Fragile X Gene Premutation: To Recognize Early and Treat Neuropsychiatric Problems

Budimirovic DB^1* and Protic D^2
*Correspondence: Budimirovic DB, Department of Psychiatry, Clinical Research Center, Clinical Trials Unit, Fragile X Clinic, Kennedy Krieger Institute, The Johns Hopkins Medical Institutions, Baltimore, MD, USA, Tel: +1-443-923-2634, Fax: +1-443-923-7628, Email:

Commentary

Mutations in the Fragile X Mental Retardation 1 (FMR1) gene cause a spectrum of genetic disorders such as neurodevelopmental in childhood and neurodegenerative in adulthood. Two types of mutations are recognized that has a different pathophysiological mechanism leading to their corresponding phenotypes under the umbrella of fragile X-related disorders (FXD). First, the full mutation of the FMR1 gene (FM, ≥ 200 CGGs) causes hypermethylation that leads to silencing of FMR1 and an absence of Fragile X Mental Retardation Protein (FMRP); and clinically fragile X syndrome (FXS) ensures. FMRP expresses in many tissues and plays an important role in the development of synapses and regulation of synaptic plasticity [1-3]. Thus, FXS emerges in an early childhood and is characterized by intellectual disability (ID) in 85% of boys and autism spectrum disorder (ASD) in up to 50% of boys and 20% of girls [4,5]. Early language and motor milestones and social-communication skills are more affected in patients with ASD and FXS than in those with FXS only [6,7]. Second, the premutation or “carriers” (PM, 55-200 CGGs) of the FMR1 gene leads to elevated levels of the FMR1 mRNA. Rapidly accumulating data on molecular pathology of FMR1 PM over the last decade has brought much insight into the field [8,9]. For example, higher length of CGGs repeats was found to correlate with the higher mRNA levels, and the high level of mRNA causes RNA toxicity related to the sequestration of proteins that are important for neuronal function [10]. These PM neurons are more susceptible to die in cell culture and are more vulnerable to environmental toxins such as alcohol and pesticides [9,11]. Importantly, cellular mechanisms such as calcium dysregulation, mitochondrial dysfunction, oxidative stress, chronic DNA damage repair changes and the formation of the toxic protein FMRpolyG are all related to the toxicity of the PM that can lead to the neurodegenerative disorder such as fragile-X-associated tremor/ataxia syndrome (FXTAS) [10,12-15]. Furthermore, the translation of mRNA with greater than 120 CGG repeats is inefficient and there is deficit of FMRP as well. The carriers are found in roughly 1:200 females and 1:400 males (1.5 million females in the US; over 20 million worldwide), the prevalence 10 times higher than in FXS [16]. Thus, an emerging potential neuropsychiatric impact of the PM is enormous worldwide, beyond FXTAS and fragile-X-associated primary ovarian insufficiency as the most serious adult-onset clinical manifestations of the PM [8,17]. Indeed, we now know of high prevalence both medical/neurological (i.e., migraine headaches, chronic pain, fibromyalgia, chronic fatigue and autoimmune problems) and adult psychiatric disorders that may be related to PM of the FMR1 gene that recently Hagerman and colleagues in 2018 elegantly labelled Fragile X-associated Neuropsychiatric Disorder (FXAND). To date, an overall lack of knowledge about these problems exists among clinicians. Not surprisingly, this is true among the medical professionals in countries in transitions [18].

Our opinion is that all primary care providers, including paediatricians, ought to be vigilant as for the FXAND that may cause psychiatric disorders in paediatric population suggesting that they also need to be screened for the FMR1 gene mutations [11]. For example, babies with the PM demonstrated a greater sensitivity to sensory stimuli compared to controls, children showed a high rate of attention-deficit/ hyperactivity disorder and ASD, and other developmental problems; and anxiety is the most common problem in the PM carriers, which typically begins in childhood. Importantly, the psychiatric problems occur usually before the neurological disorders related to the PM of the FMR1 gene. Our clinical experience is that puberty is the period when these psychiatric problems in children reach clinical significance. The aforementioned molecular studies showed a link among the psychiatric problems occurred in the PM carriers and its intracellular molecular abnormalities.

