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FXTAS and the Spectrum of FMR1 Premutation-Associated Phenotypes in Latin America: A Scoping Review Amy Schmidmajer,1 Salomon Paez-García, MD,1,2 Santiago Martínez, MD,1,2 Jacobo Ramírez-Triana, MD,1,2 Kevin O’Hara-Veintimilla, MD,3 Andr´es Ricaurte-Fajardo, MD,1,2,4 and Catalina Cerquera-Cleves, MD, MSc1,2,5,* Abstract:

Background Background: Fragile X–associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by FMR1 premutation expansions (55–200 CGG repeats). Although well described in populations of predominantly European ancestry, FXTAS remains poorly characterized in Latin America due to limited awareness, restricted access to molecular diagnostics, and scarce epidemiological data.

Objective Objective: To synthesize available evidence on FXTAS and other FMR1 premutation–associated phenotypes in Latin America, focusing on epidemiology, clinical and neuroimaging features, diagnostic approaches, and atypical presentations.

Methods Methods: A scoping review was conducted following PRISMA-ScR guidelines. PubMed, EMBASE, Scopus, and LILACS were searched without date restrictions (last search: April 2025). Eligible studies reported FXTAS cases or FMR1 premutation carriers from Latin American countries. Data were extracted on demographics, clinical manifestations, neuroimaging, molecular ﬁndings, and country of origin.

Results Results: Twenty-ﬁve studies including 5531 participants reported 38 FXTAS cases and 386 premutation carriers without FXTAS. Diagnoses of FXTAS occurred mainly between ages 53 and 85 years. Gait ataxia and tremor predominated, while parkinsonism, peripheral neuropathy, executive dysfunction, and psychiatric symptoms were also reported. Generalized cerebral atrophy was more frequent than the middle cerebellar peduncle sign. Atypical phenotypes, including spastic paraparesis and progressive supranuclear palsy–like presentations, contributed to diagnostic delays. Premutation carriers commonly exhibited fragile X–associated primary ovarian insufﬁciency and neuropsychiatric manifestations.

Conclusions Conclusions: FXTAS is likely underdiagnosed in Latin America despite recognizable clinical patterns and associated premutation-related conditions. Improving clinician awareness, access to genetic testing, and standardized diagnostic evaluation is essential. Prospective regional studies are needed to deﬁne prevalence, penetrance, and gene–environment interactions.

1Semillero de Neurociencias y Envejecimiento, Ageing Institute, Medical School, Pontiﬁcia Universidad Javeriana, Bogota, Colombia; 2Unidad de Neurología, Departamento de Neurociencias, Hospital Universitario San Ignacio, Bogota, Colombia; 3Psychogeriatric Unit, Clínica Joseﬁna Arregui, Alsasua, Spain; 4Division of Molecular Imaging and Therapeutics, Department of Radiology, Weill Cornell Medicine, New York City, NY, USA; 5Neuroscience Research Program, CHU de Québec-Université Laval Research Center, Québec City, QC, Canada *Correspondence to: Catalina Cerquera-Cleves, Unidad de Neurología, Sexto Piso, Hospital Universitario San Ignacio, Carrera 7 # 40-62, Colombia; E-mail: scerquera@javeriana.edu.co Keywords: Fragile X mental retardation 1 protein, FXTAS, Latin America, Neurodegenerative diseases, Premutation. Amy Schmidmajer and Salomon Paez-García have contributed equally to the manuscript. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Received 12 January 2026; revised 28 February 2026; accepted 19 March 2026. Published online 00 Month 2026 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mdc3.70617 MOVEMENT DISORDERS CLINICAL PRACTICE 2026. doi: 10.1002/mdc3.70617

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Introduction Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder caused by premutation expansions (55–200 CGG repeats) in the FMR1 gene.1 While the full mutation (>200 repeats) leads to Fragile X syndrome (FXS), a childhood-onset neurodevelopmental disorder, the premutation gives rise to a heterogeneous spectrum of neurological and systemic conditions in adulthood, among which FXTAS is the most recognized.

In FXTAS, the FMR1 premutation leads to toxic RNA accumulation and aberrant protein production via repeat-associated non-AUG (RAN) translation, resulting in neuronal damage, mitochondrial dysfunction, and the development of ubiquitinpositive intranuclear inclusions within neurons and glial cells.1 Diagnosis relies on integrating clinical evaluation, genetic conﬁrmation of the premutation, and neuroimaging.1,2 Clinically, FXTAS is most often characterized by intention tremor, gait ataxia, parkinsonian features, and cognitive decline. Additional manifestations such as peripheral neuropathy, autonomic dysfunction, and psychiatric symptoms have also been reported, reﬂecting the variability of its presentation.1,2 T2 hyperintensities in the middle cerebellar peduncles are considered the most distinctive radiological hallmark, although white matter changes in other regions and generalized brain atrophy are frequently observed.3 While the prevalence and impact of FXTAS have not been extensively studied in Latin America, several signiﬁcant case reports and studies provide valuable insights into its occurrence and clinical features.3,4 Colombia has one of the highest prevalences of FXS globally, particularly in the town of Ricaurte, Valle del Cauca, where the full mutation affects 1 in 19 men and

1 in 46 women, while the premutation is carried by 1 in 85 men

and 1 in 25 women.5 Over the past two decades, the clinical spectrum associated with the FMR1 premutation has expanded substantially, driven by increased awareness and wider access to molecular testing.6 Premutation alleles, once considered largely asymptomatic, are now known to be associated with several RNA toxicity–mediated conditions, including FXTAS,7 fragile X–associated primary ovarian insufﬁciency (FXPOI),8 and the more recently described fragile X–associated neuropsychiatric disorders (FXAND).9 Beyond these deﬁned syndromes, FMR1 premutation carriers may present with additional clinical manifestations that do not fulﬁll diagnostic criteria for FXTAS, FXPOI, or FXAND but occur at higher frequencies than in the general population. These include systemic and neurological features such as hypertension, myalgias, and peripheral neuropathy in the absence of classical FXTAS signs.2,10 From a psychiatric perspective, premutation carriers also exhibit increased rates of depression and anxiety disorders, which have been linked to mitochondrial dysfunction, calcium dysregulation, oxidative stress, chronic DNA damage, and inclusion formation affecting limbic and frontal–subcortical circuits.9,11,12 Despite these advances, knowledge regarding FXTAS and other

