Phelan–McDermid syndrome (PMS) is caused by 22q13 deletions including SHANK3 or pathogenic sequence variants in SHANK3 and is among the more common rare genetic findings in autism spectrum disorder (ASD). SHANK3 is critical for synaptic function, and preclinical and clinical studies suggest that insulin-like growth factor-1 (IGF-1) can reverse a range of deficits in PMS. IGF-1 release is stimulated by growth hormone secretion from the anterior pituitary gland, and this study sought to assess the feasibility of increasing IGF-1 levels through recombinant human growth hormone (rhGH) treatment, in addition to establishing safety and exploring efficacy of rhGH in children with PMS.
Methods
rhGH was administered once daily for 12 weeks to six children with PMS using an open-label design. IGF-1 levels, safety, and efficacy assessments were measured every 4 weeks throughout the study.
Results
rhGH administration increased levels of IGF-1 by at least 2 standard deviations and was well tolerated without serious adverse events. rhGH treatment was also associated with clinical improvement in social withdrawal, hyperactivity, and sensory symptoms.
Limitations
Results should be interpreted with caution given the small sample size and lack of a placebo control.
Conclusions
Overall, findings are promising and indicate the need for larger studies with rhGH in PMS.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Abkürzungen
ABC
Aberrant Behavior Checklist
AEs
Adverse events
ASD
Autism spectrum disorder
CGI-I
Clinical Global Impression—Improvement Scale
IGF-1
Insulin-like growth factor-1
PMS
Phelan–McDermid syndrome
RBS-R
Repetitive Behavior Scale—Revised
rhGH
Recombinant human growth hormone
SD
Standard deviation
SLAES
Systematic longitudinal adverse events scale
SSP
Short sensory profile
Introduction
Phelan–McDermid syndrome (PMS) is caused by deletions in the long arm of chromosome 22 which include the SHANK3 gene (MIM: 606230), or by pathogenic sequence variants in SHANK3 [1‐4]. PMS is associated with developmental delays, intellectual disability, and autism spectrum disorder (ASD), in addition to renal, cardiac, and gastrointestinal abnormalities, hypotonia, and dysmorphic features [5]. SHANK3 has been established as the critical gene in PMS [1‐4, 6] and appears to account for ~ 0.5% of ASD [7]. SHANK3 encodes for a master scaffolding protein in the post-synaptic density of excitatory synapses and is responsible for the formation and maintenance of synapses [8]. As such, SHANK3 and associated pathways represent important targets for intervention.
Evidence from both preclinical and clinical studies suggests that insulin-like growth factor-1 (IGF-1) can reverse deficits in synaptic plasticity and motor learning in mouse and human neuronal models of PMS [9, 10]. A clinical trial with IGF-1 in children with PMS also showed improvement in social withdrawal and restricted behaviors, both core features of ASD [11]. Additional evidence of the utility of IGF-1 comes from animal, human, and human neuronal studies of Rett syndrome, another rare genetic disorder associated with ASD, where IGF-1 was effective in reversing phenotypic features [12‐16].
Anzeige
IGF-1 is released mainly by the liver upon growth hormone stimulation and enters the brain from the circulation to promote brain vessel growth [17], neurogenesis, and synaptogenesis [18]. Once IGF-1 binds to the IGF-1 receptor, activation of the PI3K/mTOR/AKT1 and MAPK/ERK pathways induces its downstream effects [19]. Treatment with IGF-1 is generally administered twice daily via subcutaneous injection and requires careful monitoring due to numerous risks, including hypoglycemia. Further, IGF-1 is challenging to manufacture and while commercially approved for short stature due to primary IGF-1 deficiency, it is costly and not readily available. However, IGF-1 levels can be increased intrinsically by growth hormone [20] without the risk of hypoglycemia. Recombinant human growth hormone (rhGH) has an excellent safety profile and approved indications in pediatric and adult populations. One recent case report also supports the use of rhGH in PMS [21]. For these reasons, rhGH was chosen for this trial with the primary aims of demonstrating the feasibility of increasing IGF-1 levels in the blood and establishing safety in PMS. Furthermore, we sought to explore signals of efficacy using a battery of clinical outcome assessments, including the Aberrant Behavior Checklist—Social Withdrawal subscale (ABC-SW) [22] as the primary clinical outcome. The ABC-SW subscale was chosen based on results from the previous clinical trial with IGF-1 in PMS [11].
Methods
This study was approved by the Program for the Protection of Human Subjects at the Icahn School of Medicine at Mount Sinai, and all caregivers provided written informed consent.
Inclusion/exclusion criteria
Participants were required to have a confirmed genetic diagnosis of PMS and be between 2 and 12 years of age. Participants were excluded if they had closed epiphyses, active or suspected neoplasia, intracranial hypertension, hepatic insufficiency, renal insufficiency, cardiomegaly/valvulopathy, or allergy to growth hormone or any component of the formulation.
