Post on 24-Jul-2020
Latest Research in FXS , Carriers and FXTAS
FRAXSOCAL Conference 10-1-17
Randi Hagerman MD
Distinguished Professor of Pediatrics
Endowed Chair in Fragile X Research
MIND Institute UC Davis Medical Center
Conflicts/Funding from NICHD, Roche/ Genentech, Fulcrum
NFXF, Novartis, Zynerba, Neuren, Marinus, Alcobra, HRSA, DoD
Two different mutations in the same FMR1 gene
Fragile X syndrome (FXS)
Primary Ovarian Insufficiency (FXPOI)
Fragile X-associated
Tremor Ataxia Syndrome (FXTAS)
Depression and anxiety
ADHD, OCD, seizures and ASD
mRNA
FMRP
Clinical
Typical Premutation Full mutation (CGG) < 45 55 - 200 (CGG) > 200 (CGG)
normal
1/130-250 females
1/250-810 males 1/3600-5000
WES has identified point mutations and
CNVs in FMR1 causing FXS (Quartier et al
2017)
3 carrier daughters more
severely affected than
expected but treated with
phenobarbital for seizures
and exposure to pesticides
Ricaurte, Colombia
Benefits of the Premutation
• A subgroup have an exceptionally high IQ
probably related to high FMRP levels
• Great verbal abilities combined with high
drive for achievement and obsessive
thinking can lead to high education levels,
many MD, PhDs, lawyers, clergy, very
successful business people, pilots etc with
the premutation
Reaction time in women with the
premutation was better than controls on a magnitude estimation task (p=0.05)
Goodrich-Hunsaker et al 2011 Brain and Cognition
fragile X
syndrome
FXPOI, anxiety
neuropathy
muscle pain, lupus
FXTAS, nl cognition,
FXPOI
FXTAS
cognitive decline, dementia,
neuropathy
+ autism (mild)
89 yr
61 yr
38 yr
proband
The Fragile X Mutation
A family affair
Four generations
A different course in women with FXTAS
nucleolus
inclusion
Intranuclear inclusions Loss of brain volume
CGG repeats
< 45 (normal)
55-200
excess, toxic mRNA
Women with FXTAS were not
described until 2004
(Hagerman et al 2004 AJHG)
and only 13% have the MCP
Findings on MRI studies
(Adams et al 2007), less
dementia
Inclusions reported in 2002
(Greco et al 2002,Berman et al
2015)
amygdala
New MRI Findings in FXTAS
• White matter disease
in the pons
• Thinning of the
corpus callosum and
wmd in splenium
• Involvement of the
insula
Adams et al 2012 NFXF conf and Apartis et al 2012
65 Women with FXTAS (Schneider et al
2017 )
Diagnostic Criteria for FXTAS updated
Executive function deficits minor
Short term memory deficits minor
Parkinsonism minor
Gait ataxia major
Intention tremor major Clinical exam
Moderate to severe generalized atrophy minor
Cerebral white matter hyperintensity minor
Middle cerebellar peduncle (MCP) lesions major MRI
Inclusion criterion: 55 – 200 CGG repeats
1 clinical major
AND
1 MRI minor
2 clinical major
OR
1 MRI major AND
1 clinical minor
1 clinical major
AND
1 MRI major
Possible Probable Definite
Diagnostic categories
Inclusions (post mortem)
Neuropathy minor
minor WMH in Splenium
Brainstem Volume Change: NC Vs. PNF (Wang et al 2017)
Age
Bra
inste
m
Volu
me (
ml)
Quadratic relationship
PNF: ‒0.19± 0.67 ml, t = ‒0.29, p = 0.77
Age x group: ‒0.048 ± 0.017 ml, t = ‒2.82, p =
0.005
Annual rate of change
NC: ‒0.001 × age2 + 0.091 × age
PNF: ‒0.001 × age2 ‒ 0.044 × age