FMR1

premutation–associated phenotypes in Latin America remains limited. Low clinical awareness, scarce epidemiological data, heterogeneous reporting, and restricted access to molecular diagnostics contribute to underrecognition and delayed diagnosis in the region. Accordingly, this scoping review aimed to synthesize the existing evidence on FXTAS in Latin America, providing an overview of reported epidemiological and clinical characteristics while highlighting current challenges and research gaps. Materials and Methods We conducted a scoping review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. Eligibility Criteria We included peer-reviewed studies conducted in Latin American countries—deﬁned as those in South America, Central America, and North America (with Mexico as the sole representative in the latter), as speciﬁed in the Supporting Information—that explicitly reported individuals carrying an FMR1 premutation. Eligible studies described patients with FXTAS, other FMR1 premutation–associated phenotypes, or premutation carriers without overt FXTAS manifestations.

FXTAS cases were included when diagnosis was reported according to speciﬁed clinical, molecular, and/or neuroimaging criteria. Observational studies (including cross-sectional designs) and case reports were eligible for inclusion. We excluded studies involving individuals with FXS associated with full FMR1 CGG repeat expansions. Narrative reviews were excluded. Dissertations, conference proceedings, letters, and poster abstracts were also excluded. No restrictions were placed on publication date.

Search Strategy A systematic literature search was conducted in PubMed, EMBASE (Elsevier), Scopus, and LILACS. Database-speciﬁc controlled vocabulary terms and free-text keywords related to FXTAS, FMR1 premutation, and Latin America were used. The full search strategies are detailed in Appendix S1. The ﬁnal search was performed in April 2025.

After duplicate removal, two independent reviewers (AS and SPG) screened titles and abstracts for eligibility. Full texts of potentially relevant articles were subsequently assessed. Discrepancies were resolved by consensus and, when necessary, by consultation with a third reviewer (SM).

Data Extraction and Analysis Data extraction was independently performed by two reviewers (AS and SPG) using a standardized data extraction form. Extracted variables were deﬁned a priori to correspond directly to the descriptive domains presented in Tables 1 and 2. For each included study, we extracted ﬁrst author and year of publication, country, and study design. For studies reporting FXTAS cases, additional extracted data included the number of

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TABLE 1

Characteristics of individuals with an FXTAS diagnosis across Latin American studies Study Country Study design Number of patients with FXTAS/Total assessed (sex distribution) Age of FXTAS diagnosis FMR1 mutation status of cohort/of FXTAS patients # or range of CGG repeats in FXTAS subjects Diagnostic methods Clinical manifestations Brain MRI ﬁndings Almeida et al.

(2024)13

Brazil Case report 1/1 (1 male)

60 yo

1 PM/1 PM

100

PCR

1/1 ataxia, postural instability, spasticity 1/1 MCP sign, Hyperintensity in T2 (splenium of the corpus callosum Ramírez -Cheyne et al

(2024)14

Colombia Cross sectional 4/ 55 (3 female 1 male) Females: 53, 58,

60 yo

Male: 85 yo 19 PM, 35 FM,

1 N/4 PM

55–200 PCR, Southern Blot Not speciﬁed Not speciﬁed Davila-Ortiz de Montellano et al

(2019)15

Mexico Cross sectional 11/106 (5 males and 6 females) Not speciﬁed NR/7 PM, 3 GZ,

1 FM

PM: 124, 92,

56, 56, 87, 84

GZ: 48, 48, 52,

FM: >200

PCR

11/11 ataxia 4/11 intention tremor 4/11 parkinsonism 4/11 executive dysfunction 5/11 neuropathy 5/11 cerebral atrophy 1/11 MCP sign Saldarriaga-Gil et al

(2019)16

Colombia Cross sectional 4/25 (3 females 1 male) Females: 54,80,

53 yo

Male: 83 yo

25 PM/4 PM

55–200 PCR, Southern Blot 3/4 intention tremor 1/4 ataxia 2/4 seizures 2/4 anxiety 2/4 cerebral atrophy Salom˜ao et al

(2019)17

Brazil Case report 1/1 (1 female)

82 yo

1 PM/1 PM

PCR, Southern Blot 1/1 ataxia, parkinsonism, postural instability 1/1 Hummingbird sign Saldarriaga-Gil et al

(2017)18

Colombia Case report 1/1 (1 female)

53 yo

1 PM/1 PM

PCR, Southern Blot 1/1 tremor-at-rest, neuropathy, anxiety, cognitive impairment, FXPOI 1/1 cerebral atrophy Dos Santos Ghilardi et al

(2015)19

Brazil Case report 1/1 (1 male)

65 yo

1 PM/1 PM

150–200 Clinical criteria,

MRI, PCR

and Southern blot 1/1 intention tremor, ataxia, dysarthria 1/1 cerebral atrophy (Continues) MOVEMENT DISORDERS CLINICAL PRACTICE 2026. doi: 10.1002/mdc3.70617

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TABLE 1

Continued Study Country Study design Number of patients with FXTAS/Total assessed (sex distribution) Age of FXTAS diagnosis FMR1 mutation status of cohort/of FXTAS patients # or range of CGG repeats in FXTAS subjects Diagnostic methods Clinical manifestations Brain MRI ﬁndings Santa María et al (2014)4 Chile Case report 1/6 (1 male)

70 yo

2 PM, 4 FM/1 FM

180–410 PCR, Southern Blot and FMR1 mRNA quantiﬁcations 1/1 intention tremor, ataxia, parkinsonism, postural instability, executive dysfunction, urinary incontinence, neuropathy, mood lability, hypersomnolence 1/1 cerebral atrophy Jara - Prado et al

(2018)20

Mexico Case series 1/3 (1 female)

65 yo

1 N, 1 PM, 1 FM/1

PCR

1/1 Right-sided intention tremor, resting tongue tremor, bradykinesia, oromandibular rigidity, mild mixed hearing loss, menopause at 41 years old.

