lJournal of Neonatal and PediatricMedicine

inedic eM

Neonataed P diatrican

ISSN: 2572-4983

Yu, et al., Neonat Pediatr Med 2017, 3:1
DOI: 10.4172/2572-4983.1000128

Open Access

Case Report

Therapeutic Potential of Everolimus on Core Autism Symptoms andIncreasing Serum Ceruloplasmin and Transferrin Levels in a Pubescent
Boy with Tuberous Sclerosis
Kunio Yui1*, George Imataka2, Toru Okanishi3, Hidehiro Oka4 and Yohei Kawasaki5
1Department of Cognitive-Behavioral Medicine, Kyoto University Graduate School of Medicine, Japan
2Department of Pediatrics, Dokkyo Medical University, Japan
3Department of Neuropediatrics, Seirei Hamamasu General Hospital, Japan
4Department of Neurosurgery, Kitazato University Medical Center, Japan
5Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Japan*Corresponding author: Kunio Yui, Department of Cognitive-Behavioral Medicine, Kyoto University Graduate School of Medicine, Japan, Tel: 81 78 791 8981; E-mail:yui16@bell.ocn.ne.jp
Received date: June 05, 2017, Accepted date: June 19, 2017, Published date: June 26, 2017
Copyright: © 2017 Yui K, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract
Background: The neuropsychiatric clinical manifestations of tuberous sclerosis complex (TSC) include social
and behavioral impairment, similar to the core symptoms of autism spectrum disorder (ASD), as well as subependymal giant cell astrocytomas (SEGAs) and renal angiomyolipomas (AMLs).
Case report: The present study examined the clinical effects of 24 weeks of therapy with the mTOR inhibitor
everolimus on the social and behavioral symptoms that are similar to the core ASD symptoms and neurobiologicalmechanisms underlying the effects of everolimus in an 11-year-old boy with TSC. After the initial physical andpsychological screening and Magnetic resonance imaging (MRI) examinations, the patient received 4.4 mg/day
everolimus for 24 weeks. To study neurobiological mechanism, we examined the relationship between the efficacy of
everolimus and serum levels of superoxide dismutase (SOD) and the copper- and iron-binding antioxidants
ceruloplasmin (Cp) and transferrin (Tf). Results MRI results revealed a Subependymal giant cell astrocytoma(SEGA) located at the foramen of Monro and a renal angiomyolipoma (AML) on the patient’s kidney. Everolimus
remarkably improved the patient’s social and behavioral impairments over the course of the 24-week treatment
without apparent reduction in the size of the SEGA and AML. Serum Cp and Tf levels were gradually increased in
response to the improvement in symptoms.
Conclusion: As everolimus increased antioxidant capacity and elevated serum VEGF levels, this study firstly
revealed that increased antioxidant activity related to copper and iron may contribute to the remarkable improvementin the core social and behavioral ASD symptoms caused by 24-week everolimus treatment.

Keywords: Tuberous sclerosis; Core autism symptoms; Everolimus;
Antioxidant proteins; Ceruloplasmin; Transferrin

Introduction
Tuberous sclerosis complex (TSC) is a genetic disease characterized
by the presence of benign and tumor-like lesions called hamartoma asthat can affect multiple organ systems [1]. Neuropsychiatricmanifestations include behavioral and psychiatric deficits such as
autism spectrum disorder (ASD) [2] and TSC-specific lesions such as
sub-ependymal giant cell astrocytomas (SEGA) and renal
angiomyolipomas (AML) [3]. Hyperactivation of the mammaliantarget of rapamycin (mTOR) signaling pathway underlies thepathogenesis of TSC, and mTOR inhibitors improve ASD symptoms[4]. However, there are a few findings about the therapeutic effect ofthe mTOR inhibitor everolimus on ASD symptoms. mTOR pathway isclosely related oxidative stress [5] or antioxidant capacity [6].
Oxidative stress-induced reactive oxygen species [7] enhanced mTOR
[5], and that mTOR inhibitor everolimus blocked the enhanced
phosphorylation of mTOR [6]. Moreover, copper-related antioxidants,

