Fragile X Syndrome Case File

Fragile X Syndrome Case File
https://medical-phd.blogspot.com/2021/03/fragile-x-syndrome-case-file.html
Eugene C.Toy, MD, William E. Seifert, Jr., PHD, Henry W. Strobel, PHD, Konrad P. Harms, MD
❖ CASE 13
An 8-year-old boy is brought to his pediatrician by his mother because she was concerned that he
was having language-speech problems, was hyperactive, and was told by teachers that he may have
mental retardation. The mother reports a strong family history of mental retardation in males. The
boy on exam is found to have a large jaw, prominent ears, and enlarged testes (macroorchidism).
The mother was told her family had a genetic problem causing the mental retardation. The patient
underwent a series of blood tests and was scheduled to see a genetic counselor, who expressed that
the etiology of the genetic defect was likely transmitted from his mother. The genetic counselor
states that his mother likely has a silent mutation.
◆ What is the most likely diagnosis?
◆ Which chromosome is likely to be affected?
◆ What are some types of biochemical mutations?
◆ What is the biochemical basis of the different types of mutations?
ANSWERS TO CASE 13: FRAGILE X SYNDROME
Summary: An 8-year-old boy has mental retardation, speech-language problems, 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 silent mutation.
◆ Most likely diagnosis: Fragile X syndrome (most common form of familial mental retardation).
◆ Affected chromosome: Chromosome X
◆ Types of mutations: Silent means protein product not affected; missense means single amino

acid substitution leading to significant alteration (such as sickle cell); and nonsense means that a
stop codon is formed.
◆ 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.
CLINICAL CORRELATION
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 mental retardation.
APPROACH TO MUTATIONS
Objectives
1. Know the definitions of point mutations (silent, missense, and nonsense), insertions, deletions,
and frameshift mutations.
2. Be familiar with the defect in fragile X syndrome.
Definitions
Point mutation: The substitution of a single nucleotide in the genetic material of an organism.

These include silent, missense, and nonsense mutations.
Silent mutation: A single nucleotide is exchanged by another, but this alteration does not change
the amino acid for which the codon codes. The final protein product remains unchanged.
Missense mutation: A single nucleotide is exchanged by another, and this alteration does have an
effect on the coding amino acid. The final protein product is also modified. The modification may
or may not be deleterious to the final protein, depending on the function of the amino acid.
Nonsense mutation: A single nucleotide is exchanged by another, which produces a new stop
codon at this position. This premature stop codon generally results in a truncated form of the
protein and most often leaves it as an inactive form.
Deletion: One or more nucleotides are removed from the genetic sequence. If the deletions are
multiples of one or two, a frameshift will be the result, which will likely damage the final protein
product. A deletion of three or a multiple of three does not shift the reading frame, rather it would
merely remove a codon(s). The final protein product would lose amino acid(s), which may or may
not leave it inoperative.
Insertion: One or more nucleotides are added to the genetic sequence. These are the opposite of
deletions.
Trinucleotide repeat expansion: Amplification from one generation to the next of three
nucleotide repeats in the coding or noncoding regions of DNA. The mechanism may arise from
DNA complimentary strand slippage. This is associated with fragile X syndrome and myotonic
dystrophy.
DNA methylation: Process by which methyl groups are added to DNA bases (most often
cytosine). Methylation functions to regulate gene expression because heavily methylated genes are
not expressed. Also, bacteria use methylated DNA as a defense mechanism. Every organism has
different patterns of methylated DNA, and bacteria take advantage of this by destroying foreign
DNA via nucleases, enzymes that cut DNA at specific sites.

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Fragile X Syndrome Case File

◆ What is the most likely diagnosis?

◆ Which chromosome is likely to be affected?

◆ What are some types of biochemical mutations?

◆ What is the biochemical basis of the different types of mutations?

ANSWERS TO CASE 13: FRAGILE X SYNDROME

Summary: An 8-year-old boy has mental retardation, speech-language problems, hyperactivity,

◆ Types of mutations: Silent means protein product not affected; missense means single amino

◆ Molecular basis of disease: Mutation resulting in an increased number of CGG repeats on the X

Point mutation: The substitution of a single nucleotide in the genetic material of an organism.

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