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Psychiatric comorbidity and treatment response in patients with tuberous sclerosis complex

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Behavioral and psychiatric comorbidity are common in tuberous sclerosis complex (TSC), but information regarding psychopharmacologic management is lacking. We reviewed clinical records of patients evaluated over a 20-month period at a large, quaternary referral center specializing in the comprehensive management of patients with TSC. Data were collected regarding psychiatric diagnoses, psychopharmacologic medications used to treat these disorders, and clinical response to treatment at follow-up. There were 113 encounters by 62 pediatric and adult patients with TSC, which were included in the present analysis. Behavioral and anxiety disorders were most prevalent, as were autism spectrum disorders and attention-deficit/hyperactivity disorder. Antipsychotics, antidepressants, and anticonvulsants with mood-stabilizing properties were the most often prescribed psychoactive medications and were associated with an overall improvement or stabilization of psychiatric symptoms 65% of the time. Psychiatric comorbidity, especially behavioral disorders, is very common among patients with TSC. Pharmacologic treatment can be very effective and should be considered for optimal disease management in affected individuals.
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ANNALS OF CLINICAL PSYCHIATRY
AACP.com Annals of Clinical Psychiatry | Vol. 23 No. 4 | November 2011 263
ANNALS OF CLINICAL PSYCHIATRY 2011;23(4):263-269
RESEARCH ARTICLE
BACKGROUND: Behavioral and psychiatric comorbidity are common in
tuberous sclerosis complex (TSC), but information regarding psychophar-
macologic management is lacking.
METHODS: We reviewed clinical records of patients evaluated over a
20-month period at a large, quaternary referral center specializing in
the comprehensive management of patients with TSC. Data were col-
lected regarding psychiatric diagnoses, psychopharmacologic medica-
tions used to treat these disorders, and clinical response to treatment at
follow-up.
RESULTS: There were 113 encounters by 62 pediatric and adult patients
with TSC, which were included in the present analysis. Behavioral and
anxiety disorders were most prevalent, as were autism spectrum disor-
ders and attention-deficit/hyperactivity disorder. Antipsychotics, anti-
depressants, and anticonvulsants with mood-stabilizing properties were
the most often prescribed psychoactive medications and were associ-
ated with an overall improvement or stabilization of psychiatric symp-
toms 65% of the time.
CONCLUSIONS: Psychiatric comorbidity, especially behavioral disorders, is
very common among patients with TSC. Pharmacologic treatment can be
very effective and should be considered for optimal disease management
in affected individuals.
KEYWORDS: tuberous sclerosis complex, psychiatric comorbidities,
behavior, treatment
Thomas K. Chung, MA
Elizabeth R. Lynch, MS
Cheryl J. Fiser, MSW, LISW-S
Daniel A. Nelson, MD
Karen Agricola, FNP
Cynthia Tudor, PNP
David Neal Franz, MD
Darcy A. Krueger, MD, PhD
Psychiatric comorbidity and treatment response
in patients with tuberous sclerosis complex
CORRESPONDENCE
Darcy A. Krueger, MD, PhD
Division of Child Neurology, MLC 2015
Cincinnati Children’s Hospital
Medical Center
3333Burnet Avenue
Cincinnati, OH 45229 USA
E-MAIL
kruger_darcy@cchmc.org
PSYCHIATRIC DISORDERS IN TUBEROUS SCLEROSIS
November 2011 | Vol. 23 No. 4 | Annals of Clinical Psychiatry 264
INTRODUCTION
Tuberous sclerosis complex (TSC)
is an autosomal dominant disease
with a prevalence of 1 in 6,000 to
10,000, irrespective of sex or race.
1
Disease manifestations are the
result of mutation of either TSC1 or
TSC2, resulting in dysregulation of
mTORC1, an essential intracellular
nutrient sensor and regulator of pro-
tein translation, cell growth, and dif-
ferentiation. Multiple organ systems
are affected, including the lungs,
kidneys, heart, and skin. Neurologic
manifestations are the primary
cause of disease morbidity in TSC,
including early-onset epilepsy (90%
of patients), developmental delay
(60%), intellectual disability (50%),
and autism (25%).
2
Psychiatric disorders also are common in TSC, but
prevalence estimates vary significantly (40% to 80%).
3
Furthermore, beyond prevalence estimates little or no
attention has been given to treatment options and out-
comes in TSC patients diagnosed with psychiatric dis-
orders. As such, it is readily recognized that psychiatric
diagnoses in this patient population often are overlooked,
undiagnosed, and left untreated.
4
The multidisciplinary TSC clinic at the Cincinnati
Childrens Hospital Medical Center (CCHMC) includes
board-certified specialists in both neurology and psychi-
atry who diagnose and treat pediatric and adult patients
with TSC. Our experience confirms the high prevalence
of psychiatric and behavioral disorders in TSC. However,
the paucity of evidence-based treatment recommenda-
tions and resulting outcomes in this patient population
lead us to examine more closely the individual psychi-
atric diagnoses, pharmacologic treatments utilized, and
resulting response to treatment. The results of our analy-
sis are reported here.
METHODS
This is a retrospective review of psychiatric encounters
of patients evaluated in the Tuberous Sclerosis Clinic
and Research Center at CCHMC between September
2007 and May 2009. Permission to perform this study
was obtained from the institutional review board (IRB) at
CCHMC. The CCHMC IRB waived the informed consent
requirement in accordance with title 45 CFR 26.116.
Only patients with a definite diagnosis of TSC,
either by established clinical criteria
5
and/or genetic
confirmation of disease-associated mutation in either
TSC1 or TSC2, were included in the analysis. Data col-
lection included demographic and genotype charac-
teristics, degree of cognitive impairment (by formal
neuropsychological testing when available or clinician
assessment), psychiatric profile, type and dosing of
psychopharmacologic agents prescribed, duration to
follow-up, and outcome response. Psychiatric diagno-
ses were made by a board-certified psychiatrist (D.N.)
in accordance with DSM-IV-TR criteria.
6
When multiple
diagnoses were present in a single patient, the initial
or most prominent diagnosis was assigned as the pri-
mary and any additional diagnoses were classified as
secondary.
Outcomes data were subgrouped by diagnosis and
treatment. Primary endpoint analysis was treatment
response, which was categorized according to parent
report and/or clinician assessment as either favorable
or unfavorable. Outcome was considered favorable if
psychiatric symptoms or behaviors were improved (ie,
decreased signs, symptoms, or behaviors compared
TSC without
psychiatric
comorbidity
60%
Behavioral disorders
Autism spectrum disorders
Anxiety disorders
Attention/hyperactivity disorders
Mood disorders
Thought disorders
TSC with
psychiatric
comorbidity
40%
37%
24%
16%
13%
5%
5%
FIGURE
Prevalence of psychiatric comorbidity in patients with TSC,
by type (primary diagnosis)
TSC: tuberous sclerosis complex.
