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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
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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
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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
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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
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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