To determine the range of neurodevelopmental diagnoses associated with intermediate (45-54 repeats) and premutation (55-200 repeats) range cytosine-guanine-guanine fragile X expansions, the medical records of children with intermediate or premutation range expansions were retrospectively reviewed, and all neurodevelopmental diagnoses were abstracted. Twenty-nine children (9 female, 20 male; age, 13 months to 17 years) with intermediate (n = 25) or premutation (n = 4) range expansions were identified with neurodevelopmental diagnoses, including global developmental delay/intellectual disability (n = 15), language and learning disorders (n = 9), attention-deficit hyperactivity disorder (n = 5), epilepsy (n = 5), and motor disorders (n = 12), including 2 boys younger than 4 years of age with tremor and ataxia. Thus, children with intermediate or premutation range fragile X cytosine-guanine-guanine expansions may be more susceptible than children without such expansions to other processes, both genetic and environmental, that contribute to neurodevelopmental disability.
FarzinFPerryHHesslD. Autism spectrum disorders and attention-deficit/hyperactivity disorder in boys with the fragile X premutation. J Dev Behav Pediatr. 2006;27(2):137–144.
2.
BearMHuberKWarrenST. The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004;27(7):370–377.
3.
EschH. The fragile X premutation: new insights and clinical consequences. Eur J Med Genet. 2006;49:1–8.
4.
BassellGJWarrenST. Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron. 2008;60(2):201–214.
5.
AmiriKHagermanRHagermanP. Fragile X-associated tremor/ataxia syndrome: an aging face of the fragile X gene. Arch Neurol. 2008;65(1):19–25.
6.
ChenYTassoneFBermanRF. Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degeneration. Hum Mol Genet. 2010;19(1):196–208.
7.
AzizMStathopuluECalliasM. Clinical features of boys with fragile X premutations and intermediate alleles. Am J Med Genet B Neuropsychiatr Genet. 2003;121B(1):119–127.
8.
BaileyDBJrRaspaMOlmstedMHolidayDB. Co-occurring conditions associated with FMR1 gene variations: findings from a national parent survey. Am J Med Genet A. 2008;146A(16):2060–2069.
9.
HagermanPHagermanJ. Fragile X-associated tremor/ataxia syndrome: an older face of the fragile X gene. Neurology. 2007;3(2):107–112.
10.
CoffeySCookKTartagliaN. Expanded clinical phenotype of women with the FMR1 premutation. Am J Med Genet A. 2008;146A:1009–1016.
11.
Rodriguez-RevegnaLSantosMMSanchezA. Screening for FXTAS in 95 Spanish patients negative for Huntington disease. Genet Test. 2008;12(1):135–138.
12.
GrecoCMBermanRFMartinRM. Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain. 2006;129:243–255.
13.
HesslDTassoneFLoeschD. Abnormal elevation of FMRI mRNA is associated with psychological symptoms in individuals with the fragile X premutation. Am J Med Genet B Neuropsychiatr Genet. 2005;139B:115–121.
14.
HagermanRJHagermanPJ. The fragile X premutation: into the phenotypic fold. Curr Opin Genet Dev. 2002;12(3):278–283.
15.
SullivanAKMarcusMEpsteinMP. Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod. 2005;20(2):402–412.
16.
BourgeoisJASeritanALCasillasEM. Lifetime prevalence of mood and anxiety disorders in fragile X premutation carriers. J Clin Psychiatry. 2011;72(2):175–182.
17.
ChonchaiyaWUtariAPereiraGMTassoneFHesslDHagermanRJ. Broad clinical involvement in a family affected by the fragile X premutation. J Dev Behav Pediatr. 2009;30(6):544–551.
18.
WittenbergerMDHagermanRJShermanSL. The FMR1 premutation and reproduction. Fertil Steril. 2007;87(3):456–465.
19.
GrecoCMTassoneFGarcia-ArocenaD. Clinical and neuropathologic findings in a woman with the FMR1 premutation and multiple sclerosis. Arch Neurol. 2008;65(8):1114–1116.
20.
Berry-KravisEGoetzCLeeheyM. Neuropathic features in fragile X premutation carriers. Am J Med Genet A. 2007;143A:19–26.
21.
JaquemontSHagermanRJHagermanPJLeeheyMA. Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1. Lancet Neurol. 2007;6(1):45–55.
22.
JacquemontSHagermanRJLeeheyM. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet. 2003;72:869–878.
23.
GokdenMAl-HintiJTHarikSI. Peripheral nervous system pathology in fragile X tremor/ataxia syndrome (FXTAS). Neuropathology. 2009;29(3):280–284.
24.
Garcia-ArocenaDYangJEBrouwerJR. Fibroblast phenotype in male carriers of FMR1 premutation alleles. Hum Mol Genet. 2010;19:299–312.
25.
ChonchaiyaWSchneiderAHagermanRJ. Fragile X: a family of disorders. Adv Pediatr. 2009;56:165–186.
26.
LoeschDZBuiQMHugginsRMMitchellRJHagermanRJTassoneF. Transcript levels of the intermediate size or grey zone fragile X mental retardation 1 alleles are raised, and correlate with the number of CGG repeats. J Med Genet. 2007;44(3):200–204.
27.
BodegaBBioneSDalpraL. Influence of intermediate and uninterrupted FMR1 CGG expansions in premature ovarian failure manifestation. Hum Reprod. 2006;21(4):952–957.
28.
BretherickKLFlukerMRRobinsonWP. FMR1 repeat sizes in the gray zone and high end of the normal range are associated with premature ovarian failure. Hum Genet. 2005;117(4):376–382.
29.
ShevellMAshwalSDonleyD. Practice parameter: evaluation of the child with global developmental delay. Neurology. 2003;60:367–380.
30.
BarbaresiWJKatusicSKVoigtRG. Autism: a review of the state of the science for pediatric primary health care clinicians. Arch Pediatr Adolesc Med. 2006;160:1167–1175.
31.
LachiewiczADawsonDSpiridigliozziGMcConkie-RosellA. Arithmetic difficulties in females with the fragile X premutation. Am J Med Genet. 2006;140A:665–672.