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ANNALS OF CLINICAL PSYCHIATRY
265
with baseline accompanied by improved
social, occupational, or other areas of func-
tioning) or stabilized (ie, decreased problem-
atic signs, symptoms, or behaviors compared
with baseline but without evidence of accom-
panying improvement in social, occupational,
or other functional areas). All other out-
comes were classified as unfavorable, includ-
ing instances where response was mixed (in
patients with multiple diagnoses where some
improvement/stabilization might be seen
with 1 diagnosis but symptoms worsen in
the others) or unclear (insufficient informa-
tion to determine whether improvement or
worsening had occurred). Prevalence of indi-
vidual diagnosis was calculated by dividing the number
of a specific diagnosis by the total number of patients
included in the analysis (n = 62) and reported as a per-
centage. Frequency of treatment utilized was calculated
by dividing the number of times specific medication
was prescribed by the total number of patient encoun-
ters. Favorable outcome response was calculated by
dividing the number of patients with improved or stable
symptoms by the number of patients treated, for which
follow-up assessment was available. All calculations
were reported as mean ± standard deviation.
RESULTS
Patient characteristics
A total of 157 individual patients with TSC were evalu-
ated during the 21-month period, of which 62 were
formally diagnosed with a psychiatric comorbidity
(FIGURE). Some of the 62 patients who were diagnosed
with a psychiatric comorbidity were seen by the psy-
chiatrist multiple times, resulting in a total of 113 sep-
arate encounters for inclusion in the present study.
Four patients were seen once, without follow-up, and
therefore could not be included in outcomes analysis.
An additional 4 patients returned for follow-up once,
but not subsequently, so that outcomes analysis only
included the initial visit. In total, outcomes for 105
encounters were able to be determined: 32 patients had
1 full psychiatric assessment, 13 patients had 2 assess-
ments, and 13 patients had >3 assessments. The average
length of time from evaluation to follow-up assessment
for treatment outcome was 125 ± 81 days.
The average age at time of first encounter was
15.4 ± 9.5 years (range 3 to 48), but most (77%) were
age <21. Sex distribution was fairly equal (56% male,
44% female) (TABLE 1). With regard to baseline cogni-
tive function, 19 of the 62 patients were in the normal
or near-normal range (IQ ≥80), 22 were either border-
line or mildly disabled (IQ 60 to 79), and 30 had cog-
nitive function in the moderate-to-severe range (IQ 40
to 59). This pattern follows previous reported distribu-
tion of intellectual disability in TSC, with the excep-
tion that none in the present cohort had profound
intellectual disability that normally comprises up to
30% of patients with TSC.
7
Genetic testing results were
available for 31 patients, with 13% of patients having
mutation in TSC1, 64% in TSC2, and 23% had no muta-
tion identified. Sex and genotype characteristics are
consistent with that in the TSC patient population as
a whole.
8-10
Psychiatric diagnoses
A total of 150 psychiatric diagnoses were made in the 62
TSC patients in this cohort, providing a mean of 2.42 ±
1.27 diagnoses per patient (TABLE 2). Behavioral disor-
ders were the most common primary diagnoses (37%),
and consisted of intermittent explosive disorder, oppo-
sitional defiant disorder, and self-injurious behavior
disorder. Autism spectrum disorders (autism, pervasive
developmental disorder, and Asperger’s syndrome),
anxiety disorders (generalized anxiety disorder, panic
disorder, adjustment disorder, posttraumatic stress dis-
order, obsessive-compulsive disorder, selective mutism,
and individual phobias), and attention-deficit/hyperac-
tivity disorder (ADHD) also were frequent primary diag-
TABLE 1
Patient characteristics
Age at first visit (years) 15.40 ± 9.49
Age range (years) 3 to 48
Sex ratio (M:F) 35:27
Genotype (N = 31) TSC 1 4/31 (12.9%)
TSC 2 20/31 (64.5%)
NMI 7/31 (22.6%)
Total number of psychiatric encounters 113
Encounters with follow-up assessment 105/113 (92.9%)
Length to follow-up assessment (days) 125.5 ± 80.9
NMI: normalized mutual information; TSC: tuberous sclerosis complex.
PSYCHIATRIC DISORDERS IN TUBEROUS SCLEROSIS
November 2011 | Vol. 23 No. 4 | Annals of Clinical Psychiatry 266
noses (24%, 16%, and 13%, respectively). Mood disor-
ders and thought disorders were encountered but much
less prevalent (5%).
As a secondary diagnosis, behavioral disorders
remained the most common (61%). Anxiety disorders
(32%) and mood disorders (16%) were much more
frequently encountered as a secondary diagnosis than
as a primary diagnosis, whereas the converse was true
for autism spectrum disorders (13%). The frequency of
ADHD (15%) and thought disorder (5%) as a secondary
diagnosis were essentially the same as that for primary
diagnosis.
Pharmacologic treatments and response
As shown in TABLE 3, most patients were treated with
multiple psychoactive medications (average 2.35 ± 1.38,
range 0 to 5). Overall, medication was much more likely
to be initiated or increased (81% of encounters) than
decreased (7%) or maintained (30%) in these patients.
Upon follow-up, improvement was reported 48% of the
time and stabilization of symptoms 17% of the time.
However, in all instances the degree of this
favorable response varied significantly for
individual patients and some patients
reported a mixed response for distinct
psychiatric complaints or diagnoses.
Antipsychotic medications with
antidopaminergic properties were most
frequently prescribed for behavioral dis-
orders, and much less often for thought
disorders, in this population (TABLE 4).
Risperidone was prescribed in 46 of 113
patient encounters (41%) and favorable
outcome (improvement or stabilization)
was reported at follow-up in 30 encoun-
ters (65%). The next most frequently
prescribed medication in this class was
quetiapine, which was prescribed in 32
patient encounters (28%), which likewise
showed a positive benefit for 19 patients
at follow-up (59%). Aripiprazole was uti-
lized in only 10 encounters, 7 of which
had favorable responses. Other antipsy-
chotics such as haloperidol, olanzapine,
perphenazine, metirosine, and pimozide
were prescribed too infrequently to assess
response.
Selective serotonin reuptake inhibi-
tors (SSRIs) and related medications, such as the nor-
epinephrine/dopamine reuptake inhibitor bupropion,
were primarily prescribed for anxiety-related disorders
(particularly obsessive-compulsive and adjustment
disorders) and, to a lesser extent, mood disorders such
as depression or bipolar disorder. Most commonly,
escitalopram was utilized (38 of 113 patient encoun-
ters) and beneficial 42% of the time. Bupropion was of
benefit in 8 of 10 encounters in which it was prescribed.
