A review of fragile X premutation disorders: expanding the psychiatric perspective

Abstract

Context: Fragile X premutation conditions are associated with a significant degree of psychopathology and thus are of interest to the psychiatrist. Remarkable advances at the molecular level have enhanced our understanding of fragile X premutation disorders.

Objective: The authors review the genetic, molecular, neuroimaging, and clinical (systemic, neurologic, and psychiatric) manifestations of the premutation carrier state (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene.

Data sources: The search for the psychiatric clinical manifestations of fragile X-associated conditions was accomplished by PubMed for clinical papers published between 1970 and 2008 with the following search terms: Fragile X syndrome, depression, psychosis, anxiety, and dementia.

Study selection: Articles addressing psychiatric symptoms in premutation carriers based on review of the abstracts were reviewed. As the majority of the literature on this topic is based on case reports and small case series, these were included in the database.

Results: Reported clinical manifestations of psychiatric illness in premutation carriers include an apparently significant rate of cognitive, mood, anxiety, and other psychiatric disorders. Fragile X premutation-associated conditions are part of the clinical differential diagnosis of several psychiatric syndromes, particularly in pedigrees with known fragile X syndrome cases.

Conclusions: Fragile X-associated psychiatric manifestations serve as a useful model for a molecular genesis of neuropsychiatric illness. Because of the multigenerational expression of fragile X-associated neuropsychiatric illness, there is a prominent role for genetic testing and genetic counseling of patients and their relatives. Genetic testing is confirmatory of the FMR1 premutation and is an essential component of the clinical evaluation. Psychopharmacologic and psychotherapeutic treatment of fragile X-associated psychiatric illnesses may improve patient function and assist in adaptation to the burden of a genetic neuropsychiatric illness.

FIGURE 1

MRI image with an axial cut through the cerebellum demonstrates the middle cerebellar peduncle sign bilaterally denoted by the arrows