Age of divergence in volume: 4.1 years
Age
Linear relationship
NC: 4.13 ± 1.10 ml, t = 3.74, p = 0.0003
Age x NC: 0.16 ± 0.06 ml, t = 2.4, p =
0.016
Age x PNF: 0.31 ± 0.08 ml, t = 3.8, p =
0.0002
Annual rate of change
NC: ‒0.07 ± 0.06 ml; PNF: 0.08 ± 0.08 ml
PWF: ‒0.23 ± 0.05 ml
PWF vs. PNF: difference in volume
occurs after age 50
Cerebellar Volume Change Begins in Childhood (Wang et al 2017)
Age
Cere
bella
r V
olu
me (
ml)
Linear relationship
PNF: ‒0.24 ± 2.53 ml, t = ‒0.10, p = 0.92
Age x group: ‒0.14 ± 0.06 ml, t = ‒2.24, p =
0.026
Annual rate of change
NC: ‒0.36 ± 0.04 ml
PNF: ‒0.50 ± 0.06 ml
Age of divergence in volume: 6.4 years
Age Linear relationship
NC: 22.4 ± 1.86 ml, t = 12.1, p <
0.0001
PNF: 13.0 ± 2.17 ml, t = 5.99, p <
0.0001
Annual rate of change
‒0.54 ± 0.11 ml
PWF vs. PNF: difference in volume
occurs before age 50
Spectrum of Premutation Involvement
FMR1 CGG-repeat
toxic RNA “trigger”
Calcium
dysregulation
Upregulation of
heatshock proteins
RAN translation,
FMRpolyG
Kinase activation
Sequestration of
DROSHA,DGCR8
Sam68
Mitochondrial
dysfunction
Inclusion
formation,WMD
Background
gene effects Environmental
effects
Including
Alcoholism
Opioids
Chemotherapy
Toxins
Smoking
Stroke
CTE
Neurodevelopmental problems
Social anxiety ASD
ADHD
Cognitive deficits
Psychiatric involvement
Anxiety
Stress
Depression
Endocrine dysfunction
FXPOI
Immune dysregulation
Hypothyroidism
Fibromyalgia
Lupus- MS features
Neurological problems
Neuropathy-chronic pain
Migraine, sleep apnea, RLS
Memory problems, foggy thinking
Hypertension , erectile dysfunction
FXTAS
tremor, ataxia, Parkinsonism
autonomic dysfunction, EF deficits,
memory and cognitive decline
Cellular
dysregulation
Presymptomatic FXTAS Case 1: 50 yo man with 102 repeats
• Healthy, athletic man who played football
in high school and college and history of
multiple head trama/concussions
• insomnia and hypertension but denied
tremor and ataxia.
• Cognitive testing : VIQ of 122, PIQ of 114
and F/S IQ of 120.
• His neurological exam was normal except
for a positive snout reflex.
Case 1: MCP, Splenium sign and subtle
pons involvement
Case 3: 60 yo man with 74 repeats
• Healthy male who denied neurological
symptoms
• Smoker since age 14 and 2 drinks per day;
gradual hearing loss for 15 years
• VIQ 116, PIQ 113, F/S IQ116
• Exam: BP 152/86; no tremor or ataxia,
positive palmomental and snout reflex.
• RTC after 4 years with head tremor,
intention tremor, gait ataxia so diagnosed
with FXTAS
Case 3 at age 60yo with MCP
and splenium sign in CC
Cultured
hippocampal
neurons (HN) from
preCGG or
Wt mice
Ca2+-selective
microelectrode
Resting Ca2+ concentration is elevated in
premutation neurons (mouse) Gaelle Robin et al. (2017)
PreCGG HN Ca2+ levels are chronically > Wt
Pessah Lab
cytoplasm
nucleus
Lamin A/C
p25
Cdk5
p35
Cdk5
Cdk5
p35 p25
Calpain
activation
Ca2+
Cdk5
inclusion
H2AX
ATM
DNA-
PKcs/Ku86/Ku70
Mre11
NBS1
RAD50
MRN
MDC1
53BP1
Ctp1
ATM
p53 p53
ATM
p25
Cdk5
The DNA Damage Repair (DDR) model
Paul Hagerman 2017
Mitochondrial dysfunction in FXTAS • Reactive oxygen species (ROS) are generated in mitochondria during the
course of mitochondrial respiration.
