Fragile X Syndrome, FXPOI, FXTAS
Dr. med. Imma Rost, Dr. rer. biol. hum. Soheyla Chahrokh-Zadeh, M.Sc. Anna Munzig
Fragile X syndrome is the most frequent monogenic inherited cause of intellectual disability. Unlike other diseases with X-linked recessive inheritance, fragile X syndrome exhibits characteristics such as healthy male carriers and a proportion of affected females with severe symptoms similar to those seen in male patients. The incidence of affected males was estimated to be 1:5,164 by a 2009 study.
Fragile X syndrome is caused by a CGG triplet repeat expansion in the 5' untranslated region of the FMR1 (fragile X mental retardation) gene on the long arm of the X chromosome. Most normal alleles in the general population have a length of 29-30 CGG repeats. Alleles with 45 to 54 repeats are defined as grey-zone alleles (EMQN quality assessment scheme). This number of repeats has a certain instability regardless of the gender of the carrier; however, no expansion to a full mutation has been observed in this range in one generation.
Alleles with 55 to 200 CGG repeats are termed premutations. Premutations inherited from the mother are unstable, which usually leads to an expansion of more than 200 triplets (full mutation). From this length, methylation of the repeats cytosine residues and adjacent regulatory elements occurs, which leads to transcription inhibition resulting in an absence of the FMR1 gene product. In males, stable premutations are passed to the next generation. Mothers of children with full mutations are obligate carriers of a premutation or even a full mutation. The risk of having an affected child is up to 50%, depending on the gender and the length of the mother's premutation.
Schematic representation of the FMR1 gene with normal findings, premutation and full mutation
Developmental delay, usually affecting speech rather than motor development, is the first sign to occur in children with a full mutation. The children are frequently of above-average body length and have an above-average head circumference. Occasionally, signs of connective tissue weakness such as joint hyperextensibility and muscular hypotonia are observed. Characteristic features include hyperactivity and autistic behavior. Apart from larger outer ears, phenotypical characteristics such as a long face and prominent chin although not so obvious in childhood, are typical for adults with fragile X syndrome. Men frequently show postpubertal macroorchidism. Female carriers of the full mutation can have highly variable symptoms, ranging from an inconspicuous phenotype (approx. 30%) to a severe intellectual disability similar to that found in men. Approximately 20% of female premutation carriers undergo premature menopause (fragile X-associated primary ovarian insufficiency, FXPOI).Elderly, especially male premutation carriers show progressive neurological disease in more than 30% of all cases, consisting of intention tremor, gait ataxia, parkinsonism, autonomic dysfunction and dementia; named fragile X-associated tremor/ataxia syndrome (FXTAS).
Mila et al. 2018, Clin Genet.; 93:197 / Hall et al. 2018, Handb Clin Neurol.; 147:377 / Hagermann et al. 2017, Nat Rev Dis Primers; 3:17065 / Pugin et al. 2017, Neurologia; 32:241 / Biancalana et al. 2015, Eur J Hum Genet.; 23:417 / Spath et al. 2010, Am J Med Genet A 152A:387 / Leitlinien zur molekulargenetischen Diagnostik: Fragiles-X und Fragiles-X assoziiertes Tremor/Ataxie Syndrom 2009, medgen 21 / Rost et Klein 2005, J Lab Med 29:152 / Nolin et al. 2003, Am J Hum Genet 72:454 / Oostra et al. 2001, Clin Genet 60:399 / Oostra et al. 1993, J Med Genet 30:410