Neonat Pediatr Med, an open access journal
ISSN: 2572-4983

such as ceruloplasmin (Cp) [8] and iron-related transferrin (Tf) [9] areclosely related to mTOR signaling. For example, Cp expression mas
related to activation of mTOR pathway [8]. Tf uptake modulates themTOR signaling pathway [10]. Thus, we examined the possibility thatthe mTOR inhibitor everolimus may attenuate mTOR activity throughalteration of antioxidant proteins such as serum Cp and Tf levels.
Written informed consent was obtained from the patient and patient’s
mother before the study.

Case Presentation
Subject characteristics
The proband presented the case of a 11 year old boy with clinicallydefinite tuberous sclerosis (TSC) with core autism spectrum disorder(ASD) symptoms. The patient was born by spontaneous vaginal
delivery with a birth weight of 2856 g. At the age of 13 months, thepatient experienced infantile spasmus, and then the patient remainedon sodium valproate until 12 years of age. His epileptic seizure wasnever occurred.

Volume 3 • Issue 1 • 1000128

Citation:

Yui K, Imataka G, Okanishi T, Oka H and Kawasaki Y (2017) Therapeutic Potential of Everolimus on Core Autism Symptoms andIncreasing Serum Ceruloplasmin and Transferrin Levels in a Pubescent Boy with Tuberous Sclerosis. Neonat Pediatr Med 3: 128. doi:

10.4172/2572-4983.1000128

Page 2 of 5

MRI findings
At eight-years-old, brain magnetic resonance imaging (MRI)
revealed a subependymal giant cell astrocytoma (SEGA) (2.1 cm × 4.0cm) located at the right foramen of Monro within a coronal T2weighted image. Additionally, polycystic kidney disease and two small
renal angiomyolipomas (AML) (both were 0.8 cm × 0.8 cm) on thepatient’s left kidney and multiple renal cysts were detected by MRI. At
the age of 9 years old, he received keyhole craniotomy for SEGA in theright lateral ventricle by co-author Dr. H.O. in the Kitazato Medical
Center, Japan. Eight months after his keyhole operation (at the age of
10 years), MRI revealed small SEGA on the left foramen of Monro(Figure 1).

indicated his impaired ability to share interests and activities withothers. He was often delayed in his speech and sometimes createdneologisms and idiosyncratic language. His speech was confined tonarrow topics of expertise.
At the age of 9-10 years, he was hyperactive and sometimes showed
irritability. He exhibited delayed acquisition of motor skills and had
difficulty with motor coordination, postural control, and imitating the
movements of other people. After the age of 9 years, he graduallyexhibited restlessness and abnormal behaviors, such as crying,breaking his writing pencil and writing threatening messages like “Iwill kill you” in crayon at school. He diaplayed repetitive stereotyped
behavior such as washing his face in the morning. When his routine
was changed, he usually entered a state of panic.

Diagnosis of tuberous sclerosis and autism spectrum
disorderThe MRI revealed that two major diagnostic criteria such as a SEGA
and a renal AML, and multiple renal cysts met the diagnostic criteria
for TSC [11]. Thus, the diagnosis was confirmed without genomic
analysis. At age 11 years, the patient participated in our clinical trial at
the Department of Pediatrics at Dokkyo Medical University, Japan, andhe was diagnosed by two psychiatrists who specialize in ASD using theAutism Diagnostic Interview-Revised (ADI-R) [12]. His ADI-R scores
were above the autism diagnostic cutoff scores for qualitative
abnormalities in reciprocal interaction (his score was 18, cutoff=10),
qualitative abnormalities in communication for both the verbal (hisscore was 14; cutoff=8) and non-verbal total scores (his score was 10;
cutoff=7) and repetitive/stereotyped patterns of behavior (his score
was 4; cutoff=13). These ADI-R scores indicated a definite ASD
diagnosis.