• Superoxide is (normally) decomposed by superoxide dismutase 1 (SOD1) in
the intermembrane space and by SOD2 (MnSOD) in the matrix to form
hydrogen peroxide, thence to water.
• Under mitochondrial stress, excess superoxide (normally eliminated by
superoxide dismutases (SOD1 and 2) is converted to the reactive hydroxyl
radical (OH•), or to the potent oxidant and nitrating agent peroxynitrite
(ONOO−).
Cecilia Guilivi lab
Treatments for premutation carriers
Polussa et al 2014
Brain Disorders
and Therapy
Treatment of premutation
problems including FXTAS
• Seritan et al 2014 J Cl Psychiatry;
Controlled trial of memantine was not
helpful for tremor, ataxia or executive
function deficits in patients with FXTAS
• Subgroup of FXTAS patients underwent
event related potential (ERP) studies
(n=41) and treatment benefits in cued recall
memory and N400 repetition effects were
seen compared to placebo (Jin-Chen Yang et al 2016, 2017)
Allopregnanolone from Mike Rogawski MD PhD
• Endogenous neurosteroid
• Produced by cortical and hippocampal pyramidal neurons
• Positive allosteric modulator
• GABA(A) Receptor
• Enhance inhibitory effect of GABA
• Neuroprotection (prevention of apoptosis)
• Neurogenesis
Allopregnanolone: a natural neurosteroid
GABAA agonist
• AlloP is being studied in tramatic brain injury
and in Alzheimer’s Disease (Brinton et al 2013)
• AlloP reduced spike frequency and duration in
premutation neurons (Cao et al 2012 HMG)
• Stimulates neurogenesis,
and neuroregenerative
Open label trial (12 weeks)
in FXTAS approved by FDA
Studies in AD mouse: Wang et al 2010 PNAS;
Chen et al 2011 Plos One
Once weekly IV infusion is optimal timing for
neurogenesis and pathology reduction in AD
mouse (Brinton lab) so open label study in
FXTAS
Allopregnanolone infusion once a
week 3 to 6 mg/infusion for 3 mo (Jun Yi Wang et al 2017 Neurotherapeutics)
Cognitive improvements with Allopregnanolone
treatment
-5.00
0.00
5.00
10.00
15.00
MMSE total score changes post infusion
Point change
Percent change
0
5
10
15
20
25
sco
re(u
nit
s)
pe
rce
nta
ge (
%)
BDS-2 score change post infusion
Change
Percentage change
• BDS-2 measures executive
function, working memory
• Improvement in scores in all
patients
• Frontal cortex involved
• Majority show improvements in
scores post infusion
• No change in JN’s scores; SG slight
decrease
• Compare against a control for
natural progression of disease
Functional Outcomes
• Before infusion
– Impaired executive function,
learning, and memory
– Comprised verbal fluency
• After infusion
– Significantly improved executive
function and associative learning
– Improved memory scores and
reduced psychological
symptoms in 75-80% patients
BDS-2 Total
Score
CANTAB
PAL Total Error
BDS = Behavioral Dyscontrol Scale
CANTAB = Cambridge Neuropsychological Test Automated Battery
PAL = Paired Associates Learning
p = 0.009 p = 0.042
Before After Before After
MRI Findings
• Before infusion
– Volume atrophy
– Accelerated hyperintensity
expansion
– Corpus callosal integrity loss
Age
Hip
po
ca
mpus (
cm
3)
Hyp
erin
ten
sitie
s (
cm
3)
CC
FA
CC
MD
(µ
m2/m
s)
Age
Patients Controls CC = corpus callosum, FA = fractional anisotropy,
MD = mean diffusivity P from < 0.001 to 0.045
MRI Findings
• Before infusion
– Volume atrophy
– Accelerated hyperintensity
expansion
– Corpus callosal integrity loss
• After infusion
– Changes occur in both
directions in individual patients
– Not significant as a group
Hippocampus (cm3) Hyperintensities (cm3)
CC FA CC MD (µm2/ms)
Before After Before After
Before After Before After
CC = corpus callosum, FA = fractional anisotropy,
