Fragile X syndrome and fragile X-associated disorders

Abstract

Fragile X syndrome (FXS) is caused by a full mutation on the FMR1 gene and a subsequent lack of FMRP, the protein product of FMR1. FMRP plays a key role in regulating the translation of many proteins involved in maintaining neuronal synaptic connections; its deficiency may result in a range of intellectual disabilities, social deficits, psychiatric problems, and dysmorphic physical features. A range of clinical involvement is also associated with the FMR1 premutation, including fragile X-associated tremor ataxia syndrome, fragile X-associated primary ovarian insufficiency, psychiatric problems, hypertension, migraines, and autoimmune problems. Over the past few years, there have been a number of advances in our knowledge of FXS and fragile X-associated disorders, and each of these advances offers significant clinical implications. Among these developments are a better understanding of the clinical impact of the phenomenon known as mosaicism, the revelation that various types of mutations can cause FXS, and improvements in treatment for FXS.

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Fragile X syndrome and fragile X-associated disorders [version
1; referees: 2 approved]
AkashRajaratnam ,  JasdeepShergill , MariaSalcedo-Arellano ,
 WilmarSaldarriaga , XianlaiDuan , RandiHagerman 1,4
MINDInstitute,UCDavisHealth,Sacramento,CA,USA
DepartmentofMorphologyandObstetrics&Gynecology,UniversidaddelValle,SchoolofMedicine,Cali,ValledelCauca,Colombia
DepartmentofNeurology,TheThirdHospitalofChangsha,HunanSheng,China
DepartmentofPediatrics,UniversityofCalifornia,Davis,SchoolofMedicine,Sacramento,CA,USA
Abstract
FragileXsyndrome(FXS)iscausedbyafullmutationonthe geneandaFMR1
subsequentlackofFMRP,theproteinproductof .FMRPplaysakeyroleFMR1
inregulatingthetranslationofmanyproteinsinvolvedinmaintainingneuronal
synapticconnections;itsdeficiencymayresultinarangeofintellectual
disabilities,socialdeficits,psychiatricproblems,anddysmorphicphysical
features.ArangeofclinicalinvolvementisalsoassociatedwiththeFMR1
premutation,includingfragileX-associatedtremorataxiasyndrome,fragile
X-associatedprimaryovarianinsufficiency,psychiatricproblems,hypertension,
migraines,andautoimmuneproblems.Overthepastfewyears,therehave
beenanumberofadvancesinourknowledgeofFXSandfragileX-associated
disorders,andeachoftheseadvancesofferssignificantclinicalimplications.
Amongthesedevelopmentsareabetterunderstandingoftheclinicalimpactof
thephenomenonknownasmosaicism,therevelationthatvarioustypesof
mutationscancauseFXS,andimprovementsintreatmentforFXS.
1 1 1
1,2 1,3 1,4
1
2
3
4
 
Referee Status:
 InvitedReferees

version 1
published
08Dec2017

1 2
,UniversityofAntwerp,R Frank Kooy
Belgium
1
,NationalInstitutesofHealth,Karen Usdin
USA
2
08Dec2017, (F1000FacultyRev):2112(doi:First published: 6
)10.12688/f1000research.11885.1
08Dec2017, (F1000FacultyRev):2112(doi:Latest published: 6
)10.12688/f1000research.11885.1
v1
Page 1 of 11
F1000Research 2017, 6(F1000 Faculty Rev):2112 Last updated: 08 DEC 2017


AkashRajaratnam( ),RandiHagerman( )Corresponding authors: arajaratnam@ucdavis.edu rjhagerman@ucdavis.edu
 :Conceptualization,Software,Supervision,Writing–OriginalDraftPreparation,Writing–Review&Editing;Author roles: Rajaratnam A Shergill
:Software,Writing–OriginalDraftPreparation; :Conceptualization,Writing–OriginalDraftPreparation,Writing–Review&J Salcedo-Arellano M
Editing; :Writing–OriginalDraftPreparation; :Writing–OriginalDraftPreparation; :Conceptualization,Saldarriaga W Duan X Hagerman R
FundingAcquisition,ProjectAdministration,Resources,Supervision,Writing–Review&Editing
RandiHagermanhasreceivedfundingfromNovartis,Neuren,Marinus,andAlcobraforcarryingouttreatmentstudiesinCompeting interests:
patientswithFXSandhasalsoconsultedwithRoche,Novartis,FulcrumandZynerbaregardingtreatmentstudiesinindividualswithFXS.
