An open-label pilot trial of minocycline in children as a treatment for Angelman syndrome.

Joseph C Grieco,Edwin J Weeber,Rex M Philpot,Stephanie L Ciarlone,Maria Gieron-Korthals,Jessica L Banko,Mike R Schoenberg,Amanda G Smith,Helen S Heussler

doi:10.1186/s12883-014-0232-x

Abstract

BackgroundMinocycline, a member of the tetracycline family, has a low risk of adverse effects and an ability to improve behavioral performance in humans with cognitive disruption. We performed a single-arm open-label trial in which 25 children diagnosed with Angelman syndrome (AS) were administered minocycline to assess the safety and tolerability of minocycline in this patient population and determine the drug’s effect on the cognitive and behavioral manifestations of the disorder.MethodsParticipants, age 4-12 years old, were randomly selected from a pool of previously screened children for participation in this study. Each child received 3 milligrams of minocycline per kilogram of body weight per day for 8 weeks. Participants were assessed during 3 study visits: baseline, after 8-weeks of minocycline treatment and after an 8-week wash out period. The primary outcome measure was the Bayley Scales of Infant and Toddler Development 3rd Edition (BSID-III). Secondary outcome measures included the Clinical Global Impressions Scale (CGI), Vineland Adaptive Behavior Scales 2nd Edition (VABS-II), Preschool Language Scale 4th Edition (PLS-IV) and EEG scores. Observations were considered statistically significant if p < 0.05 using ANOVA and partial eta squared (η2) was calculated to show effect size. Multiple comparisons testing between time points were carried out using Dunnett’s post hoc testing.ResultsSignificant improvement in the mean raw scores of the BSID-III subdomains communication and fine motor ability as well as the subdomains auditory comprehension and total language ability of the PLS-IV when baseline scores were compared to scores after the washout period. Further, improvements were observed in the receptive communication subdomain of the VABS-II after treatment with minocycline. Finally, mean scores of the BSID-III self-direction subdomain and CGI scale score were significantly improved both after minocycline treatment and after the wash out period.ConclusionThe clinical and neuropsychological measures suggest minocycline was well tolerated and causes improvements in the adaptive behaviors of this sample of children with Angelman syndrome. While the optimal dosage and the effects of long-term use still need to be determined, these findings suggest further investigation into the effect minocycline has on patients with Angelman syndrome is warranted.Trial registrationNCT01531582 – clinicaltrials.gov

Highlights

Minocycline, a member of the tetracycline family, has a low risk of adverse effects and an ability to improve behavioral performance in humans with cognitive disruption
The absence of the protein product, UBE3A, a E3 ubiquitin ligase, results in the accumulation of regulatory proteins, such as arc and ephexin 5 in the postsynaptic density, which is believed to cause abnormal dendritic spine morphology and density in hippocampal pyramidal neurons leading to aberrant synaptic function [15,16]
Twenty-four children completed the 16-week open-label study; one participant withdrew at week 16 due to unrelated seizure activity

Summary

Introduction

Minocycline, a member of the tetracycline family, has a low risk of adverse effects and an ability to improve behavioral performance in humans with cognitive disruption. First described in 1965, children with Angelman syndrome (AS, DOID_1932) present clinically with physical features such as microcephaly and a puppet like gait as wells as profound developmental delays and little vocal communication ability [1,2,3,4,5] While these patients exhibit a happy demeanor and provoked laughter, this syndrome consists of other manifestations including hyper-excitability, poor motor function, and delays in adaptive behaviors. The absence of the protein product, UBE3A, a E3 ubiquitin ligase, results in the accumulation of regulatory proteins, such as arc and ephexin 5 in the postsynaptic density, which is believed to cause abnormal dendritic spine morphology (filopodial) and density in hippocampal pyramidal neurons leading to aberrant synaptic function [15,16] These alterations in spine morphology and synaptic function in neurons provides an explanation for the severe behavioral and cognitive manifestations of the syndrome. It stands to reason a therapeutic with the ability to normalize the aberrant synaptic function underlying AS could ameliorate the severity of symptoms

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