MD = mean diffusivity
ERPs N400 amplitude improvements in
verbal memory task ( Jin chen Yang in
Olichney lab)
Anavex 2-73 a Sigma-1 Receptor Agonist
Anavex 2-73 Sigma-1 receptor agonist
• Clinical validation to enhance cognition in
Alzheimer Disease in phase 2a and moving
to phase 2/3 trials
• Preclinical validation in mouse models for
depression, anxiety, epilepsy, infantile
spasms, FXS, Rett syndrome, multiple
sclerosis and Parkinson disease
• Planning 3 month controlled trial in FXTAS
and preFXTAS with wmd or neurological
symptoms followed by 1 year open label
• Submitting IND and will begin in 3 to 4 mo
Enhanced electrodermal responses to sensory
stimuli, which correlates inversely with FMRP
levels
Enhanced sympathetic activity related to lower
inhibition (GABA deficits)
(Miller et al. 1999)
Normals FXS
Sensory modulation or processing
problems in FXS
Handbiting 60% Handflapping 80% Poor eye
Contact 90%
Tactile 80%
defensiveness
Unusual
sensory
responses to
stimuli
Perseverative speech
or behavior in
almost all-routines
hyperactivity
60% of boys with FXS have ASD
FMRP mRNA targets associated with ASD, schizophrenia and
mood disorders (Fernandez, Rajan, Bagni 2014 Frontiers NS)
FMRP deficits appears to be a unifying feature
among neuropsychiatric disorders, ASD
• ASD, depression, bipolar with brain FMRP deficit (Fatemi et al 2010,2011,2012)
• Schizophrenia: FMRP deficits correlate with age
of onset and IQ (Kovacs et al 2013; Keleman et al 2013)
• Hypoxia at birth lowers FMRP levels
• Seizures can worsen autism symptoms in ASD,
Neurofibromatosis, Tuberous Sclerosis, FXS and
premutation involvement (Chonchiaya et al 2011; Berry-Kravis
et al 2012; Van Eeghen et al 2012 DMCN )
• Early life seizures disrupt FMRP (Bernard et al 2013)
Early life seizures displaces FMRP from
dendritic puncta to perinuclear location
A: control with FMRP (green color and white arrows) in puncta of dendrites in rat hippocampus at 60d
B: After early life seizures FMRP shifts to perinuclear location (yellow arrow) and enhanced LTP With focal deficits of FMRP
Bernard, Costanos, Benke 2012 SFN
Bernard et al 2013
Dramatic Up-regulation of Proteins in the CNS without FMRP
Bassell and Gross 2008
mGluR theory of FXS
Bear et al 2004
Arbaclofen
Lovastatin
mGluR5 Antagonist Trials • AFQ056 (Novartis)
– Adult (2212) and adolescent (2214) trials finished
failed to meet primary endpoint of improved behavior
on the ABC during 3 month placebo-controlled trial
– Extensions (2278 and 2279) ended (August 2014)
and development plan for trial with reading
intervention and trial with young kids stopped
• RO4927523 (Roche)
– Large phase 2/3 adult study – age 14 and up
– Small phase 2 child study – age 5-13
– Both studies completed – primary endpoints not met
Open label AFQ056 improvements
AFQ056+ PILI in 3-6yo FXS through NeuroNEXT
FX-LEARN Trial
• Effects of AFQ056 on Language Learning in Young Children with
FXS to take place at 14 NeuroNEXT centers in US
• Change paradigm/create model for development of mechanism
targeted pharmacotherapy in NDDs – effects of drug on plasticity
• Address many Quandries: incorporate young age (3-6y), longer trial,
objective measures, learning intervention, biomarkers for target
engagement
• Randomize to AFQ056 or placebo - lead-in period when adjust to
best dose (MTD), then add PILI and then open label
• Extension for 8 months on AFQ056 for all participants
Study Team PI: Elizabeth B-Kravis; Co-PIs: Randi
Hagerman, Len Abbeduto; Co-Is: Walter Kaufmann, Craig
Erickson, David Hessl, Flora Tassone
Follow
Up
Open-label Treatment
v1 v2 v3 v4 v5 v14 v15 v10 v11