Drug administration
rhGH was administered in its commercially available form as somatropin (Zomacton). Caregivers were trained by a pediatric endocrinologist (Sethuram, S) to administer rhGH subcutaneously, through demonstration and written material. rhGH was given once daily for 12 weeks using an open-label design. Doses were based on standard clinical practice for children who are not growth hormone deficient with a target dose of 0.3 mg/kg/week. All participants were initiated on half the target dose (0.14–0.16 mg/kg/week) for two weeks as a safety precaution and then increased to a full dose for the remaining 10 weeks. IGF-1 levels were measured every 4 weeks, and IGF-1 Z scores were used to guide titration of rhGH dose using two standard deviations (SD) above the population mean as the target.
Anzeige
Safety measures and laboratories
Medical and psychiatric history was collected prior to the onset of the trial. Safety laboratories, physical examinations, and IGF-1 values were collected at the baseline visit and at each follow-up visit: weeks 4, 8, and 12. Adverse events were collected at every visit using the Systematic Longitudinal Adverse Events Scale (SLAES).
Clinical measures
The primary clinical outcome was the ABC-SW subscale (ABC-SW) [22]. Additional clinical outcome assessments were used to capture a range of ASD-related symptoms, including the Repetitive Behavior Scales—Revised (RBS-R) [23], the Sensory Profile (SP) [24], other ABC subscales (Table 2), and the Clinical Global Impression—Improvement scale (CGI-I) [25].
Statistical analyses
Nonparametric Wilcoxon signed-rank tests were used to evaluate differences in clinical outcomes between baseline and week 12. All tests of statistical hypotheses were done on the two-sided 5% level of significance. We selected a single primary efficacy variable (ABC-SW) a priori and did not adjust for multiplicity of statistical tests. All raw p values are presented to allow an adjustment post hoc (Table 3). In the case of missing data, we used the last observation carried forward. The sample size was not based on statistical criteria and was determined by feasiblity for this pilot study.
Results
Participants
This trial was conducted from September 2019 to June 2020 and terminated early due to COVID-19; the original recruitment target was 10 participants. Six participants were screened, and all met inclusion criteria and were enrolled. Participants (2 males; 4 females) were between 3.2 and 11.4 years of age (7.5 ± 3.2). All participants except one female were pre-pubertal. The one child who was pubertal on physical and biochemical evaluation did not reach menarche. At baseline, all children were of average weight (− 0.85 ± 1.15 SD), height (− 1.38 ± 0.75 SD), and body mass index (-0.82 ± 1.27). All bone ages were within the normal range. Baseline IGF-1 Z scores varied between − 1.2 and 2.3 (Table 1).
Table 1
rhGH dose in mg/kg/week and IGF-1 Z scores
Participant
Baseline
Week 2
Week 4
Week 8
Week 12
1
IGF-1 Z score
0.8
–
2.6
4.8
2.2
rhGH dose
0.15
0.3
0.28
0.24a
–
2
IGF-1 Z score
1.0
–
6.0
5.0
3.9
rhGH dose
0.15
0.28
0.24a
0.16a
–
3
IGF-1 Z score
1.1
–
2.8
4.7
1.7
rhGH dose
0.14
0.3
0.29
0.24a
–
4
IGF-1 Z score
0.9
–
4.5
1.8
2.9
rhGH dose
0.16
0.29
0.21a
0.19b
–
5
IGF-1 Z score
2.3
–
4.9
4.2
1.3
rhGH dose
0.14
0.27
0.22a
0.13a
–
6
IGF-1 Z score
− 1.2
–
1.1
1.3
0.9
rhGH dose
0.15
0.31
0.33
0.32
–
aDose reduced due to high IGF-1 levels
bDose reduced due to crying spells
Safety
Recombinant human growth hormone was generally well tolerated, and there were no serious adverse events (Table 2). On average, participants experienced approximately five treatment emergent adverse events. One participant experienced gait changes, and rhGH was terminated early at week 11 out of an abundance of caution due to the risk of slipped capital femoral epiphysis. The participant was evaluated by their pediatrician, and no additional workup was deemed necessary; gait normalized within 2 days after stopping rhGH and without further sequelae. Another participant required dose reduction due to crying spells. Crying spells in all three participants were attributed to increased emotional lability. There were no clinically significant abnormalities on laboratory blood work.
Table 2
Adverse events
Adverse event
Number of participants
Increase in appetite
3
Gastroenteritis
3
Polyuria/nocturia
3
Crying spells
3
Runny nose/cough/sneezing
3
Decrease in appetite
1
Fever
3
Worsening repetitive behavior
2
Eye/ear infection
2
Diarrhea
1
Worsening hyperactivity
2
Sleep disturbance
1
Disruptive behavior
1
Bruising at injection site
1
Sweating of hands/feet
1
Limping/gait changes
1
Efficacy
There was an improvement in our primary clinical outcome, the ABC-SW subscale, between baseline and week 12 (p = 0.028) (Fig. 1). There was also an improvement in hyperactivity using the ABC hyperactivity subscale (p = 0.027), and in overall sensory symptoms as measured by the short sensory profile total score (p = 0.042). Overall, there was global improvement as measured by the CGI-I (p = 0.023). There were no significant changes in other clinical domains (Table 3).