1/1 normal Alliende et al

(2012)21

Chile Case series 9/152 (sex not speciﬁed) Not speciﬁed 58 PM, 63 FM, 6 Mo,

25 N/Not speciﬁed

Not speciﬁed PCR, Southern Blot Not speciﬁed Not speciﬁed Capelli et al

(2007)22

Brazil Case report 3/4 (3 males) 65, 73, 74 yo

3 PM, 1 N/3 PM

PM: 123, 109,

N: 30 PCR, Southern Blot 2/3 ataxia, dysmetria, dysdiadokokinesia, action tremor 1/3 intention tremor, parkinsonism, urinary incontinence 3/3 MCP sign, Cerebral atrophy Gonçalves et al

(2007)23

Brazil Case report 1/1 (1 male)

70 yo

1 PM/1 PM

PCR

1/1 ataxia, postural instability, executive dysfunction, apathy, urinary incontinence 1/1 MCP sign, cerebral atrophy (Continues)

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individuals diagnosed with FXTAS and the total number of assessed participants, sex distribution, age at FXTAS diagnosis, FMR1 mutation status in the assessed cohort, FMR1 mutation status in patients with conﬁrmed FXTAS, CGG repeat size, diagnostic methods used, reported clinical manifestations, and brain magnetic resonance imaging (MRI) ﬁndings.

For studies including FMR1 premutation carriers without FXTAS manifestations, the same data ﬁelds were extracted when available, including number of carriers without FXTAS and total assessed participants, sex distribution, FMR1 mutation status, diagnostic methods, reported clinical manifestations, and brain MRI ﬁndings. Variables not mentioned were recorded as not reported. Discrepancies in data extraction were resolved through discussion and consensus. When required, a third reviewer (SM) was consulted to adjudicate disagreements. Due to heterogeneity in study designs, outcomes, and reporting practices, the results were synthesized descriptively, without quantitative meta-analysis or formal risk of bias assessment.

In accordance with the PRISMA Extension for Scoping Reviews (PRISMA-ScR), no formal risk of bias or methodological quality assessment was performed, as the primary objective of this review was to map the existing evidence, characterize reported phenotypes, and identify knowledge gaps rather than to evaluate intervention effects or generate pooled estimates. Results Study Selection A total of 256 records were initially identiﬁed, of which 25 articles were assessed in full text. The main reasons for exclusion included duplicate entries, lack of full-text availability (abstracts only), and failure to meet the inclusion criteria (non–Latin American populations, narrative reviews, or patients without FXTAS or FMR1 premutation). The PRISMA ﬂow diagram is shown in Figure 1.

Overview of Included Studies and Populations The 25 included studies comprised a total of 5531 screened participants. Among them, within the sample that had a FMR1 expansion (premutation, gray-zone or full-mutation), 38 individuals had a conﬁrmed diagnosis of FXTAS, and 386 were FMR1 premutation carriers without clinical manifestations of FXTAS. Twelve studies included patients with FXTAS,4,13–23 seventeen studies enrolled FMR1 premutation carriers without FXT- AS,4,14,16,21,24–36 and four studies included both groups.4,14,16,21 Regarding study design, three were case–control studies,28,33,34 three case series,20,21,26 eight case reports,4,13,17,18,19,22,23,25 ten cross-sectional studies,14–16,24,27,30–32,35,36 and one retrospective cohort study.29 Geographically, studies originated from Colombia,14,16,18,24,25 Argentina,26 Brazil,13,17,19,22,23,27,28,31,33,35,36 Mexico,15,20,32,34

TABLE 1

Continued Study Country Study design Number of patients with FXTAS/Total assessed (sex distribution) Age of FXTAS diagnosis FMR1 mutation status of cohort/of FXTAS patients # or range of CGG repeats in FXTAS subjects Diagnostic methods Clinical manifestations Brain MRI ﬁndings Total 38/356 (14 males, 15 females, 9 not speciﬁed)

120 PM, 104 FM, 3

GZ, 28 N, 6 Mo, 95 NR (n = 356)/24 PM, 3 GZ, 2 FM, 9 Not speciﬁed (n = 38) Abbreviations: CGG, Cytosine-guanine-guanine trinucleotide repeat; FM, full mutation; FMR1, Fragile X mental retardation 1 gene; FXPOI, Fragile X-associated primary ovarian insufﬁciency; FXTAS, Fragile X-associated tremor/ ataxia syndrome; GZ, gray zone; MCP, middle cerebellar peduncle; Mo, Mosaic; MRI, Magnetic resonance imaging; N, normal alleles; NR, Not reported; PCR, Polymerase chain reaction; PM, premutation; yo, years-old. MOVEMENT DISORDERS CLINICAL PRACTICE 2026. doi: 10.1002/mdc3.70617

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TABLE 2

Characteristics of individuals carrying the FMR1 premutation without FXTAS manifestations across Latin American studies Study Country Study design # of patients with

FMR1

premutation without FXTAS/ Total assessed (sex distribution) Diagnostic methods Clinical manifestations other than FXTAS Brain MRI ﬁndings Ramírez-Cheyne et al (2023)*14 Colombia Cross sectional 15/55 (3 males and

12 females)

*4 with FXTAS

WES

3/19 with POI NR Saldarriaga et al

(2021)24

Colombia Cross sectional 118/1322 (22 males and 96 females) Karyotype, PCR, Southern Blot, Exome NR NR Cabal-Herrera et al (2020)25 Colombia Case report 1/1 (1 male) NR 1/1 Alcohol abuse, irritability, delusional jealousy, depression and aggressive behavior Mild frontal atrophy, mild ventriculomegaly and white matter disease in the periventricular regions Ormazabal et al

(2019)26

Argentina Case series 22/55 (3 males and

19 females)

PCR, Southern Blot 3/19 females with POI, male asymptomatic.