Blinded Treatment Period Language Intervention
v13 v12 v8 v7 v9 v6
1 month 8 months 6 months
20 month Total Dosing Period
Initiate Language Intervention
Language Intervention Baseline Screening,
Begin Dosing End Dosing
Effects of AFQ056 on Language Learning in Young Children with Fragile X Syndrome (FXS) – Protocol Design
End Placebo-Controlled Period
Begin Open Label Extension
6 months
Hagerman et al 2014 JCP
SEROTONIN SYNTHESIS CAPACITY:
Autistic vs. Non-autistic Children
Chugani et al., 1999
Syndromic and non syndromic forms of ASD
have reduced tryptophan metabolism
• Boccoto et al 2013 Mol Aut: Studied 137
lymphoblastoid cell lines of patients with
neurodevelopmental disorders with (80) and
without ASD and 78 controls (2.5 to 35yo)
• Metabolic profiling demonstrated deficits in
tryptophan metabolism in ASD with
reduced NADH, not seen in ID or
schizophrenia
• Found abnormal gene expression of
enzymes in tryptophan metabolism pathway
Tryptophan metabolic pathway
Boccoto et al 2013
Sertraline is an optimal SSRI for
FXS and ASD
• SSRIs stimulate neurogenesis in the mouse and in humans (Malberg et al 2004; Warner-Schmidt et al 2006)
• SSRIs stimulate BDNF levels (Bianchi et al 2010;Taler et al 2013)
• Sertraline in FXS has a calming effect to the anxiety and may directly stimulate speech or improve language as a secondary effect from less anxiety
• Sertraline is the only SSRI to stimulate dopamine levels in the striatum and nucleus accumbens (Kitaichi
et al 2010)
Sertraline Treatment in Early Childhood in FXS A retrospective study of 45 children followed 12 to 50 months and 11 treated
with sertraline: significant differences in expressive and receptive language in TX
vs non treated (p=0.0001 and p=0.0071 respectively)
Winarni et al 2012 Autism Treatment and Research
Expressive language
Receptive language
Randomized, double blind, controlled trial of sertraline in 2 to
6yo with FXS lasting 6 months
Laura Greiss Hess PhD, OTR
Kerrie Lemons Chitwood PhD, CCC
initiated study
Sarah Fitzpatrick
NFXF summer student fellow
finalized the study and data
Baseline and 6 month Follow-up:
1* CGI-I, MSEL Expressive Language
2* MSEL: Receptive, fine motor, visual reception,
Composite T score, Sensory Processing Measure-
(SPM) Preschool version, Visual Analogue Scale
Controlled Trial of low dose Sertraline in FXS
Mullen Scales of Early Learning (MSEL)
(Hess et al 2016 JDBP)
P=0.007
P=0.047 P=0.031
P=0.005
p=0.008
P=0.038
BDNF val/val genotype with most
improvement on sertraline in FXS
AlObaly et al 2017 Tassone lab
Conclusions • MSEL visual perception and fine motor subtests, the
composite T score, and the combined mean of all the
subtests scores were improved on sertraline vs placebo so
cognitive and motor benefits and improvement in social
participation on SPM-P. It was safe without signif AEs
• Primary outcome measure choice is difficult and N/S here
• A significantly beneficial treatment by age 2 yo reinforces
the need for early diagnosis and even newborn screening
• From a clinical perspective families liked the effects of
sertraline and all wanted to continue clinically on sertraline
after the trial
• Now a sertraline trial in young children with ASD 2-6 so
refer patient to me: rjhagerman@ucdavis.edu
GABAA receptor expression is
down-regulated in FXS • GABAA expression is down- regulated in
the KO mouse (D’Hulst et al 2007; Kooy et
al 2005)
• GABAA agonists: Ganaxolone
– Investigational medication with efficacy in infantile
spasms and other types of epilepsy: A controlled double
blind cross-over trial (each arm 7 weeks) in children
with FXS (6 -18y) funded by DOD is finished.
