TUGAS GENETIKA MEDIS

FRAGILE X SYNDROME

(MARTIN-BELL SYNDROME)

Oleh :
Dr. I Gde Yudhi Kurniawan (1214058201)
Dr. Ida Ayu Trina Anjani (1214058202)
Dr. Fatimah (1214058203)
Dr. I Ketut Arya Santosa (1214058204)

Dosen :
Dr. I G K Nyoman Arijana, M.Si.Med

Program Combined Degree / S2 Biomedik

A. History
Back in 1943, there was a family with more than one male who had mental retardation
without dismorphic features. Martin and Bell investigated them and linked the disorder to
an unidentified mode of X-linked inheritance (Jewell, 2013). Then Lubs in 1969
discovered a marker X chromosome in affected males and in their unaffected mother and
female relatives. They have a fragile site at the end of the long arm of the X
chromosome(Phadke, 2005). So the name Fragile X Syndrome was originated from this
finding. More recent, in 1991 Fu et al. identified the culprit and name the gene as FMR-1
(Fragile site Mental Retardation-1).(MSAC, 2005)
B. Prevalence
The exact number of prevalence is limited by diagnostic criteria and the effort to explore
them. But the fact that fragile X mental retardation is evident all over the world in any
ethnic groups is undisputable. Studies and reports suggest various numbers to estimate the
prevalence. Fragile X syndrome estimated to affects approximately 1 in 2500-4000 for
males and 1 in 7000-8000 for females. Female carrier estimated to be 1 in 130-250 and
male carrier estimated to be 1 in 250-800(Jewell, 2013). It is estimated that 10% of cases
of previously undiagnosed mental retardation in males and 3% in females are attributed to
fragile X syndrome(Phadke, 2005).
C. Clinical Feature
The most prominent and important feature of fragile x syndrome is mental retardation,
with Intelligence quotient (IQ) frequently indicates mild-to-severe mental retardation (20-
70). Females and less-affected males may have IQs that approach 80.Autisticlike
behavior (poor eye contact, social avoidance, and hand biting/hand flapping) is present in
16-30% of patients while Autism is diagnosed in 20% of females and 30% of males, and
30% of patients are diagnosed with autism spectrum disorder. Most of males with fragile
X syndrome show aggressive tendencies and attention deficits behaviour similar to those
observed in patients with attention deficit hyperactivity disorder (ADHD). Seizure
disorder found in 20% of male and 5% of female, with onset typically at age 6-24 months.
The phenotype of fragile X syndrome is difficult. Most physical examination findings are
harder to look for in prepubertal children and notable only after onset of
puberty.Adolescent and adult patients have a long, thin face with prominent ears, facial
 asymmetry, a head circumference higher than the 50th percentile, and a prominent
forehead and jaw.The mouth has dental overcrowding and a high-arched palate.Ears are
typically large and may protrude.Strabismus is frequently noted. Occasionally,
nystagmus, astigmatism, and ptosis are present.Hands and feet manifest nonspecific
findings, including hyperextensible finger joints, hand calluses, double-jointed thumbs, a
single palmar crease, and pes planus. Clubfeet may be present at birth.Pectus excavatum
and scoliosis are frequent findings.Macroorchidism is nearly universal in postpubertal
males. In unaffected males, average testicular volume is 17 mL; in patients with fragile X
syndrome, testicular volume is more than 25 mL and can be as high as 120 mL. During
childhood, an increased incidence of inguinal hernias is reported.A heart murmur or click
consistent with mitral valve prolapse is often auscultated and requires consultation with a
cardiologist.(Jewell, 2013)

D. Pathology
Cytogenetic testing for fragile X syndrome is not as sensitive as molecular testing, with a
false-negative result rate of approximately 20%. Thus, DNA testing for fragile X
syndrome is recommended. Karyotyping may reveal other chromosomal anomalies, and
both a standard karyotype and DNA testing are suggested when a possible diagnosis of
fragile X syndrome is considered.
The criterion standard diagnostic test involves molecular genetic techniques that detect
the FMR1 gene. The exact number of CGG triplet repeats can be determined. Southern
blot and polymerase chain reaction (PCR) are the 2 methods of genetic analysis that are
currently available. Southern blot analysis provides a more accurate estimation of the
number of CGG triplet repeats if a full mutation is present (with a large CGG expansion).
It can also be used to evaluate the degree of methylation at the CGG repeat site.
PCR is faster, requires a minimal sample, and is less expensive than Southern blot
analysis. Additionally, PCR more accurately estimates the number of CGG triplet repeats
if a premutation is present (with small-to-moderate increases in CGG repeats). Recent
success with fluorescent methylation-specific PCR and GeneScan analysis may further
expand diagnostic options.(Jewell, 2013)