NR Ferreira et al

(2019)27

Brazil Cross sectional 4/90 (4 males)

PCR,

Electrophoresis 4/4 non-syndromic

ASD

NR Saldarriaga et al (2019)*16 Colombia Cross sectional 21/25 (5 males and

20 females)

*4 with FXTAS PCR, Southern Blot 1/25 with POI 1/25 with seizures 1/25 with cognitive deﬁcit 2/25 with anxiety 1/25 with POI and seizures 1/25 with POI and anxiety 1/25 with cognitive deﬁcit and anxiety 1/25 with seizures, cognitive deﬁcit and anxiety 6/19 asymptomatic NR Miranda-Furtado et al (2018)28 Brazil Case control 4/121 (4 females)

PCR

4/4 with POI NR Santa María et al

(2016)29

Chile Retrospective cohort study 67/2321 (59 males, 8 females) PCR, Southern Blot 6/67 (5 males and 1 females) with ID, rest not speciﬁed NR Santa María et al (2014)*4 Chile Case report 2/6 (2 females) *1 with FXTAS PCR, Southern Blot Not speciﬁed NR Alliende et al (2012)*21 Chile Case series 49/152 (39 females, rest not speciﬁed) *9 with FXTAS PCR, Southern Blot Not speciﬁed (17 females with POI and 9 subjects with FXTAS, genetic proﬁle of these groups is not known) NR (Continues)

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Chile,4,21,29 and Guatemala.30 Brazil contributed the largest number of studies (n = 11), predominantly case reports and cross-sectional studies, followed by Colombia (n = 5) and Mexico (n = 4). The geographic distribution of the included studies is schematically illustrated in Figure 2.

FXTAS in Latin America Epidemiology and Demographic Characteristics Across the 12 studies that included FXTAS cases, 38 patients were identiﬁed. Speciﬁc age data were available for 18 of

38 patients (47.3% of the sample), with an age range of 53–85

years and a mean age of 66.83 years.

Both males and females were affected, although sex-speciﬁc prevalence data were reported in only a limited number of studies (Table 1). One study conducted in Ricaurte, Colombia, highlighted that symptoms suggestive of FXTAS were observed in 50% of male carriers and 33.3% of female carriers aged over

50 years.16 Although potential environmental risk factors were

infrequently assessed across studies, the Ricaurte study further reported that all affected carriers were engaged in agricultural work and had frequent exposure to pesticides through occupational activities, household storage, or contaminated food and water.16 FMR1 Mutation Status and CGG Repeat Distribution Genetic data showed substantial heterogeneity among FXTAS cases. Most patients were FMR1 premutation carriers, with CGG repeat sizes ranging from 56 to 200 repeats.13–19,22,23 A small number of individuals carried gray zone alleles (44–52 CGG repeats),15 and full mutation alleles (>200 repeats).4,15 Among the 120 patients with a conﬁrmed FMR1 premutation reported in the 12 studies that included FXTAS cases, 24 were reported to have FXTAS diagnosis (19.3%). Several studies did not report the exact CGG repeat number.4,14,16,19,21 A summary of genetic ﬁndings is presented in Table 1.

Clinical Manifestations Associated with

FXTAS

Clinical manifestations were described in nine of the eleven studies, encompassing 24 FXTAS patients. The FXTAS phenotype

TABLE 2

Continued Study Country Study design # of patients with

FMR1

premutation without FXTAS/ Total assessed (sex distribution) Diagnostic methods Clinical manifestations other than FXTAS Brain MRI ﬁndings Yuhas et al

(2009)30

Guatemala Cross sectional 10/105 (2 males and 8 females) PCR, Southern Blot Not speciﬁed NR Reis et al (2008)31 Brazil Cross sectional 1/66 (1 male)

PCR

1/1 Asymptomatic NR Barros-Núñez et al (2008)32 Mexico Cross-sectional 8/540 (sex not speciﬁed)

PCR,

Electrophoresis Not speciﬁed NR Costa et al

(2006)33

Brazil Case control 23/157 (23 females) PCR, Electrophoresis, Southern Blot 23/23 with POI NR Rosales-Reynoso et al (2005)34 Mexico Case control 3/129 (3 males)

PCR

3/3 Moderate ID NR Machado-Ferreira et al (2002)35 Brazil Cross sectional 6/26 (6 females) Southern Blot 4/6 with POI NR Mingroni-Netto et al (1996)36 Brazil Cross sectional 32/242 (sex not speciﬁed) PCR, Southern Blot Not speciﬁed NR Total 386/5413 (103 males and 233 females,

50 not speciﬁed)

*Patients with FXTAS were included but not counted in this table. Abbreviations: ASD, Autism spectrum disorder; CGG, Cytosine-guanine-guanine trinucleotide repeat; FMR1, Fragile X mental retardation 1 gene; FXS, Fragile X syndrome; FXTAS, Fragile X-associated tremor/ataxia syndrome; ID, Intellectual disability; MRI, Magnetic resonance imaging; NR, Not reported; PCR, Polymerase chain reaction; POI, Primary ovarian insufﬁciency; WES, Whole exome sequencing. MOVEMENT DISORDERS CLINICAL PRACTICE 2026. doi: 10.1002/mdc3.70617

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was dominated by motor manifestations, particularly ataxia,4,13–

19,22,23

intention tremor4,15,16,20,22 and parkinsonian features.4,15,17,20,22 Additional motor ﬁndings included postural instability,4,13,17,23 action tremor,19,22 tremor at rest,18,20 spasticity13 and cerebellar signs.22 Non-motor manifestations were less frequently reported and included executive dysfunction,4,15,23 nonspeciﬁc cognitive impairment,18 autonomic symptoms such as urinary incontinence,4,22,23 mild hearing loss,20 neuropsychiatric features (including anxiety,16,18 apathy,23 mood lability,4 and hypersomnolence4), and sensory symptoms such as peripheral neuropathy.4,15,18 Seizures and FXPOI were reported to be associated in isolated cases.16,18 Detailed clinical features are summarized in Table 1.