– Paper in press to JNDD Andrew Ligsay et al 2017
– Targeting improvement in anxiety and behavior
– Frank Kooy has studied 11 patients in Belgium and we
studied 48 patients at the MIND
Results: CGI-I
p = 0.448
0
5
10
15
20
25
30
Very Muchimproved
Much Improved MinimallyImproved
No Change Minimally Worse Much Worse Very Much Worse
Nu
mb
er
of
Sub
ject
s
CGI_I Rating Scale
Ganaxalone
Placebo
Ligsay et al 2017 JNDD in press
Post-hoc: High Anxiety (PARS>13)
VAS – Anxiety ADAMS – General Anxiety
p=0.023 p=0.035
0
1
2
3
4
5
6
7
Baseline End
Me
asu
red
Sco
re (
cm)
GNX Placebo
0
2
4
6
8
10
12
Baseline End
Sub
scal
e T
ota
l Sco
re
GNX Placebo
VAS-Anxiety ADAMS-General Anxiety
Controlled trial of lovastatin in 10 to18yo
combined with Parent Implemented Language
Intervention (PILI) • Lovastatin is an inhibitor of the rate-limiting enzyme in
cholesterol biosynthesis and an FDA-approved treatment for
hyperlipidemia (Acosta et al 2011).
• Lovastatin down-regulates the RAS-ERK1/2 pathway and
lowers the excessive protein synthesis in FXS
• In FX KO mice lovastatin rescues seizures and lowers
excess protein production in KO mouse (Osterweil et al
2013)
• Lovastatin was beneficial in open label trial in FXS
• Lovastatin has anti-inflammatory effects
Every one gets PILI intervention
• PILI is twice a week with S and L therapist
and with behavior interventionist on skype
in your home
• Controlled trial of lovastatin increasing
from 10 mg gradually up to 40 mg if
tolerated
• Total trial lasting 18 weeks ages 10 to 18yo
• Contact Erika Bickel
(esbickel@ucdavis.edu) at the MIND
institute or rjhagerman@ucdavis.edu
Maternal Use of Intervention Strategies
were significantly improved with PILI
Data from McDuffie
et al 2016
Metformin
• Originally introduced for treatment of type
2 diabetes, then expanded to treatment of
obesity and now considered to be the
“Aspirin of the 21st century with a role in
gestational diabetes, prevention of
preeclampsia and cancer, and the promotion
of longevity” (2017 Romero et al AJOG)
Metformin Targets Multiple
Pathways and improves longevity
Barzilai et al 2016 Cell Metabol
Anticancer Effects of Metformin
Irie et al 2016 Oncology Letters
Metformin a type 2 diabetes med • Known to help overeating and obesity
• Can prevent cognitive deficits in diabetics
• Helpful in several patients with Prader-Willi
Phenotype of FXS (obesity and hyperphagia),
present in less than 10% of FXS
• Drosophila FX model: elevated insulin signaling
via PI3K/Akt/mTOR pathway and metformin
improved circadian rhythm defect and memory
problems (Monyak et al 2016)
• Rescues phenotype in KO mouse (Gantois et al
2017 Nature Med)
Metformin rescues many phenotypes in
KO mouse (Gantois et al 2017 Nat Med)
Bardoni & Mandel, 2002
The Prader-Willi Phenotype (PWP) of Fragile X Syndrome
Those with the PWP have a higher rate
of autism (70%) than those with FXS
alone and lower CYFIP levels (Nowicki et al 2007 )
GH is a treatment for PWS and maybe for PWP
Old and young patients with FXS treated with metformin
mothers requested this after NFXF conference
Open label clinical use of
metformin in FXS • First in those with obesity or the Prader-
Willi Phenotype of FXS
• A rare patient with type 2 diabetes and FXS
with elevated fasting glucose and HgbA1c
• Clinical Genetics (Dy et al 2017) our
experience with 7 patients ages 4 to 60y.
