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