Neuroimaging Findings Neuroimaging data were available for 18 FXTAS patients across nine studies, with MRI being the most commonly used modality. The most frequently reported neuroimaging ﬁndings were cerebral atrophy (n = 10),13,15,22,23 middle cerebellar peduncle (MCP) sign (n = 2),13,15 and the coexistence of both ﬁndings (n = 4),22,23 observed in approximately 33%, 11.1%, and 22.2% of patients with available MRI data, respectively. Splenial T2 hyperintensities were reported less often (n = 1),13 and one Figure 2. Geographic distribution of included studies by country. Bars represent the number of published studies per country. Brazil contributed the largest number of studies (n = 11), followed by Colombia (n = 5), Mexico (n = 4), and Chile (n = 3), with single studies from Argentina and Guatemala. Created in https://BioRender.com.

Figure 1. PRISMA ﬂow diagram. A total of 256 records were identiﬁed from Embase, LILACS, Scopus, and PubMed. After removal of 70 duplicates, 186 titles and abstracts were screened, and 92 full texts were assessed for eligibility. After full text review, 25 studies from Latin America on FMR1 premutation–associated phenotypes were included.

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patient had normal MRI ﬁndings despite clinical criteria of FXTAS in the context of an FMR1 premutation.20 Atypical imaging patterns were also reported, including cases presenting with alternative brainstem signs (hummingbird sign) in the absence of the classic MCP sign.17 Neuroimaging ﬁndings are summarized in Table 1.

Atypical FXTAS Presentations Three case reports described atypical clinical presentations of FXTAS. One report detailed a male premutation carrier whose initial presentation was dominated by progressive spasticity and lower-limb weakness, leading to an initial diagnostic consideration of hereditary spastic paraplegia. Neuroimaging later revealed bilateral MCP and splenial abnormalities, supporting a diagnosis of FXTAS with a spastic phenotype.13 Another case involved a male premutation carrier identiﬁed through familial screening who developed rapidly progressive cognitive decline with a frontal–subcortical proﬁle, followed by gait ataxia and urinary incontinence, accompanied by typical FXTAS MRI ﬁndings.23 A third case described an elderly female premutation carrier with gait impairment and postural instability whose MRI showed a “hummingbird sign” and features suggestive of nigrostriatal involvement. Although initially interpreted as progressive supranuclear palsy, the overall phenotype was considered consistent with a PSP–pure akinesia with gait freezing phenotype in the context of FMR1 premutation.17 Diagnostic Approaches Diagnosis of FXTAS consistently relied on a combination of clinical evaluation, genetic testing, and neuroimaging. Several studies employed standardized clinical scales, including the Scale for the Assessment and Rating of Ataxia (SARA) and the Fahn– Tolosa–Marín tremor scale,16,18,19 the International Cooperative Ataxia Rating Scale (ICARS),16,22 and the Uniﬁed Parkinson’s Disease Rating Scale (UPDRS).22 Genetic testing of the FMR1 gene was performed in all studies, most commonly using polymerase chain reaction (PCR) and Southern blot techniques to determine CGG repeat length and, in some cases, methylation status.4,13–23 Less frequently, additional complementary approaches, such as FMR1 mRNA quantiﬁcation, were used to assess gene expression but not as primary diagnostic methods.4 One study evaluating revised FXTAS diagnostic criteria showed a sensitivity of 36% and a speciﬁcity of 43%, with a positive predictive value of 7% and a negative predictive value of 85%.15 Treatment and Management Treatment approaches were predominantly symptomatic. Pharmacological data were reported in only two studies. In one case, levodopa was administered at a dose of 800 mg/day without clinical improvement. In another report, the patient was treated with propranolol, primidone, and clonazepam, also without signiﬁcant symptomatic beneﬁt. No speciﬁc pharmacological treatment details were reported in the remaining studies. One study reported the use of deep brain stimulation targeting the ventral oral posterior nucleus and zona incerta in a patient with severe tremor and ataxia, resulting in sustained motor improvement over 30 months without adverse effects.4 Additionally, the importance of specialized multidisciplinary centers was emphasized, integrating genetic diagnosis and counseling with rehabilitative therapies and facilitating early recognition of FXTAS among premutation carriers.15 Summary of Findings in Latin American Cohorts Including Patients with FXTAS Table 3 provides a structured summary of the key epidemiological, genetic, clinical, and neuroimaging ﬁndings identiﬁed among Latin American patients diagnosed with FXTAS, synthesized from the data presented in Tables 1 and 2. The table highlights both the principal patterns and atypical features observed across cohorts, offering a consolidated reference for the most relevant and unusual ﬁndings.

FMR1 Premutation Carriers without FXTAS in Latin America Population Characteristics Across the 17 studies that included FMR1 premutation carriers without FXTAS, 386 individuals were identiﬁed among 5413 assessed participants. Sex was reported for most individuals, with a predominance of females (233 females, 103 males), while sex was not speciﬁed in 50 cases. Four of the 17 studies reporting FMR1 premutation carriers without FXTAS provided speciﬁc age data, corresponding to 41 of the 386 patients (10.6%). Among these

41 patients, the age range was 18–80 years, with a mean age of

45.29 years. Many carriers were identiﬁed through family screen-

ing of individuals with FXS. A complete description of demographic characteristics for each study is provided in Table 2. Diagnostic Approaches Genetic diagnosis was performed primarily using PCR and Southern blot analysis, either alone or in combination.4,16,20,21,24,26–36 Capillary electrophoresis was used in several studies to reﬁne CGG repeat sizing.27,32,33 Whole Exome Sequencing (WES) and karyotype analysis were reported in a minority of studies.14,24 In some studies, the diagnostic method was not speciﬁed. Clinical Manifestations outside the FXTAS Spectrum Clinical features distinct from FXTAS were described in

13 studies.14,16,20,25–29,32–36 The most frequently reported

condition was FXPOI, affecting 40 women.14,16,21,26,28,33,35 Other reported manifestations included intellectual MOVEMENT DISORDERS CLINICAL PRACTICE 2026. doi: 10.1002/mdc3.70617

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disability,16,29,34 autism spectrum disorder,27 and neuropsychiatric symptoms such as anxiety, irritability, and depression.16,25 Most carriers were asymptomatic or lacked detailed clinical descriptions.