RajaratnamA,ShergillJ,Salcedo-ArellanoM How to cite this article: et al. Fragile X syndrome and fragile X-associated disorders [version
 2017, (F1000FacultyRev):2112(doi: )1; referees: 2 approved] F1000Research 610.12688/f1000research.11885.1
©2017RajaratnamA .Thisisanopenaccessarticledistributedunderthetermsofthe ,Copyright: et al CreativeCommonsAttributionLicence
whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Thisworkwassupportedthroughthefollowinggrants:NationalInstituteofChildHealthandHumanDevelopmentgrantGrant information:
(NICHD)HD036071;theMINDInstituteIntellectualandDevelopmentalDisabilitiesResearchCenter(NICHDU54HD079125),HRSA
R40MC26641,andHHS-ADD90DD05969fortheCenterforExcellenceinDevelopmentalDisabilitiessupportandtheInternationalTraining
ProgramforNeurodevelopmentalDisordersattheMINDUCDavisMedicalCenter.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
08Dec2017, (F1000FacultyRev):2112(doi: )First published: 6 10.12688/f1000research.11885.1
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Introduction
Fragile X syndrome (FXS) is the most common inherited cause
of intellectual disability (ID) and the most common single-gene
cause of autism spectrum disorder (ASD). FXS arises from a
full mutation repeat expansion (>200 CGG repeats in the
5′ untranslated region) in the FMR1 gene on the X chromosome;
this results in the methylation and subsequent silencing of the
gene. Although FXS is the most well-known disorder caused by an
FMR1 mutation, there is also a spectrum of disorders associ-
ated with the FMR1 premutation (55–200 CGG repeats)1. Those
with the full mutation have symptoms related to the absence
or deficiency of FMRP, the protein encoded by the FMR1 gene.
These individuals are susceptible to global developmental delay,
learning disabilities, and social and behavioral deficits. In con-
trast, those with the premutation allele have symptoms related
to the elevated production of FMR1 mRNA, leading to mRNA
toxicity2. Individuals with the premutation, especially males,
are at risk for developing fragile X-associated tremor/ataxia
syndrome (FXTAS), whereas females with the premutation
have an increased likelihood of developing fragile X-associated
primary ovarian insufficiency (FXPOI) before age 403. Although
global estimates for the frequency of both the full mutation and
premutation exist, recent research has indicated that founder
effects, as well as racial and ethnic differences, can significantly
affect the risk of individuals in certain regions of the world. Thus,
prevalence estimates may be more useful on a smaller, more
regional scale4–6.
A robust clinical picture of full mutation FXS, as well as the
variety of manifestations associated with the premutation, has
existed for years; however, the improved understanding of
mosaicism has begun to blur this picture. Mosaicism can refer to
a condition in individuals who express both full mutation cells
and premutation cells (size mosaicism) or individuals who have
the full mutation but in whom only a portion of the full mutation
alleles are methylated (methylation mosaicism). This may lead
to unique cases, such as individuals with features of both FXS
and FXTAS7. Another discovery that has challenged previous
understandings of FXS is that mutations other than full muta-
tion repeat expansions have the ability to cause the disorder.
