multiplex, hepatosplenomegaly, ascites (only type 2) DRPLA 1. –7. dekade (antecipation) Choreoathetosis MERRF Very variable Muscle weakness, hypacusis According to OMIM 3/04 13 Prevention of Complications/Avoidance of wrong tretaments Progressive myoclonic epilepsies – Antiepileptic Drugs • Phenytoine in Typ Unverricht-Lundborg causes irreversible worsening of neurological signs Berkovic SF, Cochius J, Andermann E et al. Epilepsia 1993; 34 Suppl 3: S19 - S30 • Valproate in mitochondrial Cytopathies could cause irreversible liver failure Krähenbühl S, Brandner S, Kleinle S et al. Liver 2000; 20:346 -348 14 Prevention of Complications/Avoidance of wrong tretaments Progressive myoklonic-Epilepsies – Antiepileptic Drugs • Phenytoine in Typ Unverricht-Lundborg causes irreversible worsening of neurological signs Berkovic SF, Cochius J, Andermann E et al. Epilepsia 1993; 34 Suppl 3: S19 - S30 • Valproate in mitochondrial Cytopathies could cause irreversible liver failure Krähenbühl S, Brandner S, Kleinle S et al. Liver 2000; 20:346 -348 • Cave: Differential diagnosis between these two entities is especially difficult at he beginning of the disease after the first seizures. It requires molecular genetic tests Dorn T. Epileptologie 2003; 3: 116 - 122 15 Identification of treatable/modifyable diseases • Methods: – All patients with IQ/DQ < 90 seen in the Sylvia To´th Centre between 2000 and 2005 – Examinations by a neuropedatrician, a clinical genetist, an expert for inborn erors of metabolism, a neuropsychologist, an ophthalmologist and MRI – 87% of patients had been thoroughly examined before (cytogenetic and metabolic screening, see tabl. 1) – Additional analysis according to clinical presentation: CSF(glucose, proteine, lactate, celles, amino acids, org. acids, 5hydroxyindolacetoacid, 5-hydroxytryptophane, homovanilliccacid, folic acid,GABA) hunger provocation, Glucose tolerance. 16 Identification of treatable/modifyable diseases • Results: – 12 of 433 patients diagnosed with “inborn error of metabolism” by • Repetition of tests done before • Screening for CreatinineMetabolites • Changed procedures for analysis and keeping of body fluids • Special tests due to clinical suspicion – 5 of 12 patients had treatable diseases: • Creatin transporter deficiency • 5-MTHF reductase deficiency, • GLUT1- deficiency • Hyperoxaluria 17 Ethical Aspects • Right to/not to know • Patient unable to give an informed consent • Family member´s wish for genetic counseling • Sociocultural: non-western concepts of disease, consanguinity 18 Ethical Aspects Swiss Academy of Medical Siences: Medical Treatment and Care of People with Disabilities Schweizerische Ärztezeitung 2008;89: 24 19 Ethical Aspects • Aims of guidelines und recommendations of SAMW – Claim of all people with disability for adeqaute treatment and care – Good medical treatment and care as prerequisite for support of disabled persons longing for selfdetermination and social participation – Help for medical, therapeutic and nursing practice with people with disabilities and their families – Recommendations to politics and society for favorable conditions for a good medical treatment and care for people with disabilities Schweizerische Ärztezeitung 2008;89: 24 20 Ethical Aspects • Diagnosis of etiology in the SAMW guidelines – Patient´s right to an adequate diagnostic approach into the nature and cause of the health problem – Exact diagnosis is a prerequisite for preventive, curative and rehabilitative treatment and – Provides prevention, early detection and better treatment of typical complications and additional diseases as well as – Greater acceptance and integration of disability into biography and is also – A prerequisite for genetic counseling Schweizerische Ärztezeitung 2008;89: 24 21 Ethical Aspects • Respect the autonomy of patients being not compentent to judge • Include the family and friends of the patient to support the communication as far as this meets his desire and interest • Spend enough time and use tools as necessary for communication • Cave: a necessary ability to sense the patient's will through empathy can lead both the family and the care team to project their own desires and prejudices Schweizerische Ärztezeitung 2008;89: 24 22 Legal Aspects • Patients unable to give informed consent • Information of familiy members in case of genetic counseling • scientific interests vs clinical reasons/genetic counseling as cause for genetic diagnostic procedures • Quality managment /Quality assurance of genetic laboratories (Certification) 23 Financial Aspects (CH) • „Analyseliste“: List of labaratory tests paid/not paid by health insurance (www.bag.admin.ch/kv/gesetze/d/index.htm) • „Positivliste“ = Laboratory tests fulfilling the criteria effecetiveness, usefulness and economicalness • „Territorialitätsprinzip“: tests are only paid when they can be performed by a laboratory located in CH • Tests not listed in „Analysenliste“ are not paid by obligatory health