Other SSRIs were prescribed too infrequently to assess
response.
Of the 62 patients with psychiatric comorbidity, 57
(92%) reported past or current history of seizures, which
is typical for TSC.
2
Of those included in the present
study, 72% were prescribed antiepileptic drugs (AEDs)
at the time they were evaluated by the psychiatrist. While
almost exclusively being used to prevent seizures in this
population, these medications also can have significant
effect on various psychiatric and behavioral conditions.
11
As shown in TABLE 4, valproic acid (20%) and lamotrigine
(16%) were most often prescribed, followed by benzodi-
TABLE 2
Psychiatric diagnoses in patients with TSC
(N = 62)
Number of psychiatric diagnoses per patient, n (%) 2.42 ± 1.27
1 17 (27.4%)
2 21 (33.9%)
3 11 (17.7%)
4 7 (11.3%)
5 6 (9.7%)
Psychiatric diagnosis by category Primary
n (%)
Secondary
n (%)
Behavioral disorders
(IED, ODD, SIB, impulse-control)
23 (37.1%) 38 (61.3%)
Autism spectrum disorders
(autism, PDD, Aspergers)
15 (24.2%) 8 (12.9%)
Anxiety disorders (panic, mutism,
adjustment, PTSD, OCD, GAD, phobia)
10 (16.1%) 20 (32.2%)
ADHD (inattention, hyperactivity, mixed) 8 (12.9%) 9 (14.5%)
Mood disorders (MDD, bipolar,
dysthymia/cyclothymia)
3 (4.8%) 10 (16.1%)
Thought disorders (schizophrenia,
psychosis, delirium)
3 (4.8%) 3 (4.8%)
ADHD: attention-deficit/hyperactivity disorder; GAD: generalized anxiety disorder; IED: intermittent
explosive disorder; MDD: major depressive disorder; OCD: obsessive-compulsive disorder; ODD:
oppositional defiant disorder; PDD: pervasive development disorder; PTSD: posttraumatic stress
disorder; SIB: self-injurious behavior; TSC: tuberous sclerosis complex.
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ANNALS OF CLINICAL PSYCHIATRY
267
azepines (15%) and oxcarbazepine (12%). Levetiracetam,
topiramate, phenytoin, carbamazepine, gabapentin,
zonisamide, phenobarbital, and vigabatrin were each
utilized <10% of the time. Although in the majority of
cases these medications were associated with a favor-
able outcome, in most instances they were unchanged
from assessment to follow-up (data not shown). Clinical
improvement was thought to be more likely the result of
adjustment in other psychoactive medications. However,
this does not exclude the possibility that these medica-
tions may have had an adjunctive role in the treatment of
psychiatric comorbidities in these patients.
For ADHD, methylphenidate and dexmethylpheni-
date were more often of benefit than not (9 of 12 reported
improvement or stabilization of symptoms), whereas
the alpha-adrenergic agents guanfacine and clonidine
were the opposite (7 of 10 reported worsening or mixed
response).
No specific pharmacologic treatments were utilized
to target autism spectrum disorders or personality disor-
ders directly. Rather, medications were prescribed irre-
spective of whether these disorders were present to treat
associated symptoms or comorbid psychiatric disorders
as above.
Finally, there is significant interest in the impact
pharmacologic inhibitors of mTORC1 (sirolimus, evero-
limus) might have on cognitive function and psychiatric
comorbidity in this population,
12
but no clinical experi-
ence with these agents in this regard have been reported.
Therefore, we feel it important to report the response of
3 patients treated with these medications in this group.
Patients were age 10, 18, and 19, and were diagnosed with
intermittent explosive disorder (patient 1) and adjust-
ment disorder NOS (patients 2 and 3). Everolimus was
added to the regimen of patients 1 and 2 and sirolimus
to patient 3. Upon follow-up 1 to 4 months later, each
reported improvement in psychiatric symptoms.
DISCUSSION
Here we report the prevalence of psychiatric comorbidity
in patients with TSC evaluated and treated by a board-
certified psychiatrist within the multidisciplinary clinic at
the quaternary referral center of the CCHMC. Behavioral
disorders, autism spectrum disorders, anxiety disorders,
and ADHD were found to occur in the highest frequency
in this group.
Previous estimates of psychiatric comorbidity and
symptoms in patients with TSC have been highly vari-
able, likely attributable to the different patient popu-
lations and research methodologies employed. For
example, postal questionnaire responses from parents
of 300 patients with TSC found aggressive behaviors
and related difficulties in >56% of patients, including
aggression, tantrums, noncompliance with caregiv-
ers, and self-injury.
13
Behaviors associated with autism
spectrum disorder, including social impairment and
obsessive/ritualistic activities, ranged from 25% to 43%,
and hyperactivity was reported in 28% of these patients.
Another review of published case series of autism and
TSC found that the 2 disorders coexisted in 17% to 58%
of cases.
14
More recently, neuropsychological assess-
ment tools and patient or parent report of psychological
symptoms have been employed, but with inconsistent
results: anxiety disorders ranging from 5% to 56%, affec-
tive disorders ranging from 4% to 43%, and thought dis-
orders ranging from 1% to 43%.
15-19
In contrast to these earlier studies, the current
analysis was limited to patients evaluated and diag-
nosed by a board-certified clinical psychiatrist with
experience and familiarity with TSC. The importance
of clinical expertise in diagnosing psychiatric disorders
in patients with TSC cannot be overemphasized; there
is inherent difficulty in distinguishing psychiatric ill-
ness from other central nervous system (CNS) aspects
of TSC, including intellectual disability, epilepsy, and
autism. Furthermore, many treatments, particularly
for epilepsy, can cause deterioration or alteration of
CNS function such that psychiatric illness is masked or
mimicked. On a similar note, AEDs may exert a favor-
able impact on psychiatric disorders and symptoms.
11
TABLE 3
Psychoactive medications prescribed
in patients with TSC (N = 113)
Psychiatric medications prescribed
per encounter, n (%)
2.35 ± 1.38
0 11 (9.7%)
1 18 (15.9%)
2 38 (33.6%)
3 21 (18.6%)
4 16 (14.2%)
5 9 (8.0%)
TSC: tuberous sclerosis complex.
PSYCHIATRIC DISORDERS IN TUBEROUS SCLEROSIS
November 2011 | Vol. 23 No. 4 | Annals of Clinical Psychiatry 268
Although certainly more subjective than many alterna-
tive approaches, the clinical assessment utilized in the
present study does provide an opportunity for sepa-
rating psychiatric diagnoses from the important and
unavoidable confounders present in people with TSC.
This approach is also more likely to represent actual
practitioner experience.
