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Published in final edited form as: Int J Dev Neurosci. 2018 Oct 29;72:1–5. doi: 10.1016/j.ijdevneu.2018.10.002

Increased Severity of Fragile X Spectrum Disorders in the Agricultural Community of Ricaurte, Colombia

Wilmar Saldarriaga 1,2,3, María J Salcedo-Arellano 1,2,4, Tatiana Rodriguez-Guerrero 1, Marcela Ríos 1, Andrés Fandiño-Losada 1,5, Julian Ramirez-Cheyne 1,2,3, Pamela J Lein 4,6, Flora Tassone 4,7, Randi J Hagerman 4,8
PMCID: PMC6354926  NIHMSID: NIHMS1513090  PMID: 30385191

Abstract

Premutation carriers of the FMR1 gene (CGG repeats between 55 and 200) usually have normal intellectual abilities but approximately 20% are diagnosed with developmental problems or autism spectrum disorder. Additionally, close to 50% have psychiatric problems such as anxiety, ADHD and/or depression. The spectrum of fragile X disorders also includes Fragile-X-associated primary ovarian insufficiency (FXPOI) in female carriers and Fragile-X-associated tremor/ataxia syndrome (FXTAS) in older male and female carriers.

We evaluated 25 premutation carriers in the rural community of Ricaurte Colombia and documented all behavioral problems, social deficits and clinical signs of FXPOI and FXTAS as well as reviewed the medical and obstetric history.

We found an increased frequency and severity of symptoms of fragile X spectrum disorders, which might be related to the vulnerability of FMR1 premutation carriers to higher exposure to neurotoxic pesticides in this rural community.

Keywords: Fragile X syndrome, fragile X spectrum disorders, FXTAS, FXPOI, Colombia

Introduction

Fragile X syndrome (FXS) is a disease of genetic origin that has a prevalence of 1:5000 men and 1:4000–8000 women, while the prevalence of carrying the premutation is estimated at 1:400–850 males and 1 in 150–300 females 1–3. Inherited through the X chromosome, FXS is caused by the unstable expansion of the CGG triplet in the gene Fragile X Mental Retardation 1 (FMR1). Among individuals with the full mutation of FMR1 (> 200 CGG repeats), 60% of males are diagnosed with Autism Spectrum Disorders (ASD), and almost all males and 30% of females have intellectual disability (ID) 4. Female carriers of the premutation (CGG repeats between 55 and 200) can pass the mutation to 50% of their offspring, although in many cases, offspring experience expansion of the CGG repeats to the full mutation resulting in FXS. Children with the premutation usually have normal intellectual abilities but approximately 20% are diagnosed with developmental problems or autism spectrum disorder (ASD), which are part of the spectrum of fragile X disorders (FXSD) 5,6. Psychiatric problems such as anxiety, ADHD and/or depression are present in approximately 50% of children and adults with the premutation 5,7–9.

Additional disorders included in FXSD include Fragile-X-associated primary ovarian insufficiency (FXPOI), characterized by infertility and menopause prior to age 40, which occurs in approximately 20% of female carriers 10,11; in contrast, premature ovarian insufficiency (POI) is observed in 1% of the general population 12. In addition, 12.6% of female FMR1 premutation carriers without FXPOI have difficulty getting pregnant 13. Fragile-X-associated tremor ataxia syndrome (FXTAS) is a neurodegenerative disorder that occurs in some older carriers and involves an intention tremor and cerebellar ataxia. FXTAS was originally described in male carriers of the premutation who were older than 50 years 14. Later it was found to affect approximately 40% of males but also female premutation carriers with a penetrance of 16% 15–17. Seizures occur in less than 1% of female premutation carriers and approximately 8–14% of male premutation carriers 18,19.

Experimental studies have revealed that premutation neurons from the knock-in mouse die more readily in cell culture compared to neurons without the premutation20, an observation that has given rise to the hypothesis that FMR1 premutation increases the vulnerability of neurons to environmental toxins 21. Neurological deterioration in patients with FMR1 premutation has been associated with exposure to many environmental toxins, including chemotherapeutic agents 22, anesthetics23, substance abuse of opioids and or alcohol 24–26, and perhaps phenobarbital 27.

Ricaurte, a small town in Valle del Cauca, province of Colombia, has severe economic limitations. The base of the economy is agriculture and cattle raising, which are practiced without the aid of industrial equipment and often under precarious working conditions. Ricaurte, population of less than 1,500 people, has a cluster of FXS, with 1:19 men and 1:46 women carrying the full mutation, and 1:85 men and 1:25 women carrying the premutation28. We evaluated all premutation carriers to assess the frequency and severity of FXSD including FXTAS, FXPOI, seizures and behavioral problems.