Neuroimaging Findings Neuroimaging was reported in only one premutation carrier without FXTAS, showing mild frontal atrophy, ventriculomegaly, and periventricular white matter changes in association with neuropsychiatric symptoms.25 No additional imaging data were available. A summary of ﬁndings is provided in Table 2. Discussion This scoping review provides the most comprehensive synthesis to date of FXTAS and FMR1 premutation–associated phenotypes reported in Latin America. Overall, the clinical and radiological features of FXTAS described in the region are broadly consistent with those reported in cohorts of predominantly European ancestry. However, several region-speciﬁc patterns emerge that are relevant for clinical recognition and epidemiological interpretation.

Across 25 studies comprising 5531 screened participants, only

38 individuals were diagnosed with FXTAS despite the presence

of large cohorts of reported

FMR1

premutation carriers (n = 506). This apparent underrecognition likely reﬂects the insidious and slowly progressive nature of FMR1 mRNA– mediated neurotoxicity, which delays overt clinical expression, together with limited access to molecular testing, low clinical awareness of FXTAS, and substantial phenotypic heterogeneity.6,37,38 These factors are particularly relevant when early, atypical, or non-classical manifestations predominate, increasing the likelihood that FXTAS remains unrecognized or misclassiﬁed. A clear age contrast emerged between individuals with FXTAS and FMR1 premutation carriers without overt neurological involvement. Among patients with FXTAS for whom age data were available, the mean age was 66.83 years (range 53–85), whereas FMR1 premutation carriers without FXTAS had a substantially lower mean age of 45.29 years (range 18–80). Although age information was not available for the entire sample, this difference is consistent with the established age-related increase in penetrance of FXTAS. In male premutation carriers, penetrance increases markedly with age, ranging from approximately 17% in those aged 50–59 years to up to 75% in individuals aged ≥80 years39 (approximately 40–45% across age groups).40 Data in females are more limited; however, penetrance of FXTAS appears consistently lower than in males, estimated at approximately 16% in comparable age ranges.40 These ﬁndings support the interpretation that the lower frequency of FXTAS observed in this regional sample may partly reﬂect the age structure of the studied cohorts, particularly among carriers identiﬁed through family screening at younger ages.

A notable observation was the relatively balanced sex distribution among reported FXTAS cases. This contrasts with data from cohorts of predominantly European ancestry, where the FMR1 premutation is more prevalent in women (approximately 1 in 129–151 females vs. 1 in 468–649 males),41,42 yet FXTAS shows a clear male predominance.6,38 This pattern has been attributed to the higher age-dependent penetrance observed in males, particularly after 50 years of age.39,43,44 This ﬁnding should be interpreted cautiously given small sample sizes, incomplete sex reporting, and the predominance of case-based designs. Additionally, regional factors, including founder-effect populations with high FMR1 expansion frequencies in both sexes,5 may inﬂuence ascertainment patterns without implying equivalent biological penetrance.

Environmental exposures, including chronic contact with neurotoxic agricultural pesticides reported in some communities,

TABLE 3

Key epidemiological, clinical, and radiological ﬁndings in Latin American FXTAS cohorts Variable Patients with FXTAS diagnosis Demographics

• Screened participants: 5531

• FXTAS cases (n = 38 conﬁrmed)

Sex (data available for 29 patients) Male: 14/29 (48.3%) Female: 15/29 (51.7%) Age (data available for 18 patients) Mean (range): 66.8 (53–85) Environmental exposure

• Occupational pesticide

exposure: 4/38 (10.5%) From a single Colombian cluster Genetic status

• FMR1 status (data available for 29 patients)

PM: 24/29 (82.7%) GZ: 3/29 (10.4%) FM: 2/29 (6.9%) Clinical phenotype*

• Ataxia: 19/38 (50%)

• Intention tremor: 11/38 (29%)

• Parkinsonism features: 7/38 (18.4%)

• Postural instability: 4/38 (10.5%)

• Neuropathy: 7/38 (18.4%)

• Executive dysfunction / Cognitive

impairment: 7/38 (18.4%)

• Other neuropsychiatric symptoms

(eg, apathy, anxiety, mood lability):

5/38 (13.2%) Atypical presentations

• Spastic paraparesis: 1/38 (2.6%)

• Rapidly progressive dementia: 1/38 (2.6%)

• PSP-like phenotype: 1/38 (2.6%)

Neuroimaging ﬁndings

• Brain MRI (data available for 18 patients)

Cerebral atrophy: 10/18 (55.6%) MCP sign: 2/18 (11.1%) Cerebral atrophy + MCP sign: 4/18 (22.2%) Normal/nonspeciﬁc: 2/18 (11.1%) *Clinical variables were non–mutually exclusive. Abbreviations: FM, Full mutation; GZ, Gray zone; MCP, Middle cerebellar peduncle; MRI, Magnetic resonance imaging; PM, Premutation; PSP, Progressive supranuclear palsy.

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have been proposed as potential modiﬁers of disease expression; however, supporting evidence is still scarce.16 Reports outside Latin America have described earlier-than-expected FXTAS onset in premutation carriers chronically exposed to organochlorine pesticides, industrial solvents such as toluene diisocyanate and dichloromethane, hexachlorocyclopentadiene-related compounds, and herbicides.45 Additionally, chemotherapy exposure (eg, carboplatin) has also been associated with transient worsening of tremor and ataxia in susceptible carriers.46 Collectively, these observations underscore the importance of further investigation into environmental factors that may modulate FXTAS penetrance in Latin America.

