The pilot study by Tassone et al 10 was designed to determine the feasibility of screening in anticipation of a possible future scenario of NBS for FMR1 mutations, and in this respect it succeeded. However, because it identified both premutation and gray-zone allele carriers, the study findings have raised questions about carrier screening.
Carrier screening is usually seen in the context of reproductive health care whereby the outcome may inform parents about reproductive options and family planning. In the case of FXS, the identification of carriers not only can advise on the reproductive risk of having a child with FX but may also inform about personal health risks; the latter raises concerns for genetic counseling regarding the potential to develop, for example, late-onset neurological problems FXTAS , anxiety, depression, or other medical conditions associated with the FMR1 premutation.
The identification of the proband through NBS also raises the need for cascade testing of other family members and subsequent identification of individuals who may be affected by the premutation or full mutation, which can present ethical and legal issues because family members did not directly consent to the screening.
Identifying a baby with expanded alleles could lead to increased anxiety, stress, and depression in parents and related family members.
If accepted, screening for FXS should be voluntary and therefore involve a consent process, which could overwhelm parents and burden hospitals. However, recently reported data do not indicate reduced participation in screening programs because of these concerns; indeed, a high participation rate was observed.
The identification of gray-zone alleles is problematic because the research regarding clinical involvement is very limited and the prevalence of that expansion is very high. Arguments in favor of NBS for FXS include benefits of early detection and possibilities for families to access early intervention programs. While babies who have the full mutation and therefore have FXS can benefit from early intervention programs that begin in the first year, such as the Early Start Denver Model, 15 babies carrying the premutation who present with developmental delay also benefit from the Early Start Denver Model and other programs, but treatment data are lacking.
Important reasons to diagnose babies as carrying the premutation at the time of birth are similar, including treatment and follow-up for the baby and benefits for family members. Some family members may struggle with premutation or full-mutation problems and can benefit from treatment.
Reproductive counseling for the mother and other female carriers in the family tree who may present with clinical symptoms related to the premutation should be considered.
Therefore, screening could overwhelm and saturate genetic counseling resources and comprehensive care infrastructures, important factors to consider in support of the families with an identified newborn. Knowledge regarding prevalence is important to guide health policy decisions regarding the effects of FMR1 -associated disorders on public health.
Emerging, promising results from new targeted treatments for FXS and the feasibility of molecular detection could result in adding FMR1 mutations to existing NBS programs in the near future. Ideally, an NBS program should include parental education, follow-up, diagnosis, and treatment to guarantee the benefits of screening. Thus, it is imperative that services, resources, and infrastructure for early-childhood developmental interventions be expanded and that counseling and education be made available so that treatment of emotional, behavioral, and developmental problems can be recommended for identified newborns and their families when needed.
Published Online: January 6, No other disclosures were reported. Role of the Sponsor: The funding organization had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Information: This work is dedicated to the memory of Matteo.
Additional Contributions: Randi J. Hagerman, MD, provided helpful comments. Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy Continue.
Newborn Screening Process. View Large Download. Pathological plasticity in fragile X syndrome. Neural Plast. PubMed Google Scholar Crossref. No change in the age of diagnosis for fragile X syndrome: findings from a national parent survey. Newborn screening: toward a uniform screening panel and system. Genet Med. Hagerman R, Hagerman P. Lancet Neurol. Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degeneration.
Hum Mol Genet. Ovarian abnormalities in a mouse model of fragile X primary ovarian insufficiency. J Histochem Cytochem. Early mitochondrial abnormalities in hippocampal neurons cultured from Fmr1 pre-mutation mouse model. Micrograph of cortical neuronal center and astroglial left cells bearing intranuclear inclusions brown, ubiquitin immunostaining.
A, Normal lamin localization red, antilamin with control reporter plasmid. B, Collapse of lamin architecture with expanded-repeat CGG 88 reporter.
Arch Neurol. Hagerman and the M. Institute Drs R. Hagerman and P. FXTAS is principally characterized as a movement disorder with progressive intention tremor and gait ataxia, with more variable associated features of parkinsonism, dysautonomia, peripheral neuropathy, and dementia. The lack of FMRP is the pathogenic basis of the developmental disorder fragile X syndrome, the leading heritable form of mental impairment.
Thus, the same gene presents 2 opposing faces: a neurodegenerative syndrome FXTAS in older adults, caused by excess gene activity and production of a toxic RNA, and a childhood-onset disorder fragile X syndrome , caused by absence of gene activity. FXTAS is a late-onset neurodegenerative disorder with core features of intention tremor and gait ataxia with associated neurological and nonneurological features.