The advent of more frequent whole exome sequencing (WES),
whole genome sequencing (WGS) and microarray testing has led
to the identification of different mutations such as point muta-
tions, deletions, and duplications as causes of FXS. Moreover,
these other mutations not only can cause FXS but also can result
in partial FMRP functionality and lead to many subtly different
phenotypes8. There have also been rapid advances in the devel-
opment of targeted treatments for patients with FXS over
the past few years, as many animal studies as well as clinical
trials have provided researchers with encouraging results. Certain
treatments have been shown to reverse aspects of the neurobio-
logical dysfunction in FXS; if used early in development, these
treatments are likely to significantly improve the outcome of
patients9,10.
Clinical presentation of fragile X syndrome
Individuals with FXS present with varying degrees of cognitive
impairment depending on sex and the level of FMRP produced11.
Patients producing higher levels of FMRP are typically less
cognitively affected. Females with FXS, therefore, may present
with a very wide range of clinical involvement due to differences
in the activation ratio (AR). The AR refers to the proportion of
normal FMR1 alleles on the active X chromosome, which sig-
nificantly impacts the amount of FMRP a female will produce12.
FMRP production also depends on CGG repeat number as well
as the proportion of methylated full mutation alleles; there-
fore, individuals presenting with mosaicism are also likely to
produce more FMRP. In turn, these individuals are typically less
cognitively affected than non-mosaic patients with FXS13.
When FMRP levels are not significantly diminished, affected
individuals may experience only modest socioemotional and
learning deficits with relatively normal IQ levels. However,
if FMRP production is severely decreased or fully silenced,
moderate to severe cognitive dysfunction is likely to occur14. In
addition to ID, there are several physical features associated with
FXS, such as a long face, broad forehead, high-arched palate,
prominent ears, macrocephaly, and macroorchidism (Figure 1
and Table 1)11. Although not all individuals with FXS will have
Figure 1. This 7-year-old boy with fragile X syndrome demonstrates
a broad forehead (a) and a high arched palate (b). However, he does
not have a long face or prominent ears. He is a high-functioning
individual with mosaicism, and DNA testing displays a band at 300
CGG repeats that is methylated as well as bands between 100
and 790 repeats that are unmethylated; overall, 30% of his alleles
are unmethylated. He presents with a sequential IQ of 71 and a
simultaneous IQ of 83. He has done well with treatment; sertraline has
improved his anxiety symptoms, and a long-acting methylphenidate
preparation has improved his attention-deficit hyperactivity disorder
symptoms.
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Table 1. Clinical features of fragile X syndrome.
Clinical characteristics Prevalence
Physical Long face
Macrocephaly
Prominent ears
Prominent jaw
Flat feet
Joint hypermobility
Macroorchidism
83%; occurs more commonly in adults
50–81%
75%
80%; occurs in adults only
29–69%
50–70%; occurs less commonly in adults
95%; occurs in adolescents and adults
Psychological Attention-deficit
hyperactivity disorder
Anxiety
Autism spectrum disorder
80% of boys and 40% of girls
58–86%
30–60%
Developmental Intellectual disability
Language deficits
85% of boys and 25–30% of girls
~100% of boys and 60–75% of girls
Other Strabismus
Recurrent otitis
Gastrointestinal complaints
Obesity
Seizures
8–30%
47–75%; occurs in the first 5 years of life
31%
30–61%
15–20%
Clinical features of fragile X syndrome11,14,15
obviously dysmorphic features, roughly 80% of patients with FXS
will present with at least one of these common characteristics14.
A significant overlap exists between FXS and ASD. Monogenic
disorders account for nearly one fifth of all diagnosed cases of
ASD, and the most common of these monogenic causes is
FXS16. Many of the behavioral characteristics seen in individu-
als with FXS, such as impaired social communication, social
anxiety, social gaze avoidance, and stereotypic behaviors, are
the same traits seen in other causes of ASD. Moreover, a large
portion of both individuals with FXS and individuals with
ASD meet criteria for attention-deficit hyperactivity disorder
(Figure 2). Just as ASD is seen more often in males than females,
males with FXS meet ASD criteria more frequently (60%)
than do females (20%)17. The overlap between FXS and ASD
also has a molecular basis, as FMRP controls the translation of
approximately 30% of the genes associated with ASD18. These
observations demonstrate that the underlying molecular etiolo-
gies of these disorders are intertwined, and targeted treatments
of FXS may be helpful for other types of ASD.
