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Clinical features of boys with fragile X premutations and intermediate alleles
Monica Aziz1, Eleni Stathopulu, Maria Callias
1Child Mental Health Learning Disability Service, South-West London & St. George's Mental Health NHS Trust, United Kingdom. monicaaziz@btinternet.com
Insights
Boys with Fragile X premutations and intermediate alleles show similar developmental and physical features to those with full mutations. Protein expression was normal, suggesting these genetic variations may cause significant disabilities.
Area of Science:
- Genetics
- Neurodevelopmental disorders
- Clinical medicine
Background:
- Fragile X syndrome (FXS) presents a distinct behavioral and physical phenotype.
- Previous reports suggest boys with premutations and intermediate alleles may exhibit milder FXS features.
Purpose of the Study:
- To evaluate clinical, behavioral, and physical characteristics in boys with premutation or intermediate CGG triplet expansions.
- To assess Fragile X messenger ribonucleoprotein 1 (FMR1) protein levels in participants.
Main Methods:
- Detailed physical, psychiatric, psychological, and speech-language evaluations were performed.
- FMR1 protein levels were measured in hair roots of participants.
- A clinical series of 10 boys with premutation or intermediate CGG expansions was studied.
Main Results:
- Participants displayed significant resemblance in clinical, behavioral, and physical aspects to individuals with FXS full mutation.
- Normal FMR1 protein expression was observed in all assessed participants, irrespective of CGG repeat size.
- The observed similarities were unlikely due to ascertainment bias alone.
Conclusions:
- Fragile X premutations and intermediate alleles may be associated with significant developmental disabilities and physical features.
- Further research with larger samples is needed to confirm these findings.
- Clinical presentation in boys with premutation/intermediate alleles warrants careful consideration.
Abstract:
Fragile X syndrome has a characteristic behavioural and physical phenotype. Clinical experience and case reports suggest that boys with premutations and intermediate alleles may have similar, but possibly milder, clinical features than those with the full mutation. We conducted detailed physical, psychiatric, psychological and speech and language evaluations on a clinical series of 10 boys, with either premutation or intermediate CGG triplet expansions. Wherever possible we measured the levels of FMR1 protein in participants' hair roots. Many participants demonstrated striking resemblance in their clinical picture, behavioural and physical, to individuals with the fragile X syndrome full mutation. However, protein expression was normal in all participants where it was assessed, despite large variation in CGG triplet repeats. We propose that the findings are unlikely to be attributable to ascertainment bias alone. Replication on larger independent samples is required to confirm our impression that fragile X premutations and intermediate alleles may be associated with important developmental disabilities and physical features.