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Overlapping Pathways: Autism Spectrum Disorder in Fragile X Carrier States and
the Need for Greater Awareness
#MMPMID41346873
Fernandez MV
; Sirven A
; Pickles B
; Hamid S
; Nunez Selva A
Cureus
2025[Nov]; 17
(11
): e95948
PMID41346873
show ga
Fragile X syndrome (FXS), caused by a full mutation (>200 CGG repeats) in the
gene Fragile X messenger ribonucleoprotein 1 (FMR1), is the most common
single-gene cause of autism spectrum disorder (ASD). Far less is known about the
clinical significance of smaller FMR1 expansions. In this case series, we
describe four male patients with ASD who carried the FMR1 intermediate
(gray-zone) alleles (45-50 CGG; counts: 45, 49, 49, 50). All had early
speech/language delay with ASD-consistent features (social-communication
deficits, sensory sensitivities, and repetitive behaviors). Common comorbidities
included attention-deficit/hyperactivity disorder (ADHD) features and sleep
disturbance responsive to standard interventions. None of them met premutation
(55-200 CGG) or full-mutation criteria. These observations align with emerging
evidence that gray-zone alleles can be associated with neurodevelopmental
phenotypes, including ASD traits, in a subset of carriers. Clinically, the series
reinforces guidance to include FMR1 analysis in genetic evaluations for
unexplained developmental delay/ASD and to provide counseling when intermediate
results are identified. Awareness of a potential overlap between the FMR1
gray-zone states and ASD may aid comprehensive evaluation and family counseling.
Larger, controlled studies, especially those incorporating AGG interruption
analysis, are needed to quantify risk and clarify mechanisms underlying
phenotypic variability.
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