Psychometric evaluation

Figure 1: Brain and kidney MRI findings of the patient. a located at
the foramen of Monro within on coronal T2-weighted imaging(white arrow), b Most of the left SAGE was removed by keyhole
operation. At the 10 years old, small SEGA (0.5 × 0.4) cm was
detected at the foramen of Monro within on coronal T2-weighted
imaging after two years and eight months (white arrow). c MRI
showed left two low-density areas with negative Hounsfield unit
values inside the kidney, suggesting a renal angiomyolipoma (whitearrows) and four multiple renal cysts (small arrows).

Symptoms of autism spectrum disorder
From 6 to 10 years of age, the patient’s social interaction andcommunication patterns gradually exhibited deficits. The patient did
not coordinate attention between objects of mutual interest and otherpeople and did not engage in pretend play. Moreover, the patient did
not respond to many forms of non-verbal communication because he
was often unable to understand and acknowledge their needs, which

Neonat Pediatr Med, an open access journal
ISSN: 2572-4983

At the 11 years old, he took psychometric tests. His total Intelligence
Quotient of the Wechsler Intelligence Scale for Children (WISC-IV)[13] was 67, which was defined as borderline IQ [14]. The Autism
Diagnostic Observation Schedule (ADOS), which is a semi-structured,
standardized assessment designed for use in the diagnostic evaluationof individuals with suspected autism spectrum disorder (ASD) [15].
Social impairment was assessed using the Social Responsiveness Scale(SRS) [16] and the Social Communication Questionnaire (SCQ) [17].
The SRS is highly feasible for quantitative ascertainment of autisticsocial impairment [18]. The SCQ is measure for parents/caregivers toassess their child’s reciprocal social interaction, communication, andrepetitive, stereotyped domains [17] based on the ADI-R. Behavioral
symptoms were assessed using the Aberrant Behavior Checklist (ABC).
The ABC is primarily intended to evaluate treatment responses in
psychopharmacological and behavioral intervention trials for children
and adolescents with mental retardation [19] and normal IQ levels[20].
The patient’s total score on the Autism Observation Schedule(ADOS) module 2 algorithm showed a communication score of 17.0,
which was greater than the total scores of the ADOS (8.94 ± 9.71)
reported in 33 adolescents with high-functioning autism [21] and his
SRS and ABC total scores were 125 and 136, respectively. These SRS
and ABC scores were greater than the scores of ASD individuals withan age range of 13-27 years (SRS, 120.12; ABC, 60.14) [22]. Other
evaluations, including an ophthalmologic examination and dental

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Citation:

Yui K, Imataka G, Okanishi T, Oka H and Kawasaki Y (2017) Therapeutic Potential of Everolimus on Core Autism Symptoms andIncreasing Serum Ceruloplasmin and Transferrin Levels in a Pubescent Boy with Tuberous Sclerosis. Neonat Pediatr Med 3: 128. doi:

10.4172/2572-4983.1000128

Page 3 of 5
examination at the pre-treatment and post-treatment screenings,
revealed no additional abnormalities.

Biochemical measurement
Serum verolimus levels were 9.58 ng/ml at 12 weeks, increased to18.2 ng/ml, and then decreased to 7.32 ng/ml at 24 weeks after
treatment. Serum levels of VEGF-D were 252.6 pg/ml at baseline andgradually increased to peak values of 315.1 pg/ml at 12 weeks and thengradually decreased to 247.4 at 24 weeks after treatment.
Because mTOR is closely associated with antioxidant capacity[23,24], serum levels of antioxidant proteins such as Cp, and Tf were
measured using a Bering BN Nephelometer (Siemens Healthcare
Diagnostics K.K., USA) and a standard turbid metric assay and an
automated biochemical analyzer (JCA-BM8000 series, JEOL Ltd.,Tokyo, Japan). Interestingly, serum levels of Cp gradually increased
from baseline to 16 weeks and then remained higher than the baseline
levels (Figure 2). Furthermore, serum levels of Tf were gradually
increased between 4-12 weeks of treatment, in accordance withsymptom improvement.