From a molecular perspective, most FXTAS cases involved premutation alleles, but individuals with gray-zone and full-mutation alleles were also identiﬁed. This observation aligns with emerging evidence from other regions indicating that FXTAS-like phenotypes can occur outside the classical premutation range,14,47 particularly in mosaic or partially methylated contexts.1 Gray-zone FMR1 alleles have been associated with parkinsonism,48 a phenotype traditionally considered a minor feature within the FXTAS spectrum, and gray-zone expansions have even been reported to be associated with Parkinson’s disease (PD).49 In this cohort, one of three gray-zone carriers (female) presented parkinsonism, consistent with prior reports suggesting increased susceptibility in gray-zone carriers, particularly women.48 Findings across cohorts support a clinical continuum across FMR1 CGG expansion ranges. Although the small number of gray-zone cases precludes genotype–phenotype inference, this variability highlights the limitations of strict molecular cutoffs and supports a clinically driven diagnostic approach, consistent with expanded criteria recognizing that any pathogenic FMR1 expansion may confer FXTAS risk when clinical suspicion is high.50 Clinically, FXTAS presentations in Latin America closely resemble those reported elsewhere, with gait ataxia and intention tremor as the most frequent motor features.50,51 Parkinsonian signs were also commonly described, underscoring the potential for clinical overlap with idiopathic PD or atypical parkinsonian syndromes.52 This overlap is clinically relevant, as it may contribute to misdiagnosis in older adults when FMR1 testing is not routinely considered.

Non-motor manifestations, including peripheral neuropathy,15,53 executive dysfunction,4,15,18,23 and neuropsychiatric symptoms,16,18,23 were frequently reported and further emphasize the multisystem nature of FXTAS. Importantly, accumulating evidence indicates that the phenotypic expression of the FMR1 premutation differs between men and women across the entire clinical spectrum, extending beyond penetrance rates to differences in neurological, cognitive, psychiatric, and radiological manifestations. However, sex-stratiﬁed analyses were not feasible in our sample due to inconsistent and incomplete reporting of clinical manifestations by sex across the included studies.

Several cases exhibited atypical presentations, including spastic paraparesis,13 rapidly progressive cognitive decline,23 and phenotypes resembling progressive supranuclear palsy.17 These reports illustrate that FXTAS may initially involve non-cerebellar neural systems,38 potentially delaying recognition when classical tremor–ataxia features are absent. Atypical neuroimaging ﬁndings, such as non-MCP white matter changes or isolated cerebellar atrophy, further complicate diagnosis.6 Reports from cohorts outside Latin America have additionally described rare movement disorders such as chorea or generalized reﬂex myoclonus as a manifestation of FXTAS, although they are not considered core features.54–56 Retrospective analyses highlight substantial diagnostic heterogeneity prior to FXTAS recognition, with common initial diagnoses including parkinsonism (24%), tremor (20%), ataxia (17%), dementia (13%), and cerebrovascular disease (10%).57 Neuroimaging ﬁndings across studies were heterogeneous. The MCP sign was reported in only a minority of cases,13,15,22,23 whereas generalized cerebral atrophy was more frequently described.4,15,16,18,19,22,23 Normal or nonspeciﬁc MRI ﬁndings were also reported in clinically compatible cases, consistent with previous observations that imaging abnormalities may be absent in early disease stages or in women.58 These ﬁndings reinforce that neuroimaging should be interpreted as a supportive, rather than deﬁnitive, diagnostic component.1 Diagnostic approaches were broadly aligned with international recommendations, combining clinical assessment, molecular testing, and neuroimaging.58 However, standardized rating scales and formal diagnostic criteria were inconsistently applied, particularly in atypical cases. In some reports, a diagnosis of FXTAS was assigned despite incomplete fulﬁllment of classical radiological criteria (eg, absence of the MCP sign), and in a few instances the diagnosis was extended to individuals with gray-zone alleles or unmethylated full-mutation expansions rather than strictly within the premutation range. These decisions likely reﬂected a clinically driven approach in the context of suggestive neurological features and documented FMR1 expression. Some studies incorporated standardized rating scales such as SARA, ICARS, FTM, and MDS-UPDRS (part III) to quantify motor and ataxic symptoms.16,18,19,22 This variability, together with limited diagnostic resources,15 likely contributes to underrecognition and incomplete phenotypic characterization in the region. Beyond FXTAS, we identiﬁed 386 FMR1 premutation carriers without an FXTAS phenotype, many of whom presented other premutation–associated conditions, including

FXPOI,

intellectual disability, autism spectrum disorder, and affective or behavioral disturbances such as anxiety, irritability, and depression. The predominance of FXPOI among female carriers— affecting approximately 20% before age 40, particularly in those with 75–100 CGG repeats51—along with recurrent neuropsychiatric manifestations, aligns with the broader framework of FMR1 premutation–associated disorders (FXPOI, FXTAS, FXAND), thought to arise from shared mechanisms including RNA toxicity, mitochondrial dysfunction, and chronic cellular stress.11 However, clinical characterization in Latin American reports was often incomplete, with limited sex and age data, no neuroimaging report, and heterogeneous molecular diagnostic methods, particularly among asymptomatic or mildly symptomatic individuals identiﬁed through family screening. These limitations likely contribute to underrecognition of the true clinical burden and underscore a critical gap in systematically deﬁning the penetrance MOVEMENT DISORDERS CLINICAL PRACTICE 2026. doi: 10.1002/mdc3.70617

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and full spectrum of premutation-associated manifestations in the region. In this context, the underrepresentation of Latin American populations in human genetics research may further limit the generalizability of genotype–phenotype associations derived largely from predominantly European-ancestry cohorts. Our ﬁndings underscore the need for systematic, regionally grounded studies of FXTAS and other FMR1 premutation–associated phenotypes.

