Pathogenesis and inheritance
Fragile X-associated tremor/ataxia syndrome is caused by a mutation in the FMR1 gene (Fragile X Mental Retardation 1) on the X chromosome. This gene is best known for its association with the developmental disorder fragile X syndrome, which is the most common cause of hereditary developmental disability (1).
Fragile X syndrome affects more than 1 in 7 000 boys and 1 in 11 000 girls (1). It is one of three FMR1-associated disorders, the other two being fragile X-associated tremor/ataxia syndrome, and fragile X-associated primary ovarian insufficiency. All three are caused, with very few exceptions, by an expansion of CGG triplet repeats in a noncoding region of the FMR1 gene on the X chromosome.
Non-affected individuals usually have around 30 CGG triplet repeats. If the number of triplets is ≥ 45, the repeat expansion can increase from one generation to the next. Such triplet repeat expansions are unstable and are often called dynamic mutations. If the number of CGG triplets exceeds 200 – a so-called full mutation – the gene is inactivated and the key FMR1 protein is no longer produced. This leads to fragile X syndrome (1).
Shorter expansions of 55–200 CGG triplets are called 'premutations' and can give rise to both fragile X-associated tremor/ataxia syndrome and FMR1-associated primary ovarian insufficiency. The gene is not inactivated in these cases; on the contrary it becomes more active, leading to the production of large amounts of expanded mRNA containing the CGG triplets (2). The problem here is not a lack of FMR1 protein, but a toxic mechanism initiated by the expanded mRNA (3). This explains why full mutations and premutations can give rise to completely different phenotypes.
In individuals with fragile X-associated tremor/ataxia syndrome, intranuclear inclusions form in both the central nervous system and peripheral tissues (3). Neurons and astrocytes in the cerebellum, basal ganglia, hippocampus and frontal cortex are particularly affected (4). For reasons that remain unclear, however, less than half of all premutation carriers develop fragile X-associated tremor/ataxia syndrome.
FMR1-associated conditions show X-linked inheritance. However, when triplet repeat expansions are inherited paternally, they are largely prevented from expanding further by unexplained mechanisms that occur during spermatogenesis (5). Further expansion of triplet repeats usually occurs in female germ cells, and therefore fragile X syndrome almost exclusively affects children of female premutation carriers.
Because of this pattern of inheritance, diagnosing an individual with one of these disorders could reveal an entire family's risk of all three conditions (6). Family medical history is therefore central to the diagnostic workup. It is important to ask whether an individual's first- or second-degree relatives include women with early menopause; persons over the age of 50 with ataxia, tremor and/or parkinsonism, or children with developmental disorders.