Clinical presentation of premutation disorders
Premutation expansions are associated with a variety of clinical
manifestations, including psychiatric, developmental, and neuro-
logical problems. The premutation causes psychiatric problems,
such as depression and anxiety, in approximately 50% of carri-
ers. It also causes premature ovarian failure (menopause occurring
before the age of 40) in a significant number of female carriers.
This condition, known as FXPOI, occurs in 16% to 20% of female
carriers; moreover, an additional 20% of carriers will experience
menopause before the age of 45. Some clinical manifestations
seen in those with the premutation are relatively common, even
in individuals with normal FMR1 alleles; however, their preva-
lence in premutation carriers is typically higher than their preva-
lence in the general population (Table 2). The greatest clinical
involvement associated with the premutation expansion results
from the neurodegenerative phenotype known as FXTAS, which
occurs in 40% of aging males and 16% of aging females with
the premutation19. FXTAS is a late-onset condition characterized
by intention tremor, cerebellar ataxia leading to frequent falling,
neuropathy, parkinsonian features, autonomic dysfunction, and
cognitive decline20. It is the most severe phenotype of premu-
tation-associated disorders. FXTAS is also characterized by
generalized brain atrophy and white matter disease in the middle
cerebellar peduncle and the splenium of the corpus callosum. In
addition, FXTAS is accompanied by the presence of intranuclear
inclusions in both neurons and astrocytes in the central nervous
system (CNS) as well as neurons in the peripheral nervous
system19,20.
Premutation disorders in extended family members are often
identified when a proband is diagnosed with FXS, after which
the proband’s mother is typically found to have the premutation.
Moreover, if the grandfather of the proband also has the premu-
tation, this means that all of the mother’s sisters will be obligate
carriers as well. The FMR1 premutation is known to be the most
common genetic cause of primary ovarian insufficiency2; thus,
premutation disorders are now also being identified through
OB-GYN offices, when fragile X DNA testing is ordered after
seeing ovarian dysfunction. If a female is diagnosed with the
premutation, her offspring have a 50% chance of inheriting a frag-
ile X mutation; whether offspring inherit a premutation or a full
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Table 2. Clinical involvement associated with the premutation.
Phenotype Prevalence (premutation carriers versus general population)
Male carriers Female
carriers
Male
non-carriers
Female
non-carriers
FXTAS 40% 16% N/A N/A
Fragile X-associated
primary ovarian
insufficiency
N/A 16–20% N/A ~1% (primary
ovarian insufficiency)
Hypertension 57% 22% ~30% ~30%
Migraine 27% 54% ~12% ~20%
Neuropathy 62% 17% <5% <5%
Sleep apnea 32% with FXTAS 32% with FXTAS ~15% ~5%
Psychiatric problems ~50% ~50% ~ 3.6%
(>45 years old)
~10.3%
(>45 years old)
19,20,23–28 Abbreviations: FXTAS, fragile X-associated tremor ataxia syndrome; N/A, not applicable.
Figure 2. There is significant overlap between fragile X syndrome (FXS), autism spectrum disorder (ASD), and attention-deficit
hyperactivity disorder (ADHD). Approximately 60% of all patients with FXS also meet criteria for ASD, although FXS accounts for only 2% to
6% of all cases of ASD. Furthermore, nearly 80% of children with FXS and 50% of children with ASD have co-occurring ADHD21,22.
mutation depends on the number of CGG repeats in the mother
as well as on the number of AGG “anchors” present29. AGG
triplets, which typically interrupt CGG triplets after every nine or
ten repeats, have been shown to decrease the likelihood of expan-
sion to the full mutation when passed on to the next generation.
