Dementia in Fragile X-associated Tremor/Ataxia Syndrome

Abstract Fragile X-associated tremor/ataxia syndrome (FXTAS) is a cause of movement disorders and cognitive decline which has probably been underdiagnosed, especially if its prevalence proves similar to those of progressive supranuclear palsy and amyotrophic lateral sclerosis. We report a case of a 74-year-old man who presented with action tremor, gait ataxia and forgetfulness. There was a family history of tremor and dementia, and one of the patient's grandsons was mentally deficient. Neuropsychological evaluation disclosed a frontal network syndrome. MRI showed hyperintensity of both middle cerebellar peduncles, a major diagnostic hallmark of FXTAS. Genetic testing revealed premutation of the FMR1 gene with an expanded (CGG)90 repeat. The diagnosis of FXTAS is important for genetic counseling because the daughters of the affected individuals are at high risk of having offspring with fragile X syndrome. Tremors and cognitive decline should raise the diagnostic hypothesis of FXTAS, which MRI may subsequently reinforce, while the detection of the FMR1 premutation can confirm the condition.

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Delineating the Relationships Between Motor, Cognitive-Executive and Psychiatric Symptoms in Female FMR1 Premutation Carriers

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.742929 ◽

2021 ◽

Vol 12 ◽

Author(s):

Darren R. Hocking ◽

Danuta Z. Loesch ◽

Paige Stimpson ◽

Flora Tassone ◽

Anna Atkinson ◽

...

Keyword(s):

Executive Functioning ◽

Response Inhibition ◽

Rating Scales ◽

Psychiatric Symptoms ◽

Fragile X ◽

Fmr1 Premutation ◽

Symptom Dimensions ◽

Cgg Repeats ◽

Cerebellar Peduncles ◽

Ataxia Syndrome

Introduction: Premutation expansions (55–200 CGG repeats) of the Fragile X Mental Retardation 1 (FMR1) gene on the X chromosome are associated with a range of clinical features. Apart from the most severe - Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) - where the most typical white matter changes affect cerebellar peduncles, more subtle changes may include impairment of executive functioning, affective disorders and/or subtle motor changes. Here we aimed to examine whether performance in selected components of executive functioning is associated with subclinical psychiatric symptoms in non-FXTAS, adult females carrying the FMR1 premutation.Methods and Sample: A total of 47 female premutation carriers (sub-symptomatic for FXTAS) of wide age range (26–77 years; M = 50.3; SD = 10.9) were assessed using standard neuropsychological tests, three motor rating scales and self-reported measures of psychiatric symptoms using the Symptom Checklist-90-Revised (SCL-90-R).Results: After adjusting for age and educational level where appropriate, both non-verbal reasoning and response inhibition as assessed on the Stroop task (i.e., the ability to resolve cognitive interference) were associated with a range of primary psychiatric symptom dimensions, and response inhibition uniquely predicted some primary symptoms and global psychiatric features. Importantly, lower scores (worse performance) in response inhibition were also strongly correlated with higher (worse) scores on standard motor rating scales for tremor-ataxia and for parkinsonism.Conclusion: These results provide evidence for the importance of response inhibition in the manifestation of psychiatric symptoms and subtle tremor-ataxia motor features, suggestive of the presence of early cerebellar changes in female premutation carriers.

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Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications

International Journal of Molecular Sciences ◽

10.3390/ijms21124391 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4391

Author(s):

Ana Maria Cabal-Herrera ◽

Nattaporn Tassanakijpanich ◽

Maria Jimena Salcedo-Arellano ◽

Randi J. Hagerman

Keyword(s):

Neurodegenerative Disorder ◽

Fragile X ◽

Cgg Repeats ◽

Mri Features ◽

Fmr1 Mrna ◽

Cerebellar Peduncles ◽

History Of ◽

Ataxia Syndrome ◽

Psychiatric Problems ◽

Female Carriers

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55–200 CGG repeats) carriers of FMR1. The premutation has excessive levels of FMR1 mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then FMR1 DNA testing is essential in patients with these symptoms.

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Clustering of comorbid conditions among women who carry an FMR1 premutation

Genetics in Medicine ◽

10.1038/s41436-019-0733-5 ◽

2020 ◽

Vol 22 (4) ◽

pp. 758-766 ◽

Cited By ~ 2

Author(s):

Emily Graves Allen ◽

Krista Charen ◽

Heather S. Hipp ◽

Lisa Shubeck ◽

Ashima Amin ◽

...

