A 3-year-old boy is brought to the office for follow-up on intellectual disability and speech delay. Review of his developmental screening questionnaire shows that the boy does not imitate his parents' activities, have a social smile, or show interest in other children. The patient has 8-10 words in his vocabulary and does not combine them into 2-word phrases. There is also concern that his verbal comprehension is poor, and a subsequent audiological evaluation was normal. The boy is up to date on all vaccinations and has no other significant medical history. Laboratory testing shows 226 CGG trinucleotide repeats in a gene located on the X chromosome. Which of the following is the most likely cause of this patient's clinical condition?

Question

A 3-year-old boy is brought to the office for follow-up on intellectual disability and speech delay.  Review of his developmental screening questionnaire shows that the boy does not imitate his parents' activities, have a social smile, or show interest in other children.  The patient has 8-10 words in his vocabulary and does not combine them into 2-word phrases.  There is also concern that his verbal comprehension is poor, and a subsequent audiological evaluation was normal.  The boy is up to date on all vaccinations and has no other significant medical history.  Laboratory testing shows 226 CGG trinucleotide repeats in a gene located on the X chromosome.  Which of the following is the most likely cause of this patient's clinical condition?

Quizplus · Accepted Answer

11ec160b_3783_5d41_9249_0b21c2bf09d0_MD0001_00 This patient has fragile X syndrome (FXS), the most common inherited cause of intellectual disability. Physical findings include macroorchidism and dysmorphic facies (eg, long and narrow face, prominent forehead and chin). Neuropsychiatric disorders include developmental delay, attention deficit-hyperactivity disorder, and autism spectrum disorder (ASD). This patient's delayed language acquisition and poor social skills are suggestive of ASD. FXS is caused by a mutation of the fragile X mental retardation 1 (FMR1) gene on the long arm of the X chromosome. FMR1 normally has 5 to 55 CGG trinucleotide repeats and can potentially expand during meiosis in oocytes. "Full mutation" is characterized by >200 CGG trinucleotide repeats, which causes FMR1 hypermethylation. DNA methylation inactivates FMR1, preventing transcription and production of fragile X mental retardation protein, thereby impairing neural development. Southern blot analysis is used to measure the degree of methylation and determine the number of CGG repeats. (Choices A and C) Exons ("expressed codons") are protein coding regions of DNA. Introns are removed during intranuclear mRNA processing and not expressed in the final mRNA sequence. Abnormalities involving mRNA splicing do not play a role in FXS pathogenesis. (Choice D) Imprinting refers to gene expression from only one parental allele, rather than from both. A mutation in the preferentially expressed allele can result in Prader-Willi syndrome (PWS) or Angelman syndrome. PWS is caused by a paternally-inherited deletion of part of chromosome 15 while the maternal allele is not expressed. In contrast, Angelman syndrome is caused by a maternally-inherited deletion of the same portion of chromosome 15 while the paternal allele is not expressed. (Choice E) Defects in DNA mismatch repair genes cause Lynch syndrome, a condition characterized by an increased risk of hereditary non-polyposis colorectal cancer and extraintestinal malignancies (eg, endometrial cancer). Educational objective: Fragile X syndrome is caused by an increased number of CGG trinucleotide repeats on the fragile X mental retardation 1 (FMR1) gene on the long arm of the X chromosome. This leads to hypermethylation and inactivation of FMR1. __________ References: Fragile X syndrome (http://www.ncbi.nlm.nih.gov/pubmed/25767309) FMR1: a gene with three faces (http://www.ncbi.nlm.nih.gov/pubmed/19233246) Fragile X spectrum disorders (http://www.ncbi.nlm.nih.gov/pubmed/25606363)

A 3-Year-Old Boy Is Brought to the Office for Follow-Up