Therefore, higher numbers of these AGG anchors in the maternal
FMR1 gene lower the risk of the full mutation in the offspring29.
If a male has the premutation, all of his daughters will also carry
the premutation and are at risk of having children affected with
FXS20.
Mosaicism
Two types of mosaicism exist: size mosaicism and methylation
mosaicism. Size mosaicism refers to a condition in individuals
carrying both cells with the premutation and cells with the full
mutation in their blood. Furthermore, the ratio of premutation
cells versus full mutation cells in the blood may differ when com-
pared with other tissues, such as fibroblasts and brain tissue13,30.
Methylation mosaicism refers to a condition in individuals who
have the full mutation but only a portion of the cells containing
full mutation alleles are methylated; methylation status may vary
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from tissue to tissue as well30. The presence of either type (or
both types) of mosaicism can blur the boundaries between the
phenotypes of the premutation and the full mutation (FXS).
Individuals with methylation mosaicism produce more FMRP
than individuals with fully methylated full mutation alleles31.
Additionally, CGG repeat numbers in the premutation range and
FMRP expression are inversely related32; therefore, individu-
als with size mosaicism who carry premutation alleles in addi-
tion to full mutation alleles will likely also produce more FMRP
than non-mosaic individuals. Increased FMRP levels in FXS are
associated with fewer clinical symptoms and correlate directly
with IQ30; thus, individuals with mosaicism tend to be higher-
functioning. For example, one postmortem case study looked at
multiple tissues of a high-functioning patient displaying both size
mosaicism and methylation mosaicism. Only one region of the
brain, the parietal lobe, had a methylated full mutation and silenced
FMRP expression. However, FMRP was expressed in other parts
of the brain, including the superior temporal cortex, frontal cor-
tex, and hippocampus, which likely explains why this patient had
only mild cognitive and behavioral deficits33. Although mosaic
individuals with FXS may be less cognitively impaired than non-
mosaic individuals with FXS, they are more likely to develop
FXTAS if their mRNA levels are elevated1,20. This can lead to an
intriguing scenario known as the “double hit” phenomenon, in
which an individual is affected by both lowered FMRP levels and
elevated FMR1 mRNA levels34.
In 2013, Schneider and colleagues34 documented two broth-
ers in their 40s who both displayed this double hit of elevated
FMR1 mRNA levels and moderately decreased FMRP expres-
sion. The first brother, an individual with methylation mosai-
cism, presented with multiple physical features characteristic of
FXS, such as macroorchidism, flat feet, and a prominent jaw. He
was cognitively high-functioning but also displayed psychotic
symptoms, including a history of bipolar 1 disorder. The second
brother carried the premutation (118 CGG repeats); he experienced
typical development but presented with a few physical features
of FXS. Additionally, he presented with psychotic features asso-
ciated with major depressive disorder. Another case report docu-
mented a 58-year-old male with size and methylation mosaicism
and CGG repeats ranging from 20 to 80030. He presented with a
slightly below average IQ and physical features of FXS. At age
50, he experienced neurodegenerative symptoms characteristic
of FXTAS, including a worsening tremor and severe ataxia; he
eventually experienced the cognitive decline typical of males with
FXTAS. However, he was also an alcoholic, which may have
increased CNS toxicity and exacerbated his FXTAS progression.
Interestingly, he also met criteria for bipolar I disorder; taken
together, these reports indicate that individuals with a double hit
may be at an increased psychopathological risk. Additionally,
these case studies challenge the traditionally clear distinction
between FXS and premutation disorders and support the notion
of a spectrum-based nature of disorders associated with FMR1
mutations.
