predisposed to expand.

Although premutations are relatively Management

common, progression to a full mutation has been observed
No curative treatments are currently available for fragile X
only on a limited number of haplotypes; that is, there is a
syndrome. Therapy focuses on educational intervention and
hap_l�type predisposition to expansion. This haplotype predis­
pharmacological management of the behavioral problems.
posmon may relate partly to the presence of a few AGG
triplets embedded within the string of CGG repeats· these
AGG triplets appear to inhibit expansion of the string ;f CGG INHERITANCE RISK
repeats, and their absence in some haplotypes therefore may
predispose to expansion. The risk that a woman with a premutation will have an
affected child is determined by the size of the premutation, the
sex of the fetus, and the family history. Empirically, the risk
Phenotype and Natural History to a premutation carrier of having an affected child can be as
high as 50% for each male child and 25% for each female
Fragile X syndrome causes moderate intellectual disability in
child but depends on the size of the premutation. On the basis
affected males and mild intellectual deficits in affected females.
of analysis of a relatively small number of carrier mothers, the
Most affected individuals also have behavioral abnormalities
recurrence risk appears to decline as the premutation decreases
including hyperactivity, hand flapping or biting, temper tan '.
from 100 to 59 repeats. Prenatal testing is available by use of
trums, poor eye contact, and autistic features. The physical
fetal DNA derived from chorionic villi or amniocytes.
features of males vary in relation to puberty such that before
puberty, they have somewhat large heads but few other dis­
t�c�ive _ features; after puberty, they frequently have more
d1Stmct1ve features (long face with prominent jaw and fore­
head, large ears, and macro-orchidism). Because these clinical REFERENCES
findings are not unique to fragile X syndrome, the diagnosis
depends on molecular detection of mutations. Patients with Besterman AO, Wilke SA, Milligan TE, et al Towards an understanding of neuro­
_
fragile X syndrome have a normal life span. psych1atnc man1festat1ons in fragile X premutation carriers, Future Neural9:227-
239, 2014.
Nearly all males and 40% to 50% of females who inherit
Hagerman A, Hagerman P: Advances in clinical and molecular understanding of the
a full mutation will have fragile X syndrome. The severity of
FMRl premutation and fragile X-associated tremor/ataxia syndrome, Lancet
the phenotype depends on repeat length mosaicism and repeat Neural 12786-798, 2013.
methylation (see Fig. C-17). Because full mutations are mitoti­ Saul RA, Tarleton JC FMR/-related disorders. Available from http://www.ncbi
cally unstable, some patients have a mixture of cells with .nlm.nih gov/books/NB Kl 384/
repeat lengths ranging from premutation to full mutation Tassone F: Newborn screening for fragile X syndrome, JAMA Neural 71355-359,
(repeat length mosaicism). All males with repeat length mosa­ 2014.
icism are affected but often have higher mental function than
those with a full mutation in every cell; females with repeat
lenrh mosaicism _ are normal to fully affected. Similarly, some
patients have a rruxture of cells, with and without methylation
of the CGG repeat (repeat methylation mosaicism). All males
with methylation mosaicism are affected but often have higher
mental function than those with a hypermethylation in every
cell; females with methylation mosaicism are normal to fully
affected. Very rarely, patients have a full mutation that is
unmethylated in all cells; whether male or female, these
patients vary from normal to fully affected. In addition, in
females, the phenotype is dependent on the degree of skewing
of X chromosome inactivation (see Chapter 6).
Female carriers of premutations (but not full mutations)
are_ at a 20:o risk for �remature ovarian failure. Male premu­
tat10n earners are at nsk for the fragile X associated tremor/
ataxia syndrome (FXTAS). FXTAS manifests as late-onset
progressive cerebellar ataxia and intention tremor. Affected
individuals may also have loss of short-term memory execu­
tive function, and cognition as well as parkinsonism,' periph­
eral neuropathy, lower limb proximal muscle weakness
and autonomic dysfunction. Penetrance of FXTAS is age '.
dependent, manifesting in 17% in the sixth decade, in 38%
m the seventh decade, in 47% in the eighth decade, and in
thm: fourths of those older than 80 years. FXTAS may mani­
fest m some female premutation carriers.