Fragile X Newborn Screening: Lessons Learned From a Multisite Screening Study

Bailey, Donald B.; Berry‐Kravis, Elizabeth; Gane, Louise W.; Guarda, Sonia; Hagerman, Randi J.; Powell, Cynthia M.; Tassone, Flora; Wheeler, Anne

doi:10.1542/peds.2016-1159h

Cited by 27 publications

(27 citation statements)

References 62 publications

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“…33 Achieving the goal of infant intervention for FXS, including intervention targeting early developing white matter, would likely require expanded efforts to screen newborns. 57,58 …”

Section: Discussionmentioning

confidence: 99%

Development of White Matter Circuitry in Infants With Fragile X Syndrome

Swanson¹,

Wolff

Shen³

et al. 2018

JAMA Psychiatry

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IMPORTANCE Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder and the most common inherited cause of intellectual disability in males. However, there are no published data on brain development in children with FXS during infancy. OBJECTIVE To characterize the development of white matter at ages 6, 12, and 24 months in infants with FXS compared with that of typically developing controls. DESIGN, SETTING, AND PARTICIPANTS Longitudinal behavioral and brain imaging data were collected at 1 or more time points from 27 infants with FXS and 73 typically developing controls between August 1, 2008, and June 14, 2016, at 2 academic medical centers. Infants in the control group had no first- or second-degree relatives with intellectual or psychiatric disorders, including FXS and autism spectrum disorder. MAIN OUTCOMES AND MEASURES Nineteen major white matter pathways were defined in common atlas space based on anatomically informed methods. Diffusion parameters, including fractional anisotropy, were compared between groups using linear mixed effects modeling. Fiber pathways showing group differences were subsequently examined in association with direct measures of verbal and nonverbal development. RESULTS There were significant differences in the development of 12 of 19 fiber tracts between the 27 infants with FXS (22 boys and 5 girls) and the 73 infants in the control group (46 boys and 27 girls), with lower fractional anisotropy in bilateral subcortical-frontal, occipital-temporal, temporal-frontal, and cerebellar-thalamic pathways, as well as 4 of 6 subdivisions of the corpus callosum. For all 12 of these pathways, there were significant main effects between groups but not for the interaction of age × group, indicating that lower fractional anisotropy was present and stable from age 6 months in infants with FXS. Lower fractional anisotropy values in the uncinate fasciculi were correlated with lower nonverbal developmental quotient in the FXS group (left uncinate, F = 10.06; false discovery rate–corrected P = .03; right uncinate, F = 21.8; P = .004). CONCLUSIONS AND RELEVANCE The results substantiate in human infants the essential role of fragile X gene expression in the early development of white matter. The findings also suggest that the neurodevelopmental effects of FXS are well established at 6 months of age.

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“…33 Achieving the goal of infant intervention for FXS, including intervention targeting early developing white matter, would likely require expanded efforts to screen newborns. 57,58 …”

Section: Discussionmentioning

confidence: 99%

Development of White Matter Circuitry in Infants With Fragile X Syndrome

Swanson¹,

Wolff

Shen³

et al. 2018

JAMA Psychiatry

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“…Estimates of the prevalence of FXS have changed over time, with more recent suggestions of approximately 1 in 4,000 individuals (Bailey et al, ). Previous studies have also attempted to define population frequency of female premutation allele carriers.…”

Section: Introductionmentioning

confidence: 99%

FMR1 premutation frequency in a large, ethnically diverse population referred for carrier testing

Owens

Dohany

Holland

et al. 2018

American J of Med Genetics Pt A

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Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is caused by an expansion of cytosine‐guanine‐guanine (CGG) repeats in the FMR1 gene. Female premutation allele carriers (55–200 CGG repeats) are at risk to have an affected child. Currently, specific population‐based carrier screening for FXS is not recommended. Previous studies exploring female premutation carrier frequency have been limited by size or ethnicity. This retrospective study provides a pan‐ethnic estimate of the Fragile X premutation carrier frequency in a large, ethnically diverse population of women referred for routine carrier screening during a specified time period at Progenity, Inc. Patient ethnicity was self‐reported and categorized as: African American, Ashkenazi Jewish, Asian, Caucasian, Hispanic, Native American, Other/Mixed/Unknown, or Sephardic Jewish. FXS test results were stratified by ethnicity and repeat allele category. Total premutation carrier frequency was calculated and compared against each ethnic group. A total of 134,933 samples were included. The pan‐ethnic premutation carrier frequency was 1 in 201. Only the Asian group differed significantly from this frequency. Using the carrier frequency of 1 in 201, a conservative pan‐ethnic risk estimate for a male fetus to have FXS can be calculated as 1 in 2,412. This risk is similar to the highest ethnic‐based fetal risks for cystic fibrosis and spinal muscular atrophy, for which population‐wide screening is currently recommended. This study adds to the literature and supports further evaluation into specific population‐wide screening recommendations for FXS.

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“…Synaptogenesis in the human brain peaks within the first 2 years of life, however, treatment strategies for infants with FXS currently do not exist 83,84 . This is largely because children do not present with signs and symptoms of FXS until about 3‐4 years of life 85 . Although there has been a push for the institution of prenatal or newborn screening for the disease, the lack of targeted and effective therapy for infants has served as a major barrier 84 .…”

Section: Discussionmentioning

confidence: 99%

Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome

Griffiths

Wang

et al. 2020

FASEB j.

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Fragile X syndrome (FXS) is the leading known inherited intellectual disability and the most common genetic cause of autism. The full mutation results in transcriptional silencing of the Fmr1 gene and loss of fragile X mental retardation protein (FMRP) expression. Defects in neuroenergetic capacity are known to cause a variety of neurodevelopmental disorders. Thus, we explored the integrity of forebrain mitochondria in Fmr1 knockout mice during the peak of synaptogenesis. We found inefficient thermogenic respiration due to futile proton leak in Fmr1 KO mitochondria caused by coenzyme Q (CoQ) deficiency and an open cyclosporine‐sensitive channel. Repletion of mitochondrial CoQ within the Fmr1 KO forebrain closed the channel, blocked the pathological proton leak, restored rates of protein synthesis during synaptogenesis, and normalized the key phenotypic features later in life. The findings demonstrate that FMRP deficiency results in inefficient oxidative phosphorylation during the neurodevelopment and suggest that dysfunctional mitochondria may contribute to the FXS phenotype.

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Fragile X Newborn Screening: Lessons Learned From a Multisite Screening Study

Cited by 27 publications

References 62 publications

Development of White Matter Circuitry in Infants With Fragile X Syndrome

Development of White Matter Circuitry in Infants With Fragile X Syndrome

FMR1 premutation frequency in a large, ethnically diverse population referred for carrier testing

Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome

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