insurance, indpendently whether they are performed in CH or in another country. • Personal Experience: A genetic test for M. Niemann-Pick Typ C performed in germany was paid by obligatory health insurance in CH 24 Summary • In order to optimize treatment of people with intellectual disability and care of their families clarification of the underlying (often genetic) disease entity is very important. • Performance of the tests has to consider and respect ethical and legal principles • We hope that in future health insurances will pay all clinically indicated genetic tests 25 Future Developments – Genome wide analysis nature.com homepage •Jump to main content •Jump to navigation Login http://www.genetic-future.com/2008_06_01_archive.html Heike Fiegler, Richard Redon & Nigel P Carter Construction and use of spotted large-insert clone DNA microarrays for the detection of genomic copy number changes. Nature Protocols 2007; 2: 577 587 26 Future Developments – Genome wide analysis nature.com homepage •Jump to main content •Jump to navigation Login Cave: • too much data difficult to interprete • data protection http://www.genetic-future.com/2008_06_01_archive.html Heike Fiegler, Richard Redon & Nigel P Carter Construction and use of spotted large-insert clone DNA microarrays for the detection of genomic copy number changes. Nature Protocols 2007; 2: 577 587 27 nature.com homepage Future (Present?) Developments – Treament/Modification of underlying disease •Jump to main content •Jump to navigation Login Tuberous sclerosis is a serious inherited disease which poses major challenges for affected families and those caring for them. Identification of the genes causing the condition and study of their protein products has shed light on the pathogenesis of the disease and provided valuable new information about signalling pathways regulating protein synthesis and cell growth. There is now the exciting possibility of drug therapy for some of the manifestations of the disease. John R W Yates European Journal of Human Genetics 2006; 14: 1065–1073. 28 nature.com homepage Future (Present?) Developments – Treament/Modification of underlying disease •Jump to main content •Jump to navigation Login BMC Pharmacol. 2009 Apr 15;9:8. Rapamycin weekly maintenance dosing and the potential efficacy of combination sorafenib plus rapamycin but not atorvastatin or doxycycline in tuberous sclerosis preclinical models. Lee N, Woodrum CL, Nobil AM, Rauktys AE, Messina MP, Dabora SL. Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor syndrome, characterized by hamartomatous growths in the brain, skin, kidneys, lungs, and heart, which lead to significant morbidity. TSC is caused by mutations in the TSC1 or TSC2 genes, whose products, hamartin and tuberin, form a tumor suppressor complex that regulates the PI3K/Akt/mTOR pathway. Early clinical trials show that TSC-related kidney tumors (angiomyolipomas) regress when treated with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin (also known as sirolimus). Although side effects are tolerable, responses are incomplete, and tumor regrowth is common when rapamycin is stopped. Strategies for future clinical trials may include the investigation of longer treatment duration and combination therapy of other effective drug classes. RESULTS: Here, we examine the efficacy of a prolonged maintenance dose of rapamycin in Tsc2+/- mice with TSC-related kidney tumors. Cohorts were treated with rapamycin alone or in combination with interferon-gamma (IFN-g). The schedule of rapamycin included one month of daily doses before and after five months of weekly doses. We observed a 94.5% reduction in kidney tumor burden in Tsc2+/- mice treated (part one) daily with rapamycin (8 mg/kg) at 6 months <or= age < 7 months, (part 2) weekly with rapamycin (16 mg/kg) at 7 months <or= age < 12 months, and (part 3) daily with rapamycin (8 mg/kg) at 12 months <or= age < 13 months; but we did not observe any improvement with combination IFN-g plus rapamycin in this study. We also used a Tsc2-/- subcutaneous tumor model to evaluate other classes of drugs including sorafenib, atorvastatin, and doxycycline. These drugs were tested as single agents and in combination with rapamycin. Our results demonstrate that the combination of rapamycin and sorafenib increased survival and may decrease tumor volume as compared to rapamycin treatment alone while sorafenib as a single agent was no different than control. Atorvastatin and doxycycline, either as single agents or in combination with rapamycin, did not improve outcomes as compared with controls. CONCLUSION: Our results indicate that prolonged treatment with low doses of mTOR inhibitors may result in more complete and durable TSC-related tumor responses, and it would be reasonable to evaluate this strategy in a clinical trial. Targeting the Raf/Mek/Erk and/or VEGF pathways in combination with inhibiting the mTOR pathway may be another useful strategy for the treatment of TSC-related tumors. 29