E. Genetic
Genetic defect lies at the distal end of the long arm of the X chromosome, a constriction
followed by a thin strand of genetic material that extends beyond the long arm at the
highly conserved band Xq27.3. The function of the band Xq27.3, which is also termed the
fragile X mental retardation-1 (FMR1) gene, is to synthesize fragile X mental retardation
protein (FMRP), a regulatory protein that binds messenger RNA (mRNA) in neurons and
dendrites. In patients with a full mutation in the FMR1 gene, FMRP is not manufactured
because of hypermethylation of FMR1, and brain development is impaired primarily
because of abnormal synapse connections. Additionally, mutations in the FMR1 gene
lead to excessive activity of the metabotropic glutamate receptor 5 (mGluR5), which
results in many fragile X syndrome symptoms. FMRP is present in other tissues;
however, its role isless understood.
Once identified and sequenced, the gene was discovered to contain a repeating base pair
triplet (CGG) expansion, which is responsible for fragile X syndrome.Unaffected
individuals have 5-54 CGG repeats in the first exon at the 5' end of band Xq27.3.
Individuals with 45-54 repeats are unaffected, but they risk passing a premutation on to
future generations. A span of 55-199 repeats is known as a premutation, whereas 200 or
more repeats is a full mutation. Full mutation results in hypermethylation of the cysteine
bases and restricts protein binding, leading to gene inactivation and absent FMRP. Mosaic
patterns are common. The number of repeats is unstable from generation to generation,
making the pattern of inheritance difficult to predict. In addition, the degree of
methylation is directly proportional to the signs and symptoms of fragile X syndrome.
Males with a full mutation have fragile X syndrome. Mothers of nearly all males with
fragile X syndrome have premutation or fragile X syndrome. Males with fragile X
syndrome pass a premutation to their daughters because sperm cells are mosaics. Sons are
unaffected because they receive the Y chromosome from their fathers.
Half of females with the full mutation on a single X chromosome are unaffected because
of inactivation of the other X chromosome. The other half of females have fragile X
syndrome, although with less severe mental retardation than males with the disorder.
These affected females can pass the gene to their children.
Males with a premutation are usually unaffected to mildly affected and transmit the
premutation to their daughters. The mutation is stable; thus, the CGG triplets are not
increased. Sons of affected males are unaffected because they receive the Y chromosome
from their fathers.
Females with a premutation are usually unaffected to mildly affected with fragile X
syndrome. However, they have a 20% chance of having fragile X – associated primary
ovarian insufficiency. Unlike their male counterparts, the CGG triplets are unstable and
 increase in size during oogenesis. If the number of repeats exceeds 200 and the oocyte is
fertilized, a male child will have fragile X syndrome, and a female child will have a 50%
chance of having fragile X syndrome. The number of repeats is directly proportional to
the risk of the disorder in an offspring.
Although most patients with fragile X syndrome have a CGG triplet expansion, few
patients have a point mutation in the FMR1 gene or a deletion of the gene.No
spontaneous FMR1 full mutations have been reported.(Jewell, 2013)

F. Management
Workup and diagnosis of fragile X syndrome can be done on an outpatient basis. Routine
care involves treating the medical problems that these patients commonly experience,
including gastroesophageal reflux, sinusitis, and otitis media. During infant and early
childhood healthcare maintenance visits, focus examination on possible hip dislocations,
hernias, and hypotonia.
The results of folic acid supplementation to curb the inattention and aggressiveness in
prepubertal males are controversial; thus, folic acid supplementation is currently not the
standard of care in fragile X syndrome. No effect has been observed in adults treated with
folic acid.
Trials of medications, such as fenobam, that act as mGluR5 antagonists are underway.
Excess mGluR5 signaling occurs when FMRP is decreased or absent. Therefore,
downregulation of mGluR5 may improve outcomes in patients with fragile X syndrome.
Lithium also inhibits mGluR5 signaling (as well as other pathways) and may benefit
patients with fragile X syndrome.
Other trials with γ -aminobutyric acid agonists are underway.
G. Refferences

Gillham, N. W., 2011. Genes, Chromosomes, and Disease. 1st ed. New Jersey: FT Press.

Jewell, J. A., 2013. Medscape. [Online] Available at: http://emedicine.medscape.com/article/943776-

MSAC, 2005. Medical Service Advisory Comittee. [Online] Available at:

National Human Genome Research Institute, 2010. genome.gov. [Online] Available at:
http://www.genome.gov/19518828 [Accessed 14 October 2013].

Phadke, S. R., 2005. Orphanet encyclopedia. [Online] Available at:

Wright, A. & Hastie, N., 2007. Genes and common diseases. 1st ed. Cambridge: Cambridge University
Press.