CASE FILES: BIOCHEMISTRY
A N SW E R S TO C A SE 13: FR A G IL E X SY N D R O M E
An 8-year-old boy has mental retardation, speech-language prob-
lems, hyperactivity, physical findings of large jaw, prominent ears, and
macroorchidism and has a strong family history of mental retardation. The
genetic counselor informs the mother that she is the carrier and that she has a
Most likely diagnosis: Fragile X syndrome (most common form of
familial mental retardation).
Affected chromosome: Chromosome X
Types of mutations:
means protein product not affected;
means single amino acid substitution leading to significant
alteration (such as sickle cell); and
means that a stop codon
Molecular basis of disease: Mutation resulting in an increased number
of CGG repeats on the X chromosome. When the number of repeats
reaches a critical size, it can be methylated and inactivated resulting in
the disorder. Individuals who carry 50 to 199 repeats are phenotypically
normal and carry a premutation. If repeats exceed 200, the patient has a
full mutation; and if methylation occurs, he or she will be affected.
C L IN IC A L C O R R E L A T IO N
Fragile X is the most common inherited form of mental retardation, affecting
primarily males. The clinical presentation can vary, but usually the affected male
has moderate to severe mental retardation, hyperactivity, typical facies such as
large jaw and large ears. Pigmented skin lesions (café au lait) can also be seen.
Because females have two copies of the X chromosome, they are “resistant” to
mutations on one gene. Fragile X affects the long arm of the X chromosome,
with multiple copies of triplicate repeats, usually CGG, leading to methylation
of the deoxyribonucleic acid (DNA). The fragile X mental retardation (FMR)
gene product is affected and, through a little-understood mechanism, leads to
A PPR O A C H TO M U TA TIO N S
Know the definitions of point mutations (silent, missense, and non-
sense), insertions, deletions, and frameshift mutations.
Be familiar with the defect in fragile X syndrome.