An obvious limitation of the methodology used here
is the referral bias that was unavoidably introduced. Even
though the CCHMC has a psychiatrist present in clinic,
not all patients with TSC were able to be evaluated and
treated by the psychiatrist because of time and avail-
ability constraints. As a result, overall prevalence esti-
mates herein likely underestimate the true prevalence in
patients with TSC. However, those included largely repre-
sent the most symptomatic and severely affected psychi-
atric patients, and thus the reported treatments utilized
and responses thereof become all the more relevant.
Only one study to date has reported on the preva-
lence of psychiatric disorders in patients with TSC, using
evaluation by a clinical psychiatrist as in the present
study.
3
A study by Muzykewicz et al
3
included 43 patients
with an average age of 19 (range 2 to 49 years). Of these,
98% received a psychiatric diagnosis and 33% had fea-
tures of autism spectrum disorders, similar to our find-
ings here. Specific psychiatric disorder frequencies also
were consistent with our findings. The study, however,
limited analysis and discussion of treatment to only
12 patients treated with citalopram for anxiety or mood
disorders and risperidone for aggressive behaviors.
The present study expands significantly on phar-
macologic management of comorbid psychiatric dis-
orders in patients with TSC. Specific dosing practices
at our center have been published previously.
1
In the
present analysis, favorable treatment responses were
observed with risperidone, quetiapine, and aripiprazole
for aggressive behaviors 59% to 70% of the time. Benefit
with escitalopram and bupropion was observed 42% to
80% of the time for treatment of anxiety symptoms, com-
pulsive thoughts and behaviors, and mood disorders.
Similarly, methylphenidate and dexmethylphenidate
were effective in the treatment of ADHD symptoms.
All 3 patients treated with mTORC1 inhibitors dem-
onstrated clinical improvement in psychiatric symptoms.
The mechanism responsible for this improvement is not
known, but could represent a novel strategy for the treat-
ment of psychiatric disorders and other neuropsychiatric
conditions associated with TSC, as current treatments
TABLE 4
Medication response in TSC patients
with psychiatric comorbidity
CLASS Favorable response
(improvement or
stabilization)
Antipsychotics n (%)
Risperidone 30/46 (65.2%)
Quetiapine 19/32 (59.4%)
Aripiprazole 7/10 (70.0%)
Haloperidol 0/1 (0.0%)
Olanzapine 2/3 (66.7%)
Perphenazine 1/1 (100.0%)
Metirosine 0/1 (0.0%)
Pimozide 1/2 (50.0%)
Antidepressants
Escitalopram 16/38 (42.1%)
Bupropion 8/10 (80.0%)
Citalopram 2/2 (100.0%)
Fluoxetine 3/5 (60.0%)
Venlafaxine 0/2 (0.0%)
Amitriptyline 7/10 (70.0%)
Trazodone 0/1 (0.0%)
Doxepin 0/1 (0.0%)
Imipramine 1/1 (100.0%)
Mood stabilizers
Lithium 2/2 (100.0%)
Lamotrigine 14/18 (77.8%)
Oxcarbazepine 11/14 (78.6%)
Valproic acid 16/23 (69.6%)
Stimulants
Methylphenidate 6/8 (75.0%)
Dexmethylphenidate 3/4 (75.0%)
Alpha-adrenergic agonists
Guanfacine 2/5 (40.0%)
Clonidine 1/5 (20.0%)
Anxiolytics
Lorazepam 10/14 (71.4%)
Clonazepam 0/2 (0.0%)
Chlordiazepoxide 0/1 (0.0%)
Other
Naltrexone 2/2 (100.0%)
Sirolimus 1/1 (100.0%)
Everolimus 2/2 (100.0%)
TOTAL
(includes combined treatment)
73/113 (64.6%)
TSC: tuberous sclerosis complex.
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ANNALS OF CLINICAL PSYCHIATRY
269
almost exclusively target neurotransmitter release and
uptake. In contrast, a variety of mechanisms have been pos-
tulated which could impact CNS function at the molecular
and neuronal level, including changes in neuronal den-
drite structure, synaptic plasticity, surface receptor expres-
sion, and long-term potentiation and depression.
12,20,21
CONCLUSIONS
Psychiatric comorbidity is highly prevalent and should
not be overlooked in the comprehensive management of
patients affected with TSC. Treatments are readily avail-
able and effective for the treatment of psychiatric symp-
toms in these patients.
DISCLOSURES: Ms. Tudor is a speaker for Novartis. Dr.
Franz receives grant/research support from Novartis,
is a consultant to Novartis, and is a speaker for UCB
Pharma and Novartis. Dr. Krueger receives grant/
research support from Novartis and Lundbeck, and
is a speaker for Novartis. Mr. Chung, Dr. Nelson,
Ms. Agricola, Ms. Lynch, and Ms. Fiser report no finan-
cial relationship with any company whose products
are mentioned in this article or with manufacturers of
competing products.
Thomas K. Chung, MA
Elizabeth R. Lynch, MS
Departments of Pediatrics and Neurology
Cincinnati Children’s Hospital Medical Center
Cincinnati, OH, USA
Cheryl J. Fiser, MSW, LISW-S
Division of Social Services
Cincinnati Children’s Hospital Medical Center
Cincinnati, OH, USA
Daniel A. Nelson, MD
Division of Child and Adolescent Psychiatry
Cincinnati Children’s Hospital Medical Center
Cincinnati, OH, USA
Karen Agricola, FNP
Cynthia Tudor, PNP
David Neal Franz, MD
Darcy A. Krueger, MD, PhD
Departments of Pediatrics and Neurology
Tuberous Sclerosis Clinic and Research Center
Cincinnati Children’s Hospital Medical Center
Cincinnati, OH, USA
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injurious behavior and tuberous sclerosis complex: fre-
quency and possible associations in a population of 257
patients. Epilepsy Behav. 2008;13:650-653.
20. Ess KC. The neurobiology of tuberous sclerosis
complex. Semin Pediatr Neurol. 2006;13:37-42.
21. Jaworski J, Sheng M. The growing role of mTOR in
neuronal development and plasticity. Mol Neurobiol.
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REFERENCES
... Individuals with severe intellectual disability due to TSC have higher levels of verbal disability that do those with severe intellectual disability from other causes [39]. Many individuals with TSC have more than one neuropsychiatric disorder [40,41]. ...
... Autism 25-61% [21,23,24,40,[42][43][44][45][46][47] Intellectual impairment and the presence of infantile spasms are associated with higher risks for both autism and ADHD [36,48]. ...
... A study on individuals with TSC in transition from pediatric treatment found frequent sadness and depression in 60% of patients and high anxiety in 40% [53]. Chung et al. [40] demonstrated in a retrospective analysis that behavioral problems and mood disorders can be successfully treated medically in about two-thirds of afflicted individuals. ...