Fragile X syndrome has been recognized for more than a quarter of a century, and the causative gene FMR1 was identified 17 years ago. First, geneticists who were studying fragile X syndrome were focused on a developmental disorder ie, a childhood condition affecting cognition. Because the gene was unknown before , it was nearly impossible to establish any association with late-onset problems in adults carriers who had been essentially normal in childhood. Furthermore, the grandfathers of children with fragile X syndrome rarely came to the pediatric clinics, so their own age-associated symptoms were generally not recognized as being linked to their carrier status.
Therefore, clinical abnormalities were not expected among carriers of premutation alleles. The second reason for the delay in recognition was that adult neurologists, geriatricians, and psychiatrists who were treating the carriers unidentified as such were generally unaware of fragile X syndrome, a childhood-onset disorder. Thus, cases now known to be FXTAS were generally regarded as being any one of a number of sporadic neurological disorders in older adults, with no obvious genetic basis.
The first clue to any form of clinical involvement in carriers came about through discussions with mothers and grandmothers of the fragile X syndrome probands, who themselves were premutation carriers and who often described their own problems with premature ovarian failure POF cessation of menses before age 40 years. A typical presentation is a progressive intention tremor that interferes with handwriting, followed by interference with other activities of daily living use of eating utensils, pouring liquids, dressing and progressive problems with balance.
From the onset of the initial motor sign, median delay of onset of ataxia was 2 years; onset of falls, 6 years; dependence on a walking aid, 15 years; and death, 21 years. Preliminary data on life expectancy are variable, ranging from 5 to 25 years. Associated features include a neuropathy, usually in a stocking distribution 3 , 13 ; psychiatric problems, including reclusive behavior, anxiety, mood instability, depression, and apathy 10 ; and autonomic dysfunction, including orthostatic hypotension, impotence, and eventually urine and stool incontinence.
As more cases are described, it has become evident that presenting features may include not only intention tremor and ataxia, which would direct these individuals to movement disorders clinics, but also neuropathy or cognitive problems, including dementia, which might result in initial visits to neuropathy, pain management, or psychiatric clinics.
Women also present with FXTAS, although the movement disorder is less common in female carriers compared with male carriers presumably because of the protective effect of the second X chromosome.
In a study of 36 male premutation carriers, the CGG repeat within the premutation range correlated with reductions in both IQ and cerebellar volume, increased ventricular volume, and volume of whole-brain white matter disease. At the time individuals present with motor symptoms, they usually already have mild cognitive features, including memory problems and executive function deficits. In our studies of adult carriers, we found a significant positive association between the psychiatric problems in men, including obsessive-compulsive behavior on Symptom Checklist—90 a psychiatric questionnaire , and the level of FMR1 mRNA.
These findings suggest that RNA toxicity in the limbic system may be responsible for the psychiatric problems seen in some carriers. However, this upper-bound estimate is biased by the ascertainment of FXTAS cases within known fragile X syndrome families, where transmission of full-mutation alleles fragile X syndrome probands is highly biased toward larger CGG repeats in the premutation range. The magnitude of this bias can be gauged from epidemiological studies demonstrating that the penetrance among carriers of larger premutation alleles is greater than among carriers of smaller premutation alleles.
A simple correction for this size bias would reduce the expectation for lifetime risk among males in the general population to about 1 in to This number is much lower than Parkinson disease or essential tremor and similar in prevalence to inherited ataxia, progressive supranuclear palsy, multiple system atrophy, and amyotrophic lateral sclerosis.
Clearly, better prevalence estimates are needed based on larger-scale screens of US populations. The principal feature of the neuropathology of FXTAS is the presence of ubiquitin-positive intranuclear inclusions in neurons and astrocytes but not oligodendroglia in broad distribution throughout the brain Figure 1. Inclusions are only rarely detected in Purkinje cells despite substantial cerebellar Purkinje cell dropout.
When Brighton was diagnosed at five, we had Avery tested. She was nine months old. My dad is a carrier and so are my sisters. I felt so alone when I got the diagnosis. I also wish that in my time of mourning I would have been able to look into the future and see how happy my kids are and how happy our lives are. There are tough times, there really are.
Skip directly to site content Skip directly to page options Skip directly to A-Z link. Section Navigation. Facebook Twitter LinkedIn Syndicate. Minus Related Pages. On This Page. Ruth's Story Rachael's Story. Ruth says she would tell parents of younger children with FXS that it does get better. Top of Page. Links with this icon indicate that you are leaving the CDC website. Linking to a non-federal website does not constitute an endorsement by CDC or any of its employees of the sponsors or the information and products presented on the website.
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