Molecular Inconsistencies in a Fragile X Male with Early Onset Ataxia
Yun Tae Hwang1,2, Tracy Dudding3,4, Solange Mabel Aliaga5,6,7
1Department of Neurology, Gosford Hospital, Gosford 2250, Australia. y.hwang@ucl.ac.uk.
Abstract:
Mosaicism for FMR1 premutation (PM: 55-199 CGG)/full mutation (FM: >200 CGG) alleles or the presence of unmethylated FM (UFM) have been associated with a less severe fragile X syndrome (FXS) phenotype and fragile X associated tremor/ataxia syndrome (FXTAS)-a late onset neurodegenerative disorder. We describe a 38 year old male carrying a 100% methylated FM detected with Southern blot (SB), which is consistent with complete silencing of FMR1 and a diagnosis of fragile X syndrome. However, his formal cognitive scores were not at the most severe end of the FXS phenotype and he displayed tremor and ataxic gait. With the association of UFM with FXTAS, we speculated that his ataxia might be related to an undetected proportion of UFM alleles. Such UFM alleles were confirmed by more sensitive PCR based methylation testing showing FM methylation between 60% and 70% in blood, buccal, and saliva samples and real-time PCR analysis showing incomplete silencing of FMR1. While he did not meet diagnostic criteria for FXTAS based on MRI findings, the underlying cause of his ataxia may be related to UFM alleles not detected by SB, and follow-up clinical and molecular assessment are justified if his symptoms worsen.
Insights
A fragile X syndrome patient with a full mutation FMR1 gene showed mosaicism for unmethylated alleles, explaining milder symptoms and ataxia. This highlights the importance of sensitive testing for fragile X associated tremor/ataxia syndrome.
Area of Science:
- Genetics
- Neurodegenerative Disorders
- Molecular Biology
Background:
- Fragile X syndrome (FXS) is caused by a full mutation (FM) in the FMR1 gene, typically leading to severe neurodevelopmental impairment.
- Mosaicism for premutation (PM) or FM alleles, and unmethylated FM (UFM) alleles, are linked to milder FXS phenotypes and fragile X associated tremor/ataxia syndrome (FXTAS).
Observation:
- A 38-year-old male diagnosed with FXS presented with a 100% methylated FM allele detected by Southern blot (SB), suggesting complete FMR1 gene silencing.
- Despite the methylation pattern, his cognitive scores were less severe than typical FXS, and he exhibited tremor and ataxia.
Findings:
- Sensitive PCR-based methylation testing revealed a 60-70% proportion of UFM alleles in blood, buccal, and saliva samples.
- Real-time PCR confirmed incomplete FMR1 gene silencing, indicating the presence of UFM alleles missed by SB.
Implications:
- The presence of UFM alleles, not detected by SB, likely explains the patient's milder FXS phenotype and ataxic gait, potentially related to FXTAS.
- Further clinical and molecular monitoring is warranted, especially if symptoms progress, to fully understand the role of UFM alleles in this patient.
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