Article
Full-text available
Objective: This review will summarize current knowledge on the burden of illness (BOI) in tuberous sclerosis complex (TSC), a multisystem genetic disorder manifesting with hamartomas throughout the body, including mainly the kidneys, brain, skin, eyes, heart, and lungs. Methods: We performed a systematic analysis of the available literature on BOI in TSC according to the PRISMA guidelines. All studies irrespective of participant age that reported on individual and societal measures of disease burden (e.g. health care resource use, costs, quality of life) were included. Results: We identified 33 studies reporting BOI in TSC patients. Most studies (21) reported health care resource use, while 14 studies reported quality of life and 10 studies mentioned costs associated with TSC. Only eight research papers reported caregiver BOI. Substantial BOI occurs from most manifestations of the disorder, particularly from pharmacoresistant epilepsy, neuropsychiatric, renal and skin manifestations. While less frequent, pulmonary complications also lead to a high individual BOI. The range for the mean annual direct costs varied widely between 424 and 98,008 International Dollar purchasing power parities (PPP-$). Brain surgery, end-stage renal disease with dialysis, and pulmonary complications all incur particularly high costs. There is a dearth of information regarding indirect costs in TSC. Mortality overall is increased compared to general population; and most TSC related deaths occur as a result of complications from seizures as well as renal complications. Long term studies report mortality between 4.8 and 8.3% for a follow-up of 8 to 17.4 years. Conclusions: TSC patients and their caregivers have a high burden of illness, and TSC patients incur high costs in health care systems. At the same time, the provision of inadequate treatment that does not adhere to published guidelines is common and centralized TSC care is received by no more than half of individuals who need it, especially adults. Further studies focusing on the cost effectiveness and BOI outcomes of coordinated TSC care as well as of new treatment options such as mTOR inhibitors are necessary.
... İki haftadır hareketlilik, sinirlilik, saçma konuşma, uygunsuz gülme, şüphecilik ve saldırganlık yakınmaları olan hastaya daha önce bipolar bozukluk tanısı konduğu, fakat düzenli psikiyatrik tedavi ve kontrollerinin yapılmadığı TS'de görülen psikiyatrik bozukluklar arasında; MR, davranışsal bozukluklar, otizm ilk sıralarda gelmekte (2,(15)(16)(17), anksiyete bozuklukları ve DEHB'nin de sık görüldüğü belirtilmektedir (16,17). Duygudurum ve düşünce bozukluklarına ise daha az rastlanmaktadır (16). ...
... İki haftadır hareketlilik, sinirlilik, saçma konuşma, uygunsuz gülme, şüphecilik ve saldırganlık yakınmaları olan hastaya daha önce bipolar bozukluk tanısı konduğu, fakat düzenli psikiyatrik tedavi ve kontrollerinin yapılmadığı TS'de görülen psikiyatrik bozukluklar arasında; MR, davranışsal bozukluklar, otizm ilk sıralarda gelmekte (2,(15)(16)(17), anksiyete bozuklukları ve DEHB'nin de sık görüldüğü belirtilmektedir (16,17). Duygudurum ve düşünce bozukluklarına ise daha az rastlanmaktadır (16). ...
... İki haftadır hareketlilik, sinirlilik, saçma konuşma, uygunsuz gülme, şüphecilik ve saldırganlık yakınmaları olan hastaya daha önce bipolar bozukluk tanısı konduğu, fakat düzenli psikiyatrik tedavi ve kontrollerinin yapılmadığı TS'de görülen psikiyatrik bozukluklar arasında; MR, davranışsal bozukluklar, otizm ilk sıralarda gelmekte (2,(15)(16)(17), anksiyete bozuklukları ve DEHB'nin de sık görüldüğü belirtilmektedir (16,17). Duygudurum ve düşünce bozukluklarına ise daha az rastlanmaktadır (16). Duygudurum bozukluklarından en sık gözlenen majör depresif epizodlardır (18). ...
Article
Full-text available
Tuberoskleroz beyin, deri, göz, kalp ve böbrek gibi çok sayıda organda hamartomatöz büyümenin gözlendiği genetik bir has- talıktır. Merkezi sinir sistemi belirtileri hastaların çoğunda bildirilmiştir ve sıklıkla beyinde yapısal lezyonlara rastlanır. Tube- roskleroz hastalarında en sık rastlanan psikiyatrik bozukluklar arasında otizm, duygudurum bozuklukları ve dikkat eksikliği hiperaktivite bozukluğu sayılmaktadır. Şizofreni dahil psikotik bozukluklar da bildirilen eştanılardandır. Burada epileptik nöbetler, psikotik belirtili bipolar bozukluk ve şiddet davranışı gözlenen, antiepileptik ve antipsikotiklerin yanısıra lityumla tedavi edilen bir olgu sunulmuştur. Yirmi iki yaşında, önceden bilinen tuberoskleroz tanısı olan erkek hasta, ailesi tarafından acil psikiyatri ünitesine getirilerek, şiddet davranışı (annesine bıçakla saldırma) nedeniyle yatırıldı. Psikiyatrik muayenede irritabl duygudurum, görsel varsanılar ve perseküsyon sanrıları, dezorganize konuşma, fakirleşmiş düşünce içeriği saptandı ve içgörüsü az olarak değerlendirildi. Has- tanın nöbetleri topiramat ve okskarbazepinle, psikotik belirtileri risperidon ve ketiyapinle tedavi edildi. Duygudurum belirtileri ve agresif davranışları ise lityumla kontrol altına alındı. Tuberoskleroz olgularının önemli bir kısmında psikiyatrik bozukluklar görülmektedir ve bunlardan bir kısmını duygudurum bozuklukları ve psikoz oluşturmaktadır. Bu olgularda agresif ve yıkıcı davranışlar da bildirilmiştir. Etkin tedavi hastaların psiki- yatrik belirtilerini iyileştirmenin yanı sıra yaşam kalitesini arttırmada da büyük önem taşımaktadır. Tuberoskleroz olgularında lityum, hem duygudurum belirtilerinin hem de agresif davranışların kontrolünde yararlı bir seçenek olabilir.
... It is important to note that studies reporting on psychiatric comorbidities (e.g. [121,122]) were largely based on psychiatric or clinical evaluation, and the specific details of diagnostic measures used were not provided. IQ measures included assessments such as the Bayley Scales of Infant Development, second edition [123] and the Wechsler Intelligence Scale for Children, third edition [124]. ...