Materials and Methods

This study was conducted from January, 2016 to May, 2016. The protocol was reviewed and approved by the Institutional Review Board (IRB) of the School of Health of Universidad del Valle (Cali, Colombia). We evaluated all premutation carriers, 20 women and 5 men, age range between 11 months and 83 years, all of whom are of Hispanic ethnicity. To be included in the study subjects had to be a native of Ricaurte, Colombia and diagnosed as being a premutation carrier using polymerase chain reaction (PCR) and Southern blot to quantify the number of CGG repeats in the FMR1 gene28. All patients signed an informed consent authorizing an in-depth review of their clinical history including medical problems and reproductive issues as well as a physical evaluation that included the use of standardized rating scales and interview-based measures, specifically, the Scale for the Assessment and Rating of Ataxia (SARA)29, and the Fahn-Tolosa-Marín Clinical Rating Scale for Tremor (FTM)30 to assess neurological findings during the exam of those carriers older than 50 years of age (n=14). SARA is a valid clinical rating scale administered by the physician that has proven to be significantly correlated with results obtained using the International Cooperative Ataxia Rating Scale (ICARS)31 and the Modified Barthel Index (MBI)32,33. FTM is the most commonly used scale to evaluate essential tremor; it assesses postural, kinetic and rest tremor34. General mental status was measured by the raw total score on the Mini Mental State Exam (MMSE)35 and the Short Test of Mental Status (STMS)36,37 was used to explore mild cognitive impairment; however, the calculation subpart was left out since most of the older participants did not have the educational level required to perform the tasks. Executive abilities were evaluated with the Behavioral Dyscontrol Scale (BDS)38,39. BDS was previously used to report dysexecutive syndrome in carrier males with FXTAS40.

All carriers were also evaluated for behavioral problems including anxiety and depression, as well as social deficits, including social anxiety, as determined using the Generalized Anxiety Disorder 7 (GAD-7) scale 41, the Mayor Depression Inventory (MDI) 42 and, the Brief Fear of Negative Evaluation (BFNE) scale 43, respectively. GAD-7 measures severity of anxiety, it has an overall sensibility of 89% and specificity of 82%41,44; MDI is a self-report mood questionnaire developed by the WHO, and BFNE is a self-report questionnaire that measures the cognitive component of social anxiety45,46. Despite being self-report questionnaires, all surveys were administered by the physician as interview-based measures in order to overcome the educational barrier encountered with most of the participants. Further explanation was offered when needed. In the case of one participant who had mutism and ID, the assessments were answered by her sister. One participant, who was an infant, was excluded from the assessment. We did not measure IQ since most premutation carriers have normal IQ 21,47,48.

Results

FXTAS

All of the female premutation carriers in the study population were evaluated (n= 20). Twelve of them (60%) were 50 years of age or older. These twelve patients underwent a further clinical evaluation, including a neurological examination, using SARA and FTM to assess the presence and severity of ataxia and tremor. Two subjects (16.6%) had ataxia and two (16.6%) had tremor; none had both. Out of the 5 male carriers, two were over 50 years old; one had a distal tremor without ataxia and the other had no tremor or ataxia, but presented with executive dysfunction, which is a FXTAS-associated cognitive deficit 40,49 (see Table 1).

Table 1.

Summary of Results.*

Age Gen Allele Exp ** LOE Obstetric History Children with FM Children with PM Menopau se (Age) FXPOI FXTAS Seizures Cognit Anxiety Comments
71 F 30,57 Y 40  G0P0  0  0  39  *
38 F 30,55 N  G3P3L3  0  1 (M)  NO
44 F 30, 142 Y 15  G2P2  2 (M)  0  38  *  * Mild anxiety
54 F 30,55 N  G4P5L4  0  1 (F)  51
53 F 30,69 Y 10  G0P0  0  0  51  * Mutism
60 F 30,110 Y 30  G0P0  0  0  55  * Cerebral atrophy
54 F 45,135 Y 20  G1C1  1 (M)  50  *  * Cerebellar atrophy, ataxia started at 42 yo
80 F 29,86 Y 35 G9P9  3 (M)
1 (F) 		 1 (F)  51  * Tremor started at 75 yo
68 F 29,105 Y 15  G4P4  1 (M)  1 (F)  57
53 F 30,82 Y 25  G5P3C2 L2  0  0  35  *  * * Cerebral atrophy, hysterectomy 35 yo, moderate anxiety, tremor started at 46 yo
26 F 39,77 N  G2C1L0  0  0  NO
71 F 30,67 Y 40  G0P0  0  0  50  *  *  * Intellectual disability, severe anxiety
49 F 30,79 N  G2P2  1 (M)  1 (F)  47
47 F 30,82 N  G1P1  0  0  NO
57 F 30,80 N  G2P2  2 (M)  0  48
47 F 30,71 N  G3P3L2  0  0  45  * Moderate anxiety
39 F 30,66 Y 21  G3P2C1  0  1 (M)  36  *  *
65 F 29,82 N  G1P1  0  1 (F)  50
62 F 30,121 Y 35  G4P2C2 L3  2 (F)  0  51
38 F 29,102 N  G1P1  0  0  NO
11 m M 55 N  0  0  0  NA
16 M 55 N  0  0  0  NA  * Mild anxiety
83 M 69 Y 40  3 (F) 4 (M)  0  3 (F)  NA  * Tremor started at 75yo
70 M 61 Y 40  4 (F) 3 (M)  0  3 (F)  NA  *  * Disinhibition and emotion regulation problems, moderate anxiety
14 M 123 N  0  0  0  NA
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*