Serum levels during the maintenance dose were 9.58 ng/ml at the 12
week, 18.1 ng/ml at the 16 week, 15.1 ng/ml at the 20 week, and 7.3
ng/ml at the 24 week after the treatment. No severe or life-threatening
side effects related to everolimus treatment were observed. Everolimus
gradually induced a remarkable improvement in the patient’s social
and behavioral symptoms without dose adjustment during the 24
weeks of treatment.
Everolimus treatment greatly improved behavioral deficits,
cognition, attention, social interaction, and language development in
the patient. The patient gradually communicates with his family
members and classmates. He began to exhibit an effective response toothers.
The patient’s ADOS, ABC and SRS scores gradually decreased,
which indicated a decrease in the severity of the social and behavioral
consequences of ASD symptoms. Particularly, the ABC and SRS total
scores decreased from 115 before treatment to 52 after treatment (45%decrease) and from 126 before treatment to 76 following treatment(58% decrease), respectively, at the end of the 24-week treatment
period compared to baseline. Thus, the everolimus treatment induced
significant improvements in the patient’s social and behavioral
symptoms.
The size of SEGA and two AML were slightly reduced 3 mm and 4mm respectively after everolimus treatment.

Discussion
The present study demonstrated for the first time that everolimus
treatment for 24 weeks remarkably improved the core social andbehavioral symptoms of ASD such as deficits in social interaction,verbal and non-verbal communication, inflexible adherence toroutines, and repetitive stereotyped behaviors. Serum everolimus levels
were 9.85 ng/ml at the 12th week and 15.1 ng/ml at the 24th week after
the treatment. A previous study of pharmacokinetics of everolimus
reported similar blood levels (10.1 ± 0.7 ng/ml) of everolimus at 20th
week after treatment in 25 healthy adolescents [25]. Serum everolimus
levels in this study were similar to those in this previous study,
suggesting maintained adequate levels of everolimus in this patient
The decreased percentages of the ABC and SRS total scores wereapproximately 50%, which were consistent with the criteria for theefficacy of a pharmacological treatment [26]. Thus, proper treatment
with everolimus may exert a life-enhancing clinical effect on the social
and behavioral outcomes of the core ASD symptoms.

Figure 2: Indicated alteration of serum levels of ceruloplasmin (a)and transferrin (b).

Treatment with treatment for 24 weeks and serum
everolimus levels
After the initial screening, the patient received 4.4 mg everolimus
every day for 24 week. The patient’s body surface area was 1.47 m2, andthe median maintenance dose of everolimus was 4.4 mg/m2/day basedon 3 mg/m2 in the Novartis indication.

Neonat Pediatr Med, an open access journal
ISSN: 2572-4983

Consistent with our findings, a previous case report showed that
everolimus treatment improved the ABC and Pervasive Developmental
Disorders-Autism Society Japan Rating Scale subscale scores of
irritability, stereotypic behavior, and lethargy/social withdrawal [27]. A
recent case report has indicated that everolimus treatment improved
behavioral deficits, such as swaying, twirling and preoccupation withflowing water, and social interaction, cognition, attention, language
development, and size reduction (11 mm) of SEGA [1]. In addition, 2of 7 children who showed a 50% reduction in SEGA size showed
improvement in learning abilities [28]. A few studies have reported asignificant decrease in AML size (65%) with everolimus treatment [29].
A recent review article indicated that TSC-associated neuropsychiatric
symptoms are rarely assessed and treated, suggesting that thesemanagement should be coordinated with treatment of other organsystems [30]. Although everolimus induced significant reduction of
SEGA size [31], a previous clinical study reported that everolimus

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Yui K, Imataka G, Okanishi T, Oka H and Kawasaki Y (2017) Therapeutic Potential of Everolimus on Core Autism Symptoms andIncreasing Serum Ceruloplasmin and Transferrin Levels in a Pubescent Boy with Tuberous Sclerosis. Neonat Pediatr Med 3: 128. doi:

10.4172/2572-4983.1000128

Page 4 of 5treatment did not change the histopathological characteristics of SEGA
in a 15 years old girl [32]. Moreover, everolimus’s effect is not easily
characterized within TSC lesion such as SEGA and AML [32].
Considering these definitive effects of everolimus on reduction of
SEGA size, small size reduction observed in this study may bereasonable. Many previous studies have reported that the therapeutic
benefit of everolimus treatment may prevent the development of AML
and SEGA (3,33,34). Importantly, these considerations taken together
suggest that the neuropsychiatric symptoms of TSC may depend on
another neurobiological mechanism of everolimus in addition tomTOR inhibition.
In this study, serum VEGF levels at baseline were below the range
reported in 19 normal children 306.1 ± 39.4 pg/ml [33-35]. Serumlevels of VEGF were 252.6 pg/ml at baseline and gradually increased topeak values of 315.1 pg/ml at 12 weeks and then gradually decreased to247.4 at 24 weeks after treatment serum. Everolimus potentially inhibit
early and mid-stag of VEGF expression, but later stage formation of
VEGF was an affected [36]. An animal study indicated significant
increase at the early stage and decrease at the end of 14-day
experiments [37]. These studies indicated a change in upper and low
serum concentrations of VEGF. The alteration pattern of serum VEGF
levels observed in this study is comparable to a change in upper andlower concentrations described in the above study [36,37].
Considering that serum VEGF levels are considered as a biomarker oftreatment response [38], the changes in serum VEGF-D levels
observed in the present study indicate the response to everolimus
treatment.
Importantly, everolimus-treated mice exhibited higher activity ofantioxidant enzymes glutathione reductase [39]. Everolimus reversed
the accumulation of oxidative stress-related reactive oxygen species[40] and attenuates oxidative stress by altering antioxidants [6].
Moreover, survival activity of everolimus subjected to high oxidative
insult [41]. Drawing these strands together, pharmacological effects of
everolimus may be related to increases in serum levels of antioxidants.
Cp is an important serum antioxidant [42] and the main copper
binding protein in blood plasma [43]. Previous studies have reported
that increased intracellular copper levels suppressed mTOR signaling[44], and that copper treatment down regulated mTOR signaling [45].
With respect to increased serum Tf levels, the mTOR signaling pathway
modulates Tf uptake [10], and mTOR regulates iron homeostasis
through the Tf receptor [9]. Additionally, the Tf receptor may be usefulfor measuring intracellular changes in mTOR activity [46]. Thesefindings suggest that everolimus may induce increases in serum Cp
and Tf levels in relation to the improvement of social and behavioral
symptoms. In respect to the association between Cp and Tf, a previous
review article suggested that the transfer of iron was regulated by both
CP and Tf and that activity of Cp was modulated by Tf [47]. Cp plays aimportant role in iron metabolism [48]. These strands support thepresent finding that everolimus might act mTOR signaling byincreasing serum levels of Cp and Tf. However, further studies will beneeded to explore the cooperation between of Cp and Tf.

Conclusion
The present study revealed that everolimus treatment for 24 weeks
induced a remarkable improvement in the core social and behavioral
symptoms of ASD concomitant with increased copper- and ironrelated antioxidant activity in a pubescent boy with TSC.

Neonat Pediatr Med, an open access journal
ISSN: 2572-4983

Ethical Statement
All of the procedures in this study were in accordance with the
ethical standards of Dokkyo Medical University, Tochigi, Japan (NO.
27014, Japanese Medical Association, Clinical Trial Registration(JMAS-IIA00258), and with the 1964 Declaration of Helsinki. Allprocedures were performed at the Department of Psychiatry; Dokkyo
Medical University Written informed consent was obtained from thepatient and/or the patient’s mother.

Acknowledgement
This study was supported by Research grant of the Japan Agency for
Medical Research and Development (AMED).

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Yui K, Imataka G, Okanishi T, Oka H and Kawasaki Y (2017) Therapeutic Potential of Everolimus on Core Autism Symptoms andIncreasing Serum Ceruloplasmin and Transferrin Levels in a Pubescent Boy with Tuberous Sclerosis. Neonat Pediatr Med 3: 128. doi:

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Volume 3 • Issue 1 • 1000128