Article
Full-text available
Background Tuberous sclerosis complex (TSC)–associated neuropsychiatric disorders (TAND) is an umbrella term for the behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations of TSC. Although TAND affects 90% of individuals with TSC during their lifetime, these manifestations are relatively under-assessed, under-treated and under-researched. We performed a comprehensive scoping review of all TAND research to date (a) to describe the existing TAND research landscape and (b) to identify knowledge gaps to guide future TAND research. Methods The study was conducted in accordance with stages outlined within the Arksey and O’Malley scoping review framework. Ten research questions relating to study characteristics, research design and research content of TAND levels and clusters were examined. Results Of the 2841 returned searches, 230 articles published between 1987 and 2020 were included (animal studies = 30, case studies = 47, cohort studies = 153), with more than half published since the term TAND was coined in 2012 (118/230; 51%). Cohort studies largely involved children and/or adolescents (63%) as opposed to older adults (16%). Studies were represented across 341 individual research sites from 45 countries, the majority from the USA (89/341; 26%) and the UK (50/341; 15%). Only 48 research sites (14%) were within low–middle income countries (LMICs). Animal studies and case studies were of relatively high/high quality, but cohort studies showed significant variability. Of the 153 cohort studies, only 16 (10%) included interventions. None of these were non-pharmacological, and only 13 employed remote methodologies (e.g. telephone interviews, online surveys). Of all TAND clusters, the autism spectrum disorder–like cluster was the most widely researched (138/230; 60%) and the scholastic cluster the least (53/200; 27%). Conclusions Despite the recent increase in TAND research, studies that represent participants across the lifespan, LMIC research sites and non-pharmacological interventions were identified as future priorities. The quality of cohort studies requires improvement, to which the use of standardised direct behavioural assessments may contribute. In human studies, the academic level in particular warrants further investigation. Remote technologies could help to address many of the TAND knowledge gaps identified.
... There is no specific treatment for the disease but a 20th month follow-up study of 113 patients reported that antipsychotic medication can improve the mental symptoms and stabilize the mood of individuals with TS (Chung et al.). 3 Current guidelines on the management of epilepsy in TS emphasizes greatly on early recognition and prompt treatment of epilepsy. 12 Multiple drug therapies are ongoing and research projects are being carried out in the world for further workup of the genes involved and treatment strategies. ...
... The mTOR inhibitor rapamycin was shown to have dramatic benefits for patients with tuberous sclerosis and giant cell astrocytomas; demonstrable tumor shrinkage was noted in the majority of patients, which was durable as long as the medication was maintained [4,5]. Rapamycin 106 о Б З о Р л И т е Р А т У Р ы treatment also resulted in clinical benefit for patients, including, in some, improved seizure control [6,7]. A second generation mTOR inhibitor everolimus (RAD001), has also benefited some patients with sporadic and NF1-associated PAs and possibly other ...
... There is no specific treatment for the disease but a 20th month follow-up study of 113 patients reported that antipsychotic medication can improve the mental symptoms and stabilize the mood of individuals with TS (Chung et al.). 3 Current guidelines on the management of epilepsy in TS emphasizes greatly on early recognition and prompt treatment of epilepsy. 12 Multiple drug therapies are ongoing and research projects are being carried out in the world for further workup of the genes involved and treatment strategies. ...
Article
Full-text available
Tuberous sclerosis (TS) is a rare disorder of genetic origin, caused by mutations in the genes TSC1 and TSC2. It is characterized by benign tumors with multisystem involvement resulting in dermatological, nephrological, neurological and psychiatric manifestations. We are presenting a case of a 21 years old male with tuberous sclerosis presenting with dermatological manifestations, seizures, intellectual disability and psychiatric manifestations including delusions and hallucinations, developing extrapyramidal symptoms after antipsychotic administration. Neuroimaging showed characteristic subependymal calcified nodules. With appropriate anticonvulsant and antipsychotic medications he showed clinical improvement.
... Examination of overactivity and impulsivity has also primarily considered psychiatric diagnostic status of attention deficit hyperactivity Disorder (ADHD) rather than behavioral presentation, with few studies even differentiating ADHD subtypes (Chung et al., 2011;Huang, Peng, Weng, Su, & Lee, 2015). Evidence suggests that in children and adolescents, overactivity and impulsivity correlate strongly with the presence or absence of ID , and there is some indication that overactivity may decrease with age (see Table 2). ...
Article
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Tuberous sclerosis complex (TSC) is associated with a wide range of behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties, which are often underdiagnosed and undertreated. Here, we present a clinical update on TSC‐associated neuropsychiatric disorders, abbreviated as “TAND,” to guide screening, diagnosis, and treatment in practice. The review is aimed at clinical geneticists, genetic counselors, pediatricians, and all generalists involved in the assessment and treatment of children, adolescents and adults with TSC, and related disorders. The review starts with a summary of the construct and levels of TAND, before presenting up‐to‐date information about each level of investigation. The review concludes with a synopsis of current and future TAND research.
Article
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Objective: Tuberous sclerosis complex (TSC) is a rare multisystem disorder, often associated with epilepsy. This retrospective study aimed to identify patients with TSC, including those with epilepsy, from a French healthcare claims database, and to report incidence, prevalence, and healthcare costs and resource utilization. Methods: The anonymized French health insurance database (SNDS) covers almost the entire French population. Patients with TSC were identified as having ≥1 International Classification of Diseases, Tenth Revision (ICD-10) diagnosis code Q85.1 or a long-term disease (LTD) registration over the inclusion period (2006-2017). Patients with an ICD-10 epilepsy code or who were dispensed ≥1 antiseizure medication (ASM) in the same year or after their TSC diagnosis were identified as having TSC with epilepsy. Newly diagnosed patients over the inclusion period constituted the incident cohort. Healthcare costs (patients with recorded costs only), healthcare resource use, and ASM dispensation are reported for patients with 2018 data. Results: In 2018, 3139 prevalent patients with TSC were identified (crude prevalence, 4.69 per 100 000); the incident cohort comprised 2988 patients (crude incidence, 0.44 per 100 000). Among patients with TSC, 67% (2101/3139) had epilepsy (mean [standard deviation, SD] age: 28.8 [18.8] years; male: 48%). Among patients with epilepsy, total mean (SD) annual healthcare costs were €11 413 (27 620) per capita (outpatient, 63%; inpatient, 37%), 46% were hospitalized during 2018 (mean [SD]: 1.8 [10.9] acute care visits per patient), and 65% visited a hospital specialist. Among patients with epilepsy, medication (mean [SD]: €4518 [12 102] per capita) was the greatest contributor (63%) to outpatient costs, and in 2018, 74% were dispensed ≥1 different ASM and 9% were dispensed ≥4 ASMs. Significance: TSC with epilepsy was associated with substantial healthcare costs and resource utilization, particularly outpatient and medication costs. Many patients with TSC with epilepsy were prescribed multiple ASMs, suggesting refractory epilepsy.