All patients are Hispanic. Gen=Gender; Exp=Exposed to pesticides; Y=yes; N=no; LOE=Length of pesticide exposure (in years); Cognit=Cognitive; PM=premutation; FM=full mutation; NA=not applicable; M=male and F=female; G=gravida (number of pregnancies), P=para (number of pregnancies reaching viable gestational age) C=cesarean delivery and L= living children.

**

Those exposed have worked in the field, some of them since childhood. The length of exposure to each specific pesticide is unknown since their use depends on the type of crop. Products commonly grown include cotton, milo, tomato, papaya, pineapple and sugar cane. Younger generations have had better educational resources and have transitioned to more diverse job opportunities in nearby cities. However; agriculture remains to be the main economic activity of the region. No one is exempt from exposure one way or another.

FXPOI

Sixteen (80%) out of the twenty female premutation carriers were older than 40 years of age, and were asked to answer a questionnaire regarding gynecological and reproductive issues including infertility and early menopause. Three (18.7%) had absence of their menstrual cycle for more than a year before reaching 40 years, which meets the absolute criterion of FXPOI. Of the three women who met this criterion, one has two sons affected with FXS, one has three children, one of whom is a carrier of the premutation allele, and the third has no children. In addition, from the remaining 13 premutation carriers older than 40 years of age, one woman underwent hysterectomy at 35 years old due to persistent vaginal bleeding associated with perimenopause symptoms (headache, hot flashes, mood swings) and three others had a gravida 0, para 0 (G0P0) obstetric history despite having a sexual partner and seeking reproduction by natural methods. Therefore a total of four women (25%) had findings suggestive of ovarian insufficiency (abnormal bleeding and reproductive issues) in addition to the 3 women with FXPOI (see Table 1).

Seizures

Five (25%) out of twenty female premutation carriers presented with seizures, most of them since childhood, with poor control and noticeable cognitive decline. Two of them also presented symptoms of FXTAS before age 50; one with cerebellar atrophy and one with cerebral atrophy reported on clinical MRI 27. Four of the five subjects with seizures had concomitant symptoms of ovary insufficiency (see Table 1).

Cognition and behavioral problems

Two female and one male premutation carrier presented with cognitive deficits. Of these three, one presented with lifelong mutism, another one with intellectual disability and the third with executive dysfunction (deficit in behavioral self-regulation); one of the females and the male also presented with moderate to severe anxiety. Of the 25 subjects in the study, 6 individuals (24%) were experiencing symptoms of general and social anxiety at the time of their medical evaluation, which was untreated because these symptoms are not identified by the patients as a medical problem that they brought to the attention of a physician.

Discussion

In Ricaurte, the frequency and severity of symptoms of FXTAS, FXPOI and seizures in carriers of the FMR1 premutation are higher than those reported in the literature 16,17,21.

We found that in male and female carriers, 50% and 33.3% respectively, of those older than 50 years of age presented symptoms and clinical signs suggestive of FXTAS. Patients with tremor and ataxia had an early onset of symptoms and severity, none of them reported a history of exposure to chronic use of opioids and/or alcohol or general anesthesia; however, all of these carriers worked in agriculture, either in the fields or in their home gardens since childhood, as ascertained from the medical history. We also found that 18.7% of the women who were carriers had FXPOI and 25% of the women without FXPOI had findings suggestive of ovarian insufficiency (see Table 1).