Epidemiology
The reported rates of prevalence of FXS in the general popula-
tion have been estimated to be approximately 1:5,000 males and
1:4,000 to 1:8,000 females35–37. However, the estimated preva-
lence of the mutation has varied because of the differing testing
methodologies that have been used over time. Since FMR1 test-
ing began, the primary means of diagnosis has moved from cytoge-
netic testing for the presence of a folate-sensitive fragile site, to
Southern blot analyses, to polymerase chain reaction (PCR)-based
techniques. Additionally, wide variations in prevalence that are
seen in different populations make global prevalence estimates
difficult38,39.
To attempt to address these issues, Hunter and colleagues car-
ried out a systematic literature review and meta-analysis of the
prevalence of expanded FMR1 alleles by using a random effects
statistical model to analyze 54 epidemiological studies39. After
accounting for characteristics of the populations (that is, sub-
jects with or without ID) and including only studies that used
PCR and Southern blot techniques, obtaining screening data on
over 90,000 females and 50,000 males; the determined rates of
prevalence of the full mutation were 1:7,143 males and 1:11,111
females39. Additionally, meta-analyses investigating the preva-
lence of premutation alleles among the general population have
determined estimated frequencies of 1:150–300 females and
1:400–850 males35,39,40. Although we are gaining a better under-
standing of the prevalence of repeat expansions, this is not the only
type of mutation that can cause the disorder; a growing number
of deletions and point mutations on FMR1 have been identi-
fied in patients with FXS41,42. However, because repeat expan-
sions are tested far more frequently than these other mutations,
it is likely that the number of patients with FXS with non-repeat
mutations has been underestimated. Ideally, this epidemiologi-
cal shortcoming will be ameliorated through the increased use of
WES and microarray testing going forward.
The frequency of expanded FMR1 alleles varies globally because
of both founder effects and racial differences in haplotypes that
may predispose individuals in certain regions of the world to
CGG expansions43. Recently, the highest prevalence of expanded
alleles has been reported in Ricuarte, a small town in Colombia4.
In Ricuarte, the rates of prevalence of the full mutation are 1:21
males and 1:49 females, whereas the frequencies of the premu-
tation are 1:71 males and 1:28 females. This genetic cluster is
likely a consequence of a strong founder effect from founding
families that migrated from Spain. In sharp contrast to Ricuarte
is Ireland, which has extremely low rates of prevalence of the full
mutation: 1:10,619 males and 1:43,540 females. Researchers in
Ireland speculate that a lineage-specific haplotype is responsible
for this low incidence43. China also has a relatively low reported
incidence of FXS; however, owing to a gap between China and
Western countries regarding FXS awareness, it is likely that a
significant number of potential patients with FXS in China have
been misdiagnosed or underdiagnosed6. Other genetic clusters of
fragile X mutations can be found in various parts of the
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world, including Indonesia, Finland, and the Spanish island of
Mallorca5,44,45. These observations suggest that the prevalence
of FXS should be estimated separately in different countries or
continental regions, as certain shared predispositions or strong
instances of founder effects can lead to significantly different
prevalence rates.
Non-traditional ways of developing fragile X syndrome
FXS is almost always diagnosed through molecular testing for
a CGG repeat expansion in the triplet repeat sequence of FMR1,
as this is by far the most frequent cause of FXS8. However, recent
studies have implicated other mutations, such as point mutations
and deletions, in those with FXS41,42,46. There is nothing inher-
ent about repeat expansions in the full mutation that cause the
disorder; rather, it is the reduced FMRP production that leads to
FXS8. Thus, it is likely that any FMR1 mutation that adversely
affects the production of functional FMRP will lead to FXS.
Indeed, a review of non-expansion FMR1 mutations documented
various deletions causing FXS; over 20 case reports documented
FXS in patients who had normal CGG repeat numbers but had
deletions of varying sizes in the triplet repeat sequence or flanking
regions42.
