Fragile X syndrome

Kimon Bekelis MD (Dr. Bekelis of Dartmouth-Hitchcock Medical Center has no relevant financial relationships to disclose.)
Robert J Singer MD (Dr. Singer of Dartmouth-Hitchcock Medical Center/Geisel School of Medicine at Dartmouth has no relevant financial relationships to disclose.)
Bernard Maria MD, editor. (Dr. Maria of Icahn School of Medicine at Mount Sinai and Director of Pediatric Neurology and Developmental Medicine at Goryeb Children)
Originally released March 25, 1994; last updated September 12, 2016; expires September 12, 2019

This article includes discussion of fragile X syndrome, Martin-Bell syndrome, fragile X-linked mental retardation, and fra X syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Fragile X syndrome is a classic neurologic disease with unique manifestations on the clinical and molecular level. It is the most common cause of mental retardation and can render symptoms of speech and developmental delay. Further, it represents one of the many important inherited diseases that are caused by expansions or amplification of short DNA repeats on specific genes. This article will help elucidate the significance of the fragile X syndrome as well as the newly described fragile X tremor-ataxia syndrome (FXTAS) for both younger and older patients and will provide insight on the potential benefits of a diagnostic workup and particular situations where a screening may be beneficial. It will also point to current research that has lead to possible future treatments for symptoms of fragile X syndrome.

Historical note and terminology

Fragile X syndrome is the most common inherited cause of mental retardation. It is named for the folate sensitive fragile site Xq27.3 and is caused by an expansion or amplification of a CGG trinucleotide repeat in the first exon of the fragile X mental retardation gene (FMR1), located on the long arm of the X chromosome. It affects males more severely and more frequently than females. It is a paradigm of a neurologic disease with a well-recognized phenotype and a clearly defined genetic and molecular basis that explains a complex mode of inheritance and the associated phenomenon of anticipation.

Martin and Bell first described this syndrome in 1943 (Martin and Bell 1943). In 1969, Lubs was the first to demonstrate a fragile site on the X chromosome (Lubs 1969). In 1977, Sutherland showed this to be a reliable finding in cells cultured in a folate deficient medium (Sutherland 1977). In 1980, Turner and colleagues recognized the combination of macroorchidism and mental retardation in males in conjunction with a fragile site to be a distinct clinical entity (Turner et al 1980). Verkerk and colleagues discovered the molecular basis of the condition in 1991 (Verkerk et al 1991).

In 2001, Hagerman and colleagues first recognized Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset progressive neurologic disorder. FXTAS develops in a subset of fragile X premutation carriers and involves gait ataxia, action tremor, parkinsonism, peripheral neuropathy, autonomic disorders, cognitive impairment (Hagerman et al 2001), and essential tremor (Gorman et al 2008). The elevated mRNA in fragile X premutation carriers are vulnerable to neurotoxin, leading to early cell death and brain disease, consistent with FXTAS exhibiting neuropsychiatric and neurologic symptoms (Paul et al 2010).

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