Article
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by a multisystemic involvement. In TSC, reduced function of TSC1 and TSC2 genes products (hamartin and tuberin, respectively) leads to an hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and to a consequent cell growth dysregulation. In TSC patients, neurological and neuropsychiatric manifestations, especially epilepsy and neuropsychiatric comorbidities such as autism or intellectual disability, represent the most disabling features. In particular, epilepsy occurrs up to 80% of patients, is often drug resistant and is frequently associated with neurological impairment. Due to the burden of this morbidity, different treatment strategies have been proposed with the purpose to make patients epilepsy free, such as the use of different antiepileptic drugs like vigabatrin, carbamazepine, valproic acid, and levetiracetam. More recently, a mTOR inhibitor (i.e. everolimus) has showed promising results in terms of seizures reduction.
Article
Objective: To describe the prevalence and characteristics of comorbidities in persons with rare epilepsies. Study design: Persons with rare epilepsies and caregivers of those affected were recruited through the Epilepsy Foundation and more than 30 rare epilepsy advocacy organizations affiliated with the Rare Epilepsy Network (REN). A web-based survey was conducted using a questionnaire consisting of core sections to collect data from affected persons on various aspects, including comorbidities. Comorbidity information was grouped into 15 classes, 12 of which had a stem question followed by detailed branch questions and 3 that were created from a combination of related questions. Results: Of 795 persons with more than 30 different rare epilepsy diagnosis groups, one-half had ≥5 comorbidity classes and 97% were classified as complex chronic disease (C-CD). The highest number of comorbidity classes reported per person were persons with Aicardi syndrome, Phelan-McDermid syndrome (median, 7.0; IQR, 5.0-9.0), and tuberous sclerosis complex (median, 6.0; IQR, 4.0-8.0). The most common comorbidity classes were learning/developmental disability (71%), mental health issues (71%), sleep disorders (60%), brain abnormalities (52%), oral issues (49%), bone-joint issues (42%), hyper/hypotonia (42%), and eye-vision disorders (38%). The prevalence of brain abnormalities, hyper/hypotonia, eye, and cardiac disorders was significantly higher in persons first diagnosed with epilepsy at a younger age (<9 months) than in those first diagnosed at an older age (P < .05 for trend). Conclusions: Nearly all persons with rare epilepsies are medically complex, with a high prevalence of multiple comorbidities, especially those who were diagnosed with epilepsy in the first year of life. Comorbidities should be carefully considered in the diagnosis and management of persons with rare epilepsies.
Article
Full-text available
Tuberous sclerosis complex (TSC) is an important cause of epilepsy, autism, and renal and pulmonary disease in children and adults. The clinical course of TSC and the prognosis and appropriate therapy for TSC patients are often different than that for individuals with epilepsy, renal tumors, or interstitial lung disease from other causes. This article reviews the current therapeutic recommendations for medical and surgical management of neurologic, renal, and pulmonary manifestations of TSC. In addition, recent clinical trials using inhibitors of the mammalian target of rapamycin (mTOR) have demonstrated regression of astrocytomas, angiofibromas, and angiomyoliomas, as well as improved pulmonary function in persons with TSC.
Article
Tuberous sclerosis complex (TSC, MIM 191090 and 191100) is an autosomal dominant, multisystem disorder characterised by the development of a variety of hamartomatous growths.1 The TSC phenotype includes renal involvement (in over 80% of patients) with angiomyolipomas and cysts; skin involvement with facial angiofibromas, hypomelanotic macules, shagreen patches, and periungual fibromas; and cardiac, ophthalmic, and pulmonary involvement. Many of the frequent and serious complications of TSC, including epilepsy, mental retardation, and a wide range of psychiatric and behavioural disorders, reflect the cerebral involvement that occurs in over 90% of cases. Structural abnormalities in the brain include: cortical tubers that are localised areas of loss of normal hexalaminar cortical organisation, and that contain abnormal and enlarged cells categorised as cytomegalic neurones and balloon cells; subependymal nodules that are localised proliferations of abnormal cells in the periventricular zone; and migration tracts through the white matter linking subependymal and cortical lesions. Mental retardation is estimated to occur in approximately 45% of cases.2 It is virtually always associated with a history of seizures correlated with early seizure onset, poor seizure control, and type of seizure at onset with the greatest risk for infantile spasms.3 The association between mental retardation and infantile spasms is particularly strong in the context of TSC.4 People with TSC are also reported to have high rates of autistic disorder, attention deficit hyperactivity disorder (ADHD), and sleep disorder. Although autistic disorder is a feature of several genetic disorders of childhood, its frequency is highest in TSC,5 and the strength of the association does not appear to be explained simply by the frequency of infantile spasms in TSC.6 Sleep disorder in TSC is associated with the presence of other behavioural problems and can be exacerbated by nocturnal seizures.7,8 There are also anecdotal reports of …
Article
Autism is a behavior disorder with genetic influences indicated from twin and family studies and from the cooccurrence of autism with known genetic disorders. Tuberous sclerosis complex (TSC) is a known genetic disorder with behavioral manifestations including autism. A literature review of these two disorders substantiates a significant association of autism and TSC with 17–58% of TSC subjects manifesting autism and 0.4–3% of autistic subjects having TSC. In initial data collected on 13 TSC probands and 14 autistic probands in our family study of autism and TSC, we identified 7 TSC subjects with autism. The seven TSC autistic probands are similar to non-TSC autistic probands on the Social and Communication domains of the Autism Diagnostic Inventory (ADI) (Le Couteur et al., 1989), but show fewer Repetitive Rituals. There are more male TSC probands with autism than female, despite an equal sex ratio among TSC probands. The TSC probands with autism have significantly more seizures and mental retardation than those without autism; however, the extent and etiology of associations require further study. Our preliminary findings suggest that a fruitful approach for delineating genetic influences in autism may come from further investigation of possible mechanisms underlying the association of autism and TSC.
Article
The Symptom Checklist-90-Revised, a standardized self-report measure of psychological symptoms, was administered to 42 adults with tuberous sclerosis complex (TSC). Approximately 45% reported high overall psychological distress, most commonly involving interpersonal sensitivity, psychoticism, depression, and obsessive-compulsive symptoms. Symptoms were related to number of organ systems affected by TSC and, in some cases, to seizure history, but not to genotype, IQ, education, severity of epilepsy, or use of anticonvulsant or psychiatric medication.