As the knowledge in the field of fragile X continues to grow in the 21^st century that ought to expand to the PM of the FMR1 gene, and in paediatric population as its early recognition of their psychiatric problems can improve quality of life of these individuals and their families.

References

1. Hessl D, Wang JM, Schneider A, Koldewyn K, Le L, et al. (2011) Decreased fragile X mental retardation protein expression underlies amygdala dysfunction in carriers of the fragile X premutation. Biol Psychiatry 70: 859-865.
2. Pretto DI, Mendoza-Morales G, Lo J, Cao R, Hadd A, et al. (2014) CGG allele size somatic mosaicism and methylation in FMR1 premutation alleles. J Med Genet 51: 309-318.
3. Ludwig AL, Espinal GM, Pretto DI, Jamal AL, Arque G, et al. (2014) CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size. Hum Mol Genet 23: 3228-3238.
4. Budimirovic DB, Subramanian M (2016) Neurobiology of autism and intellectual disability: Fragile X syndrome. In: Neurobiology of Disease (2nd edn), Oxford University Press, New York, United States.
5. Kaufmann WE, Kidd SA, Andrews HF, Budimirovic DB, Esler A, et al. (2017) Autism Spectrum Disorder in fragile X syndrome: Co-occurring conditions and current treatment. Pediatrics 139: S194-S206.
6. Hinton R, Budimirovic DB, Marschik PB, Talisa VB, Einspieler C, et al. (2013) Parental reports on early language and motor milestones in fragile X syndrome with and without autism spectrum disorders. Dev Neurorehabil 16: 58-66.
7. Budimirovic DB, Kaufmann WE (2011) What can we learn about autism from studying fragile X syndrome? Dev Neurosci 33: 379-394.
8. Hagerman R, Hagerman P (2013) Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome. Lancet Neurol 12: 786-798.
9. Hagerman R, Hagerman P (2016) Fragile X-associated temor/ataxia syndrome - features, mechanisms and management. Nat Rev Neurol 12: 403-412.
10. Hagerman PJ, Hagerman RJ (2015) Fragile X-associated tremor/ataxia syndrome. Ann N Y Acad Sci 1338: 58-70.
11. Chen Y, Tassone F, Berman RF, Hagerman PJ, Hagerman RJ, et al. (2010) Murine hippocampal neurons expressing FMR1 gene premutations show early developmental deficits and late degeneration. Hum Mol Genet 19: 196-208.
12. Robin G, López JR, Espinal GM, Hulsizer S, Hagerman PJ, et al. (2017) Calcium dysregulation and Cdk5-ATM pathway involved in a mouse model of fragile X-associated tremor/ataxia syndrome. Hum Mol Genet 26: 2649-2666.
13. Napoli E, Ross-Inta C, Wong S, Omanska-Klusek A, Barrow C, et al. (2011) Altered zinc transport disrupts mitochondrial protein processing/import in fragile X-associated tremor/ataxia syndrome. Hum Mol Genet 20: 3079-3092.
14. Napoli E, Ross-Inta C, Song G, Wong S, Hagerman R, et al. (2016) Premutation in the fragile X mental retardation 1 (FMR1) gene affects maternal Zn-milk and perinatal brain bioenergetics and scaffolding. Front Neurosci 10: 159.
15. Todd PK, Oh SY, Krans A, He F, Sellier C, et al. (2013) CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron 78: 440-455.
16. Tassone F, Hagerman PJ, Hagerman RJ (2014) Fragile X premutation. J Neurodev Disord 6: 22.
17. Hagerman RJ, Protic D, Rajaratnam A, Salcedo-Arellano MJ, Aydin EY, et   al. (2018) Fragile X-Associated Neuropsychiatric Disorders (FXAND). Front Psychiatry 9: 564.
18. Budimirovic DB, Bukumiric Z, Cvetkovic S, Phan D, Protic D (2018) Fragile X-associated disorders in Serbia: Baseline quantitative and qualitative survey of knowledge, attitudes and practices among medical professionals. Front Neurosci 12: 652.