Though less common, numerous point mutations in FMR1 have
also been discovered in individuals with FXS and other develop-
mental delays. In 2014, researchers documented FXS in a patient
with a loss-of-function missense mutation (p.(Gly266Glu)) and
a CGG repeat number of only 238. A separate case study attrib-
uted a patient’s FXS to a loss-of-function nonsense mutation
(p.(Ser27X); this patient’s CGG repeat number was just 2946. These
case studies corroborate the notion that any mutation that inter-
feres with the function of FMRP, not just full repeat expansions,
can lead to FXS. Furthermore, two related studies sequenced the
FMR1 gene of hundreds of developmentally delayed males who
did not meet diagnostic criteria for FXS; these mass sequenc-
ings revealed a total of three novel FMR1 missense mutations41,47.
Usually, developmentally delayed individuals with point muta-
tions on FMR1 have some of the features of FXS, although their
phenotype may vary in some ways from that of the typical patient
with FXS8,48.
Targeted treatments
Significant advances have been made in the development of
treatments for FXS. Animal models, including the FMR1 knock-
out (KO) mouse and the Drosophila fly model, have provided
researchers with several promising leads regarding effective
pharmacological interventions for patients with FXS. In addi-
tion, many clinical trials have been carried out in the past few
years and have been summarized in multiple comprehensive
reviews49,50. Moreover, a number of these trials have led to medi-
cations that are now available for use by treating physicians.
Minocycline, for example, is a semisynthetic tetracycline deriva-
tive that was first proven to be effective in improving anxiety
and cognition in KO mice51. A 3-month, double-blind control-
led trial of minocycline in children and adolescents with FXS
resulted in an improvement in global functioning as well as sig-
nificant improvements in anxiety and mood-related behaviors52.
Lovastatin, a specific inhibitor of the cholesterol biosynthesis
enzyme 3HMG-CoA reductase, has also shown promising results
in KO mice; in these mice, lovastatin decreased excessive pro-
tein production and blocked epileptiform activity in the mice
hippocampi9. A controlled trial combining lovastatin treatment
with parent-implemented language intervention (PILI) is currently
being carried out at the UC Davis MIND Institute, investigating
whether this combination of pharmacological and behavioral
interventions will improve spoken language and behavior in
children with FXS.
Another targeted treatment for FXS informed by animal studies
is metformin, a drug that is currently approved by the US Food
and Drug Administration for both obesity and type 2 diabetes.
Drosophila fly models of FXS, as well as KO mice, have dis-
played metformin’s ability to improve defects in circadian rhythm,
memory deficits, and social novelty53–55. Clinically, a recent
open-label study saw anecdotal reports of improved behav-
ior and language in children and adults with FXS56,57. Although
initially metformin was hypothesized to be helpful in only those
with the Prader-Willi phenotype (PWP) of FXS, associated with
hyperphagia and severe obesity56, this study suggests that patients
without PWP or obesity may also benefit. This study demon-
strates the need for a large controlled trial of metformin to see
whether improvements in behavior, cognition, and language can
be seen in children and adults with FXS.
The neurobiological overlap between ASD and FXS has led to
the trial of a selective serotonin reuptake inhibitor (SSRI), spe-
cifically sertraline, to help alleviate the low serotonin levels seen
in the CNS of those with ASD10,58. Metabolomic studies in vari-
ous cases of ASD have demonstrated depressed levels of enzymes
with the ability to metabolize tryptophan into serotonin, indicat-
ing that an SSRI may be helpful59. An initial retrospective study of
young children with FXS demonstrated a significantly improved
receptive and expressive language trajectory in those on sertraline
compared with those not on sertraline60. A subsequent double-
blind controlled trial of low-dose sertraline in young children with
FXS found significant improvements in fine motor skills, visual
reception, and the composite T score on the Mullen Scales of
Early Development (MSEL). In a post-hoc assessment, the chil-
dren with FXS together with ASD (60% of the study population)
demonstrated significant improvement in expressive language on
the MSEL when on sertraline61.
