Fragile X Syndrome
Single-Gene Mutation Diseases
Autosomal dominant disorders
Autosomal recessive disorders
X-linked disorders
Autosomal Dominant Disorders
A single mutant allele from an affected parent is transmitted to an offspring
regardless of sex
The age of onset is delayed, and the signs and symptoms of the disorder do
not appear until later in life
May manifest as a new mutation
Reduced penetrance
Variable expressivity
The gene products usually are regulatory proteins involved in rate-limiting
components of complex metabolic pathways or key components of
structural proteins such as collagen.
Autosomal Recessive Disorders
Are manifested only when both members of the gene pair are affected
The age of onset is frequently early in life; the symptomatology tends to be
more uniform than with autosomal dominant disorders; and the disorders
are characteristically caused by deficiencies in enzymes, rather than
abnormalities in structural proteins
Margin of safety
Include almost all inborn errors of metabolism
X-Linked Disorders
Are almost always associated with the X chromosome, and the inheritance
pattern is predominantly recessive
Fragile X Syndrome
X-linked disorder associated with a fragile site (FMR1 which is located in the
region between bands Xq27 and Xq28) on the X chromosome where the
chromatin fails to condense during metaphase
Affects male more often (1 in 1000) and are impaired more severely than
affected females
Is never transmitted from father to son
CCG triplet code undergoes repeated duplication (>200 repeats)
Later generations are more likely to be affected than earlier generations.
Premutations can expand the number of repeats during oogenesis, but not during
spermatogenesis.
For example, brothers and sisters of nonpenetrant transmitting males are 18% and 10%
penetrant (Sherman paradox or genetic anticipation), whereas grandsons and
granddaughters of transmitting males are 80% and 32% penetrant.
Approximately 20% of males who have been shown to carry the fragile X mutation are
clinically and cytogenetically normal.
Offspring of affected females, penetrance is 100% in sons and 56% in daughters
Offspring of unaffected carrier females, , penetrance is 80% in sons and 32% in daughters
Because male carriers transmit the trait through all their daughters (who are
phenotypically normal) to affected grandchildren, they are called transmitting males.
Approximately 50% of female carriers are affected (mentally retarded), a proportion that
is higher than with other X-linked disorders.
Clinical Manifestations (Males)
Small joint hyperextensibility
Mild hypotonia
Macroorchidism
Mild coarsening, large ears
Prominent forehead and mandible
Long face
Relative macrocephaly
High arched palate
Mitral valve prolapse
Flat feet
Developmental delay
ADD (Attention Deficit Disorder) / ADHD (Attention Deficit Hyperactivity Disorder)
Autistic behaviors
Social anxiety
Stereotypic movements
Poor eye contact
Sensory disorders
Increased risk for aggression
Clinical Manifestations (Females)
Mild mental retardation
Subtle impairment of visuospatial ability
Family history of mental retardation in maternally related males
Emotional/mental health issues
Social anxiety
But they are…
Very social and friendly
Have excellent imitation skills
Have a strong visual memory/long term memory
Like to help others
Nice
Thoughtful
Wonderful sense of humor
Diagnosis
PCR
Southern blotting
CVS
Amniocentesis
Medication
Speech therapy
Behavioral therapy
Sensory integration occupational therapy
Special education
Treatment of physical abnormalities
SSRIs
Anticonvulsants
Prognosis
12 years lower than the general population