All had improvements in weight gain,
appetite control, behavior on the ABC
especially with irritability rating but most
remarkably better speech and language
abilities
Controlled trial of metformin in FXS
• Ages 6 to 40yo with FXS private foundation
funding
• Randomized, double blind controlled trial
lasting 4 months so baseline, 2 month and 4
month visits to the MIND and then open label
with clinical follow-up with PCP
• Baseline and outcome measures with language
sampling, NIH toolbox for cognition, behavior
measures, ERP, eye tracking with Tobii,
biomarkers (NFXF funded biobank)
• Contact rjhagerman@ucdavis.edu if interested
A flood of referrals of young children
with FXS wanting metformin
Case No./Initials
Age in Years (Starting on Metformin)
Treatment Length
(Months) Dose Labs ASD
Diagnosis Concomittant Medications
1 - TB 2.2 4 50mg75mg
BID Non-ASD Sertraline, Folic Acid, NAC,
Probiotic, Melatonin
2 - JD 4.2 3 50mg BID -->
100mg BID ASD Sertraline, Clonidine,
Melatonin
3- GF 6 3 50mg QD -->
BID HbA1C: 5.3 Non-ASD Sertraline, Quillivant XR,
Minocycline
4 - JR 4.2 3 50 mg BID ASD Sertraline, Guanfacine,
Methyl Folate
5 - FS 4.5 4 50mg BID -->
150mg BID Non-ASD Guanfacine, Minocycline
6 - OS 4.5 4 50mg BID -->
150mg BID Non-ASD Guanfacine, Minocycline
Side effects of metformin • Mainly loose stools, although if you increase the
dose slowly then you are less likely to see diarrhea.
So in young children begin with 50 mg at dinner
then go to 50 mg bid (solution 500 mg/5ml made
by Riomet)
• Hypoglycemia is not thought to be a problem with
metformin ( check fasting blood glucose in F/up)
• One patient had a seizure a week after starting
metformin (glucose was normal in ER; MRI had
heterotopias) uncertain if related to metformin
New treatments for FXS andASD • Cannabidiol: CBD (not THC) will likely be helpful for
ASD, FXS and premutation involvement especially for
anxiety, sleep disturbances and pain (GABAA agonist).
Study with Zynerba CBD cream not funded by DOD
• Suramin: purigenic antagonist (Naviaux et al 2015)
– Many effects including decreasing PI3K,AKT,APP and
TDP43 in ASD and FXS mouse
• Bumetanide: diuretic (Tyzio et al 2014)
– bumetanide to mother rescues the GABA developmental
sequence and autistic phenotype in rodents with FXS or
ASD. Now in patient trials for ASD.
• Fulcrum: Wants to up regulate FMRP
• Press Release: 9-30-17
• Zynerba Pharmaceuticals today announced positive top
line results from an open label exploratory Phase 2 FAB-C
(Treatment of Fragile X Syndrome Anxiety and Behavioral
Challenges with CBD) clinical trial evaluating ZYN002
cannabidiol (CBD) gel in pediatric and adolescent patients
with Fragile X syndrome (FXS). The study successfully
met its primary endpoint, achieving a 46% improvement
(p<0.0001) in the total score of Anxiety, Depression, and
Mood Scale (ADAMS) at week twelve compared to
baseline. ZYN002 also achieved clinically meaningful
improvements in all measures of the Aberrant Behavior
Checklist for Fragile X (ABC-FXS), which address the key
symptoms of FXS including social avoidance, temper
tantrums, repetitive movements, and hyperactivity.