Article
Tuberous sclerosis (TSC) is a multi-system disorder caused by heterozygous mutations in the TSC1 or TSC2 gene and is often associated with neuropsychiatric symptoms, including intellectual disability, specific neuropsychological deficits, autism, other behavioural disorders and epilepsy. Here, we review evidence from animal models of TSC for the role of specific molecular and cellular processes in the pathogenesis of cognitive, developmental and epilepsy-related manifestations seen in the disorder. Recent evidence shows that, in animal models, disinhibited mTOR (mammalian target of rapamycin) signalling substantially contributes to neuropsychiatric phenotypes, including cognitive deficits and seizures. We discuss potential pathogenetic mechanisms involved in the cognitive phenotypes of TSC and present implications regarding mTOR inhibitor-based treatments for TSC-related neuropsychiatric features. Results suggest that reversing the underlying molecular deficits of TSC with rapamycin or other mTOR inhibitors could result in clinically significant improvements of cognitive function and neurological symptoms, even if treatments are started in adulthood.
Article
Self-injurious behavior (SIB) has been observed in people with tuberous sclerosis complex (TSC), although the frequency of SIB in TSC is largely unknown. SIB is associated with intellectual and developmental disabilities, but there is no single cause of SIB. We retrospectively examined the frequency of SIB in a population of 257 patients with TSC and determined possible associations with SIB. We found a 10% frequency of SIB in our TSC population. When compared with patients without psychiatric symptoms, we identified a significantly higher rate of electroencephalographic interictal spikes in the left frontal lobe and a significantly lower number of tubers in the left occipital, parietal, and posterior temporal lobes. We also found that frequency of TSC2 mutation, history of infantile spasms, history of seizures, mental retardation, and autism are significantly associated with SIB.
Article
An estimate of the prevalence of autism in tuberous sclerosis (TSC) was made by interviewing the parents of 21 children between ages 3 and 11 ascertained during a previous population study of the condition in the West of Scotland. Five of the children (24%) were rated autistic and a further four (19%), all of whom were girls, had socially impaired behavior categorized as pervasive developmental disorder, without fulfilling all the DSM-III-R criteria for autism. One further boy had disruptive attention-seeking behavior that had excluded him from his normal school. The estimated prevalence from this study of autism in TSC is 1 in 4 children in general, and 1 in 2 of those with mental retardation. Tuberous sclerosis could be a significant cause of autism and pervasive developmental disorders, particularly in girls.
Article
At the recent tuberous sclerosis complex consensus conference, the clinical diagnostic criteria for tuberous sclerosis complex were simplified and revised to reflect both new clinical information about tuberous sclerosis complex and an improved understanding of the disorder derived from molecular genetic studies. Based on this new information, some clinical signs once regarded as pathognomonic for tuberous sclerosis complex are now known to be less specific. No single sign is present in all affected patients, and there is no proof that any single clinical or radiographic sign is absolutely specific for tuberous sclerosis complex. Accordingly, the clinical and radiographic features of tuberous sclerosis complex have now been divided into major and minor categories based on the apparent degree of specificity for tuberous sclerosis complex of each feature. A definitive diagnosis of tuberous sclerosis complex now requires two or more distinct types of lesions, rather than multiple lesions of the same type in the same organ system. Although diagnosis on purely clinical grounds can continue to be difficult in a few patients, there should be little doubt about the diagnosis for those individuals who fulfill these strict criteria. Couples with more than one child with tuberous sclerosis complex, no extended family history, and no clinical features of tuberous sclerosis complex are more likely to have germline mosaicism for tuberous sclerosis than nonexpression of the mutation. Germline mosaicism, while fortunately rare, will not be suspected from either diagnostic criteria or molecular testing until a couple has multiple affected children. Genetic counseling for families with one affected child should include a small (1% to 2%) possibility of recurrence, even for parents who have no evidence of tuberous sclerosis complex after a thorough diagnostic evaluation.
Article
Tuberous sclerosis (TSC [MIM 191090 and MIM 191100]) is an autosomal dominant disorder characterized by hamartomas in many organs. Two thirds of cases are sporadic and are thought to represent new mutations. TSC is caused by mutations affecting either of the presumed tumor-suppressor genes, TSC1 and TSC2. Both appear to function as tumor suppressors, because somatic loss or intragenic mutation of the corresponding wild-type allele is seen in the associated hamartomas. Here we report the first comprehensive mutation analysis of TSC1 and TSC2 in a cohort of 150 unrelated TSC patients and their families, using heteroduplex and SSCP analysis of all coding exons and using pulsed-field gel electrophoresis and conventional Southern blot analysis and long PCR to screen for large rearrangements. Mutations were characterized in 120 (80%) of the 150 cases, affecting TSC1 in 22 cases and TSC2 in 98 cases. TSC1 mutations were significantly underrepresented in sporadic cases (P=. 000185). Twenty-two patients had TSC2 missense mutations that were found predominantly in the GAP-related domain (eight cases) and in a small region encoded in exons 16 and 17, between nucleotides 1849 and 1859 (eight cases), consistent with the presence of residues performing key functions at these sites. In contrast, all TSC1 mutations were predicted to be truncating, consistent with a structural or adapter role for the encoded protein. Intellectual disability was significantly more frequent in TSC2 sporadic cases than in TSC1 sporadic cases (P=.0145). These data provide the first representative picture of the distribution and spectrum of mutations across the TSC1 and TSC2 loci in clinically ascertained TSC and support a difference in severity of TSC1- and TSC2-associated disease.
Article
Tuberous sclerosis (TSC) is a relatively common hamartoma syndrome caused by mutations in either of two genes, TSC1 and TSC2. Here we report comprehensive mutation analysis in 224 index patients with TSC and correlate mutation findings with clinical features. Denaturing high-performance liquid chromatography, long-range polymerase chain reaction (PCR), and quantitative PCR were used for mutation detection. Mutations were identified in 186 (83%) of 224 of cases, comprising 138 small TSC2 mutations, 20 large TSC2 mutations, and 28 small TSC1 mutations. A standardized clinical assessment instrument covering 16 TSC manifestations was used. Sporadic patients with TSC1 mutations had, on average, milder disease in comparison with patients with TSC2 mutations, despite being of similar age. They had a lower frequency of seizures and moderate-to-severe mental retardation, fewer subependymal nodules and cortical tubers, less-severe kidney involvement, no retinal hamartomas, and less-severe facial angiofibroma. Patients in whom no mutation was found also had disease that was milder, on average, than that in patients with TSC2 mutations and was somewhat distinct from patients with TSC1 mutations. Although there was overlap in the spectrum of many clinical features of patients with TSC1 versus TSC2 mutations, some features (grade 2-4 kidney cysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver angiomyolipomas) were very rare or not seen at all in TSC1 patients. Thus both germline and somatic mutations appear to be less common in TSC1 than in TSC2. The reduced severity of disease in patients without defined mutations suggests that many of these patients are mosaic for a TSC2 mutation and/or have TSC because of mutations in an as-yet-unidentified locus with a relatively mild clinical phenotype.