Strengths and Limitations This scoping review provides the ﬁrst regionally focused synthesis of FXTAS and FMR1 premutation–associated conditions in Latin America, integrating evidence across countries with important genetic and environmental particularities. A comprehensive search strategy across multiple databases strengthened the inclusion of studies from diverse settings, and the structured extraction of clinical, genetic, and neuroimaging data enabled a multidimensional characterization of affected individuals. However, several limitations must be acknowledged. Most available studies were case reports or small observational cohorts, limiting the precision of prevalence estimates and reducing the strength of causal inferences. Clinical documentation was heterogeneous and typically incomplete, particularly regarding neuropsychological and autonomic assessments, which may underestimate the true extent of non-motor involvement. Neuroimaging ﬁndings were inconsistently reported and frequently limited to qualitative descriptions. Age was not systematically reported for all patients, restricting more robust comparisons between FXTAS and non-FXTAS premutation carriers and limiting inferences regarding age-dependent penetrance. Additionally, selection bias is likely, since individuals undergoing genetic testing in Latin America often originate from clinically complex or familial cases rather than representative population samples. Finally, the absence of standardized diagnostic criteria for premutation–associated neuropsychiatric and systemic manifestations restricts the ability to delineate the full clinical spectrum in asymptomatic or mildly symptomatic carriers.

Future Directions Addressing these gaps will require coordinated regional research efforts. Prospective, longitudinal cohort studies with standardized neurological, cognitive, psychiatric, and imaging evaluations are essential to clarify disease trajectories and penetrance, particularly among female carriers and individuals with gray-zone or fullmutation expansions. Environmental and occupational exposure assessments should be incorporated to better characterize potential gene–environment interactions, especially in agricultural communities with known neurotoxic risks.

Expanding access to molecular diagnostics and specialized neurological care is also crucial to reduce diagnostic delays and capture earlier disease stages. Screening programs targeting highrisk families and founder-effect populations could improve case detection and enhance genetic counseling infrastructure. Harmonization of diagnostic criteria and systematic surveillance across Latin America would facilitate inter-country comparisons and guide public health strategies. Future reports should also ensure systematic documentation of key clinical and molecular variables, including age, sex, CGG repeat number (range and mean), and pharmacological treatments used in patients with FXTAS. Standardized reporting of these variables would strengthen genotype– phenotype correlations, allow more accurate age-stratiﬁed penetrance estimates, and improve comparability across cohorts. Finally, translational research exploring biomarkers, modiﬁable risk factors, and emerging therapeutic interventions may contribute to more precise and preventive approaches to FMR1– associated neurodegeneration in the region.

Conclusions This scoping review demonstrates that FXTAS is reported in Latin America with clinical, radiological, and molecular features largely consistent with global descriptions, but with notable regional particularities, including a more balanced sex distribution and frequent atypical presentations. FXTAS appears to be underrecognized in the region, and phenotypic heterogeneity likely contributes to diagnostic delay.

Given the broad spectrum of FMR1 premutation–associated manifestations, FXTAS should be considered in the differential diagnosis of late-onset movement, parkinsonian, or cognitive disorders. Diagnosis should rely on integrated clinical assessment, molecular testing, and neuroimaging rather than on classical phenotypes alone. Improving access to molecular diagnostics and increasing clinician awareness are key steps to reduce missed or delayed diagnoses. Future studies should prioritize prospective, population-based approaches to better deﬁne prevalence, penetrance, and modiﬁers of disease expression in Latin America. Author Roles

(1)

Research project:

Conception, B.

Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution,

C. Review and Critique; (3) Manuscript Preparation: A. Writing

of the ﬁrst draft, B. Review and Critique; A.S.: 1B, 1C, 2B, 2C, 3A, 3B S.P.G.: 1B, 1C, 2B, 2C, 3A, 3B S.M.: 1C, 2B, 2C, 3A J.R.T.: 1C, 2B, 2C, 3A K.O.V.: 1C, 2A, 3B A.R.F.: 2C, 3B C.C.C.: 1A, 1B, 2C, 3B Disclosures Ethical Compliance Statement: This scoping review does not involve human participants or identiﬁable data and, therefore, does not require approval from an ethics committee or informed

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consent. We conﬁrm that we have read the Journal’s position on issues involved in ethical publication and afﬁrm that this work is consistent with those guidelines.

Funding Sources and Conﬂicts of Interest: The authors received no ﬁnancial support for the research, authorship, or publication of this article. All authors meet the authorship criteria as deﬁned by the International Committee of Medical Journal Editors (ICMJE), declare that they have no conﬂicts of interest, and conﬁrm that no related papers from the same study, nor any similar manuscripts, have been published elsewhere. Financial Disclosures and Conﬂicts of Interest Author disclosures are available in the Supporting Information. Data Availability Statement The data analyzed in this scoping review were derived from publicly available sources cited in the article. ■ References

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Supporting Information Supporting information may be found in the online version of this article.

Appendix S1. Search strategy. Database-speciﬁc search strategies for FXTAS/FMR1 in humans across Latin America, detailing controlled vocabulary and keywords used in Embase, PubMed, LILACS, and Scopus.

Data S1. COI_disclosure.

MOVEMENT DISORDERS CLINICAL PRACTICE 2026. doi: 10.1002/mdc3.70617

REVIEW

FXTAS AND FMR1 SPECTRUM IN LATIN AMERICA

Cita: Schmidmajer, Amy, Paez García, Salomon, Martínez, Santiago, Ramírez Triana, Jacobo, O’Hara Veintimilla, Kevin, Ricaurte Fajardo, Andres, Cerquera Cleves, Catalina (2026), FXTAS and the Spectrum of FMR1 Premutation-Associated Phenotypes in Latin America : A Scoping Review, Pontificia Universidad Javeriana, p. N. http://hdl.handle.net/10554/73769