Zynerba Data
CBD oils: here 25:1 CBD :THC
anecdotal reports are positive
Yoga and Mindfulness Meditation
improves GABA inhibition
NNZ-2566 (Neuren) Trofinetide
ERK and AKT biomarkers
Growth hormone IGF-1/GPE (glypromate) analog
Works on overactive ERK/AKT pathway in FXS mouse
ERK/ARK in signaling pathway for mGluRs/other receptors
Normalizes hyperactivity, social behavior, cognition, dendritic spines,
ERK/AKT, even testis size in FXS mouse
Neuren Phase 2 placebo controlled trial
with IGF1 analogue Trofinetide • Safe in males14-40 yo with FXS over 42
days of treatment carried out at 5 US
centers. Highest dose was most effective
Vitamins and antioxidants in Fragile X mouse and
man
• Vit E (Alpha tocopherol) and N acetyl L cysteine (NAC) improved
behavior and cognition in KO mouse (de Diego et al 2009)
• Controlled trial of Vit E and C in 6 to 18yo with FXS 10 mg/kg/day
for 24 weeks (de Diego-Otero et al 2014)
• Omega 3 diet increased sociability in KO mouse and BDNF in DG of
hippocampus (Pietropaolo et al 2014 Psychoneuroimmunology)
n-3 PUFAs = omega 3 Polyunsaturated fatty acids
New treatments for ASD and FXS
• Cannabidiol: CBD (not THC) will likely be helpful for
ASD, FXS and premutation involvement especially for
anxiety, sleep disturbances and pain (GABAA agonist).
Study with Zynerba CBD cream not funded by DOD
• Suramin: purigenic antagonist (Naviaux et al 2015)
– Many effects including decreasing PI3K,AKT,APP and
TDP43 in ASD and FXS mouse
• Bumetanide: diuretic (Tyzio et al 2014)
– bumetanide to mother rescues the GABA developmental
sequence and autistic phenotype in rodents with FXS or
ASD. Now in patient trials for ASD.
Targeted Treatments must be combined with
innovative educational programs • If synaptic connections are improved with
targeted treatment we must enhance these
connections with educational interventions
• Combine treatment trials with educational
interventions (PILI), digital programs such as
CogMed, Headsprout for reading, AT devices,
iPAD apps
FX tracking game CHAT Alt CHAT 40
Co-Writer and write out loud iPAD apps
MIND Institute
Kyoungmi Kim
Len Abbeduto
Kathy Angkustsiri
David Hessl
Susan Rivera
Andrea Schneider
Mary Jae Leigh
JunYi Wang
Norman Brule
Laura Potter
Patrick Adams
Jasdeep
Erika Bickel
Susan Harris
Lisa Makhoul
Jen Cogswell
Maria Diez
Dept. Radiology
James Brunberg
NTRI Researchers
Isaac Pessah
Rob Williamson
Rob Berman
Dept. Neurology
Lin Zhang
John Olichney
Ricardo Maselli
Mike Rogawski
Dept of Psychiatry
Andreea Seritan
Support: NICHD, HRSA, DOD, NIA, NFXF, CDC, NFXF, Alcobra
Neuren, Roche, Novartis, Marinus
University of Colorado Health Sciences Center (Denver) Nicole Tartaglia Maureen Leehey James Grigsby ; Karen Riley at DU
RUSH-Presbyterian-St. Luke’s Medical Center (Chicago)
Elizabeth Berry-Kravis Deb Hall Christopher Goetz
*Latrobe University, Melbourne Australia*
Danuta Loesch Richard Huggins
Dept. Biochem & Molec. Medicine
Paul Hagerman Flora Tassone
Anna Ludwig
Greg Mayeur Chris Raske
Dept. Biostatistics now at UC Irvine
Danh Nguyen
Department of Pathology
Claudia Greco
Department of Rehabilitation
Veronica Martinez-Cerdeno
UC Davis School of Medicine
Collaborators