Keyword(s):

Fragile X ◽

Age At Onset ◽

Comorbid Conditions ◽

Fmr1 Premutation ◽

History Of ◽

Medical Histories ◽

Ataxia Syndrome ◽

Anxiety Depression ◽

Single Cluster ◽

Health Profiles

Abstract Purpose Emerging evidence indicates that women who carry an FMR1 premutation can experience complex health profiles beyond the two well-established premutation-associated disorders: fragile X–associated primary ovarian insufficiency (FXPOI, affects ~20–30% carriers) and fragile X–associated tremor–ataxia syndrome (FXTAS, affects ~6–15% carriers). Methods To better understand premutation-associated health profiles, we collected self-reported medical histories on 355 carrier women. Results Twenty-two health conditions were reported by at least 10% of women. Anxiety, depression, and headaches were reported by more than 30%. The number of comorbid conditions was significantly associated with body mass index (BMI) and history of smoking, but not age. Survival analysis indicated that women with FXPOI had an earlier age at onset for anxiety and osteoporosis than women without FXPOI. Cluster analysis identified eight clusters of women who reported similar patterns of comorbid conditions. The majority of carriers (63%) fell into three categories primarily defined by the presence of only a few conditions. Interestingly, a single cluster defined women with symptoms of FXTAS, and none of these women had FXPOI. Conclusion Although some women with a premutation experience complex health outcomes, most carriers report only minimal comorbid conditions. Further, women with symptoms of FXTAS appear to be distinct from women with symptoms of FXPOI.

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Fragile-X-Associated Tremor/Ataxia Syndrome or Alcohol-Induced Cerebellar Degeneration? A Case Report

Case Reports in Neurology ◽

10.1159/000511954 ◽

2020 ◽

Vol 12 (3) ◽

pp. 466-471

Author(s):

Giulia Grigioni ◽

Christian Saleh ◽

Phillip Jaszczuk ◽

Dorothea Wand ◽

Stefanie Wilmes ◽

...

Keyword(s):

Cognitive Impairment ◽

Case Report ◽

Neurodegenerative Disorder ◽

Fragile X ◽

Disease Diagnosis ◽

Cerebellar Degeneration ◽

Gait Ataxia ◽

Intention Tremor ◽

Triplet Expansion ◽

Ataxia Syndrome

Fragile-X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that manifests with intention tremor, progressive gait ataxia, and cognitive impairment. The disease is genetically characterized by a premutation of the <i>FMR1</i>gene on the X-chromosome manifesting with a CGG triplet expansion between 55 and 200. Given the phenotypical variety of this disease, diagnosis is frequently delayed. We present and discuss a male patient whose diagnosis of FXTAS was delayed due to his concomitant alcohol abuse.

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Prodromal Markers of Upper Limb Deficits in FMR1 Premutation Carriers and Quantitative Outcome Measures for Future Clinical Trials in Fragile X‐associated Tremor/Ataxia Syndrome

Movement Disorders Clinical Practice ◽

10.1002/mdc3.13045 ◽

2020 ◽

Vol 7 (7) ◽

pp. 810-819

Author(s):

Joan A. O'Keefe ◽

Deborah Bang ◽

Erin E. Robertson ◽

Alexandras Biskis ◽

Bichun Ouyang ◽

...

Keyword(s):

Clinical Trials ◽

Outcome Measures ◽

Upper Limb ◽

Fragile X ◽

Fmr1 Premutation ◽

Ataxia Syndrome

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Mothball ingestion as a manifestation of pica, leading to paradichlorobenzene CNS toxicity

African Health Sciences ◽

10.4314/ahs.v20i2.48 ◽

2020 ◽

Vol 20 (2) ◽

pp. 932-935

Author(s):

Joon Yau Leong ◽

Margarita Gianniosis ◽

Saman Zafar ◽

Yan Zhang

Keyword(s):

Iron Deficiency ◽

Iron Deficiency Anemia ◽

Fragile X ◽

Hypochromic Anemia ◽

High Index ◽

Deficiency Anemia ◽

Neurological Assessment ◽

Cerebellar Peduncles ◽

Ataxia Syndrome ◽

High Index Of Suspicion

Background: Pica is a poorly understood psychiatric disorder that presents with the ingestion of non-nutritious substances for unclear reasons. A high index of suspicion for unusual toxin exposure aids in the diagnosis of pica patients presenting with unexplained neurodegenerative features. Methods: We present a 47-year-old female with worsening gait over the past year. Prior to this, she was fully independent with activities of daily living, but is now mostly housebound due to frequent falls. Past medical history is significant for menorrhagia, iron deficiency anemia and pica. CBC and iron studies revealed iron deficiency with microcytic hypochromic anemia. MRI brain demonstrated symmetrical T2 hyperintensities within the middle cerebellar peduncles. Results: Differential diagnoses for her clinical deficits and imaging, including Spinocerebellar Ataxia, Multiple System At- rophy and Fragile X Tremor-Ataxia Syndrome, were excluded based on neurological assessment, family history and genetic PCR testing. Collateral history revealed a regular habit of mothball ingestion and serum paradichlorobenzene levels were elevated to 15mcg/mL. The patient was treated with iron replacement therapy and her symptoms gradually improved over several months. Conclusion: Iron deficiency anemia is commonly associated with pica, which can lead to toxin ingestion. A high index of suspicion for toxin ingestion in pica patients can immensely aid in the diagnosis. Mothball abuse secondary to pica may affect the CNS and can present with nonspecific neurodegenerative changes. To our knowledge, there have been no reported cases in the literature with paradichlorobenzene neurotoxicity predominantly affecting the middle cerebellar peduncles. Keywords: Mothball; paradichlorobenzene; PDCB; toxicity; pica; middle cerebellar peduncles.

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