Overexpression of FMR1 mRNA leading to RNA toxicity is thought to be the cause for most clinical problems associated with the FMR1 premutation 21,49. Neurotoxic effects of elevated cellular FMR1 mRNA levels leads to sequestration of important proteins for neuronal function, calcium dysregulation, mitochondrial dysfunction, impaired DNA damage repair and formation of intranuclear inclusions in the brain of premutation carriers with FXTAS 49,50. Mitochondrial dysfunction and increased oxidative stress are also observed in brain and tissue samples of premutation carriers both with and without FXTAS 51. These deficits predispose premutation neurons to early death compared to neurons without the premutation20. Furthermore, the mitochondrial deficits and calcium dysregulation in premutation neurons leads to excessive spike discharges and greater vulnerability to toxic environmental contaminants that converge on these same pathways of neurotoxicity, thereby exacerbating neurological symptoms and contributing to increased penetrance of seizures, and symptoms of FXTAS and FXPOI, the latter problem related to toxicity directly to the ovary 27,52,53.

The relationship between male carriers and seizures has been described in children. Bailey and colleagues 18 conducted a National Parental Survey to assess co-occurring conditions in patients with full mutation and premutation and found that 14% of males (8 out of 57 premutation carriers) reported seizures while 1.2% of male controls without the premutation reported seizures. Also, Chonchaiya and colleagues 19 found an increased prevalence of seizures among young premutation boys with co-morbid ASD: 1 out of 26 subjects without ASD had seizures (3.85%), whereas 6 out of 24 subjects with ASD had seizures (25%). In female carriers of the premutation, seizures have been described as a rare co-occurring condition: in the National ParentalSurvey,seizureswereobserved in 0.5% (1 out of 199) of female premutation carriers and 1.7% of female controls 18.

In Ricaurte, among the women with premutation, 25% (5/20) had seizures, two of them were sisters and the other three were relatives in the fourth degree of consanguinity; all five had a common ancestor. possible explanation for the origin of the seizures in these five women could be a second genetic hit; however, the two sisters previously had a genome-wide assessment of 2,391,739 SNPs18 to assess copy number variants (CNVs), and no disease-associated CNVs were found 27. Two of the women also fulfilled the clinical and radiological criteria of FXTAS and an additional one had ASD (see Table 1).

Ricaurte is a small rural town where the base of the economy is agriculture, and the inhabitants are exposed to pesticides through their work in the fields, the common practice of storing pesticides inside their homes and/or contact with contaminated water or food. The most commonly used pesticides in the fields include neonicotinoids, avermectins, organophosphorus compounds and pyrethroids54. An association of these neurotoxic environmental contaminants with the exacerbation of neurological deterioration in FMR1 premutation carriers has yet to be described; however, this possibility is supported by experimental evidence demonstrating that these pesticides converge on pathways of neurotoxicity inherent in premutation neurons. Specifically, there is evidence that these classes of pesticides can interfere with neuronal morphogenesis 55–57, alter axonal and mitochondrial transport 58–60, dysregulate calcium signaling in neurons 61,62, induce neuronal apoptosis 63–65 or inhibit GABA activity 66. Thus, expression of the FMR1 premutation likely confers increased vulnerability to pesticide neurotoxicity, and interactions between this genetic vulnerability and these pesticides would be predicted to amplify the neurotoxic effects of either factor alone. If true, then exposure to neurotoxic pesticides could explain the increased frequency and severity of sclinical symptoms of FXTAS, FXPOI and seizures in carriers of the FMR1 premutation in this rural population.

Conclusion

The identification of specific environmental factors that interact with the FMR1 premutation is warranted since it would enable the development of interventions that would lower the incidence and severity of clinical symptoms. This information may also provide useful insight in identifying genetic subgroups in the population that are more vulnerable to pollution. This should hopefully lead to better laws to protect the general population from this type of pollution.

Highlights.

  • FMR1 premutation carriers were natives of Ricaurte, Colombia

  • Earlier onset of symptoms and severity of FXTAS

  • Increased frequency of seizures in female carriers

  • Exposure to neonicotinoids, avermectins, organophosphorus compounds and pyrethroids

Acknowledgments

Funding: This research was supported by the National Institute of Child Health and Human Development (grants R01 HD036071and U54 HD079125), the National Institute of Environmental Health Sciences (grant P01 ES011269), the Environmental Protection Agency (grant R83543201), and the Universidad del Valle (grant 1771). The contents of this work are solely the responsibility of the grantee and do not necessarily represent the official views of the USEPA or NIEHS. Further, the USEPA and NIEHS do not endorse the purchase of any commercial products or services mentioned in the publication.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Disclosure statement: RH has received funding from Roche, Novartis, Neuren, Marinus and Alcobra for carrying out treatment studies in patients with fragile X syndrome. She has also consulted with Fulcrum, Ovid and Zynerba regarding treatment studies in individuals with fragile X syndrome. The other authors declare no conflicts of interest.

Geolocation information: Ricaurte, Valle del Cauca, Colombia, South America

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