Mavoglurant, an mGluR5 antagonist, has also been helpful in
animal models, but efficacy has not been demonstrated in ado-
lescents and adults with FXS62. Similarly, arbaclofen, a GABAB
agonist, has not shown efficacy in adults; however, outcome
data for a limited number of measures in children look more
promising63. There may be a number of reasons for the failure
of some trials to demonstrate efficacy. The outcome measures in
many previous studies included only behavioral checklists, which
are subject to parental bias62,63. Additionally, studies of arbaclofen
and sertraline suggest that young children may respond bet-
ter to targeted treatments than adults with FXS21,61. Addressing
some of these concerns, a current trial of mavoglurant combined
with PILI in young children with FXS is using novel outcome
measures such as event-related potentials (ERPs), eye tracking
Page 7 of 11
F1000Research 2017, 6(F1000 Faculty Rev):2112 Last updated: 08 DEC 2017

methodology, and language sampling to better detect cognitive
benefits and improvement in CNS function. Overall, a multitude
of targeted treatments for FXS have provided researchers with
encouraging results; however, much more research is needed
before we can establish which interventions, or combinations of
interventions, are the most effective for this population.
Whereas a significant amount of research has been dedicated
toward treatments for FXS, research into targeted treatments for
FXTAS and other premutation disorders is just beginning. A con-
trolled trial of memantine, an N-methyl-D-aspartate (NMDA)
receptor antagonist commonly used to treat Alzheimer’s disease,
did not demonstrate improvements in tremor, ataxia, or execu-
tive function deficits in individuals with FXTAS64. However, ERP
studies demonstrated improvements in brain processing and
attention in individuals with FXTAS when treatment was meman-
tine versus placebo65,66. A more recent open-label study dem-
onstrated that a weekly dose of intravenous allopregnanolone,
a GABAA agonist, over the course of 12 weeks in patients with
FXTAS resulted in improvements in both neuropsychological
testing and neuropathy symptoms67. As mentioned earlier,
researchers are still in the early stages of finding effective targeted
treatments for FXTAS and other premutation disorders, and there
are many more clinical trials expected to come.
Conclusions
Our understanding of FXS and other fragile X-associated
disorders has grown significantly in recent years. It has become
clear that disorders related to FMR1 mutations are associated with
a wide range of clinical presentations; there is a continuum of
clinical involvement from premutation disorders into full muta-
tion disorders due to both low FMRP and high FMR1 mRNA.
Some studies, such as reports indicating that high-functioning
individuals with mosaicism are at risk for FXTAS, illustrate the
ability of mosaicism to cloud the clinical picture of FXS and
premutation-related phenotypes. Additionally, the number of
detected deletions and point mutations in FMR1 will continue
to increase with the more widespread use of WES, WGS and
the identification of these non-repeat mutations is further widen-
ing the spectrum of clinical involvement in FXS. Lastly, there is
a promising outlook for effective targeted treatments; several
medications have shown encouraging results in both animal
models and clinical settings, and there are likely many more
effective interventions to be found.
Ethics
Written informed consent for the publication of the image found
in Figure 1 was obtained from the child’s parent.
Competing interests
Randi Hagerman has received funding from Novartis, Neuren,
Marinus, and Alcobra for carrying out treatment studies in
patients with FXS and has also consulted with Roche, Novartis,
Fulcrum and Zynerba regarding treatment studies in individuals
with FXS. The other authors declare that they have no competing
interests.
Grant information
This work was supported through the following grants: National
Institute of Child Health and Human Development grant
(NICHD) HD036071; the MIND Institute Intellectual and
Developmental Disabilities Research Center (NICHD U54
HD079125), HRSA R40MC26641, and HHS-ADD 90DD05969
for the Center for Excellence in Developmental Disabilities
support and the International Training Program for Neurodevelop-
mental Disorders at the MIND UC Davis Medical Center.
The funders had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
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