Fig. 1
Domains of clinical improvement. Lower ABC scores indicate improved behavior, and higher SSP scores indicate improved behavior
Table 3
Summary statistics for clinical outcomes
Measurea
Variable
Baseline
Mean (SD)
Week 12
Mean (SD)
p value
Wilcoxon r effect
ABC
Irritability
10.31 (7.6)
4.6 (2.3)
0.225
0.50
Social withdrawal
14.8 (7.4)
6.2 (3.4)
0.028
0.90
Stereotypy
8.8 (6.9)
5.1 (1.8)
0.249
0.47
Hyperactivity
33.3 (6.2)
16.5 (7.7)
0.027
0.90
Inappropriate speech
3.3 (4.3)
2.3 (3.8)
0.285
0.44
RBS-R
Stereotyped behavior
4.3 (1.7)
4.0 (2.4)
0.577
0.23
Self-injurious behavior
0.7 (0.8)
1.3 (1.8)
0.157
0.58
Compulsive behavior
2.8 (3.2)
1.3 (1.6)
0.083
0.71
Ritualistic behavior
1.2 (1.2)
0.8 (1.2)
0.414
0.33
Sameness behavior
2.3 (2.4)
2.0 (1.7)
0.680
0.17
Restricted behavior
2.0 (2.2)
1.2 (1.5)
0.129
0.62
Total
13.3 (6.1)
10.7 (3.1)
0.248
0.47
SSP
Tactile
31.5 (2.1)
31.7 (2.0)
1.00
0.00
Taste/smell
18.2 (3.6)
19.4 (1.3)
0.317
0.41
Movement
13.3 (1.6)
13.7 (1.8)
0.157
0.58
Sensation
17.5 (4.8)
20.0 (2.4)
0.416
0.33
Auditory
20.0 (1.9)
22.0 (2.4)
0.144
0.60
Low energy/weak
16.5 (6.9)
20.5 (5.2)
0.141
0.60
Visual/auditory
22.3 (2.3)
22.7 (1.5)
0.414
0.33
Total
139.3
148.8
0.042
0.83
CGI
Improvement score
–
1.7 (0.5)
0.023
0.93
ABC Aberrant Behavior Checklist, CGI Clinical Global Impressions scale, RBS-R Repetitive Behavior Scales—Revised, SSP Short Sensory Profile
aFor the ABC and RBS-R, lower scores indicate better performance; for the SSP and CGI-Improvement scale, higher scores indicate better performance
×
Discussion
The results of this pilot open-label clinical trial demonstrate that standard clinical doses of rhGH increased levels of IGF-1 in children with PMS by at least 2SD from baseline for all participants; final levels of greater than or equal to 2SD were reached in all except one participant. Further, we show that rhGH was well tolerated without serious adverse events. As rhGH is already FDA-approved and established as safe in children with growth-related problems and in adults with growth hormone deficiency, these results provide preliminary evidence of safety in a new patient population without specific growth issues. rhGH treatment was also associated with clinical improvement that parallels the effects of IGF-1 on social withdrawal in this population. In addition, rhGH was associated with benefits in hyperactivity and sensory symptoms, all leading to global improvement based on the CGI-I. Studies of rhGH in PMS are ongoing using a randomized, placebo-controlled, crossover design. In addition, it will be critical to discover biomarkers to predict treatment response to rhGH in PMS, and potentially, within subgroups of ASD more broadly.
Limitations
Results should be interpreted with caution given the small sample size and open-label design of the study.
Anzeige
Conclusions
Taken together, these findings support the development of rhGH as treatment for children with PMS. Future studies of the effects of rhGH in PMS using an adequately powered placebo-controlled design are warranted.
Acknowledgements
The authors would like to thank the families who participated and the Phelan–McDermid Syndrome Foundation for their support in recruitment.
Declarations
Ethics approval and consent to participate
The protocol was approved by the Mount Sinai Program for the Protection of Human Subjects, and all caregivers signed informed consent.
Consent for publication
Not applicable.
Anzeige
Competing interests
AK receives research support from AMO Pharma and consults to Acadia, Alkermes, Jaguar, Neuren, GW Pharma, and Ovid Therapeutics. JDB has a shared patent with Mount Sinai for IGF-1 in Phelan–McDermid syndrome. No other authors have competing interests to disclose.
Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Akuter Schwindel stellt oft eine diagnostische Herausforderung dar. Wie nützlich dabei eine MRT ist, hat eine Studie aus Finnland untersucht. Immerhin einer von sechs Patienten wurde mit akutem ischämischem Schlaganfall diagnostiziert.
Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.
Ist die Tau-Last noch gering, scheint der Vorteil von Lecanemab besonders groß zu sein. Und beginnen Erkrankte verzögert mit der Behandlung, erreichen sie nicht mehr die kognitive Leistung wie bei einem früheren Start. Darauf deuten neue Analysen der Phase-3-Studie Clarity AD.
Neue arznei- und zellbasierte Ansätze, Frühdiagnose mit Bewegungssensoren, Rückenmarkstimulation gegen Gehblockaden – in der Parkinsonforschung tut sich einiges. Auf dem Deutschen Parkinsonkongress ging es auch viel um technische Innovationen.
