Fragile X‐associated tremor/ataxia syndrome (FXTAS) is caused by a small expansion with 55 to 200 CGG repeats, termed “premutation,” in the promoter region of the fragile X mental retardation 1 (FMR1) gene. The elevated CGG repeat messenger RNA has deleterious consequences, causing the phenotypic features of FXTAS.1 After the initial description of FXTAS in 5 patients2, Jacquemont et al. described FXTAS in 26 male patients, all older than 50 years, who had intention tremor and/or cerebellar ataxia with magnetic resonance imaging (MRI) of the brain showing T2 hyperintensity in the bilateral middle cerebellar peduncles.3 Since then, several females with FXTAS have been reported. We report the youngest case of FXTAS in an adolescent girl.
Case Report
A 16‐year‐old girl with a normal birth history presented with complaints of tremor. By age 2 to 3 years, the family noticed an impairment of her language, and she was diagnosed with Asperger's syndrome. At age 3, she developed a tremor in both hands. Tremor was mild until age 15 years, when she noticed difficulties with feeding herself, buttoning her shirts, and holding her pencil. On her initial evaluation, at age 16, she had a prominent postural and kinetic tremor in the bilateral upper extremities and a mild head tremor. Her gait exhibited a normal base and step length, but she had difficulty with tandem walking. The remainder of the neurologic examination, including muscle tone, strength, sensory evaluation, and reflexes, was normal. A multichannel surface electromyogram showed a 6‐Hz postural and kinetic tremor. MRI of the brain revealed hyperintensity of the middle cerebral peduncle (“MCP sign”) with no other hyperintense lesions (Fig. 1A) There was no evidence of cortical or cerebellar atrophy. Fragile X molecular studies revealed a premutation of the FMR1 gene with an expanded CGG repeat of 60 on 1 X arm. She was started on propranolol and had an excellent response for several years.
Figure 1.
On magnetic resonance imaging (MRI) of the brain, axial fluid‐attenuated inversion recover (FLAIR) sequences at (A) ages 16 years and B) 26 years reveal hyperintensity of the middle cerebral peduncles.
Her family underwent testing for FMR1 gene mutations. The patient's father (age 65 years) and sister (age 31 years) reported that they had a “premutation” of the FMR1 gene. They were both asymptomatic. The paternal grandmother (age 86 years) also had the premutation and was diagnosed with Parkinson's disease in her 80s. The patient's 2 brothers and mother had normal FMR1 repeats. The family's specific test results were not available for our review.
On her second evaluation at age 26 years, she noted worsening of the tremor, which affected her quality of life with significant difficulty in cooking, buttoning, writing, and eating. Cognitively, the patient had graduated from high school with special education. She had normal menstrual cycles. There was no history of seizures. Examination revealed a prominent postural, kinetic, and intention tremor in the upper extremities, with gait ataxia and an inability to tandem walk. The remainder of the neurologic examination was negative except for symmetric brisk reflexes throughout with withdrawal plantar response. Repeat MRI of the brain was unchanged (Fig. 1B).
We report the youngest case of FXTAS in a female patient who fulfilled criteria for definite FXTAS at age 16 years. She had developmental delay at a very young age with a mild tremor by age 3 years. Intellectual disability and autism spectrum disorders have been previously reported in premutation carriers in both males and females.4, 5, 6 Developmental delay as early as 12 months of age is seen in premutation patients.7 Our case is a classical phenotype with autism spectrum disorder and brain MRI findings. The patient clearly inherited the abnormal X chromosome from her paternal side.
To our knowledge, the youngest patient reported to date is a 23‐year‐old woman with the onset of symptoms at age 20 years.8 FXTAS has age‐dependent penetrance: approximately 30% of male premutation carriers older than 50 years have the disorder, and greater than 75% of male premutation carriers over the age of 75 manifest symptoms.9
Females with FXTAS have a slightly different phenotype compared with males. They have a higher prevalence of hormonal, psychiatric, and medical conditions, such as central pain sensitivity syndrome, sleep disturbances, thyroid dysfunction, fibromyalgia, and migraine.10, 11 Females were thought to be protected from this disorder due to the presence of the second X chromosome, however, females with this syndrome have been reported.12 X chromosome inactivation is the transcriptional silencing of 1 X chromosome in the somatic cells of women. Statistically, women who are carriers of the premutation should have one‐half somatic cells with the active premutation allele and one‐half with the active normal allele. However, some individuals have skewing of this ratio, with a higher percentage of active premutation allele, which may result in substantial phenotypic heterogeneity. This variation in the activation ratio (the ratio of cells carrying the normal FMR1 allele on the active X chromosome) could explain the young onset of her symptoms.11 Early diagnosis of FXTAS is helpful in young patients, who can subsequently undergo genetic testing and receive counselling. This case emphasizes the need to consider FXTAS in both men and women of all ages who present with tremor and ataxia.
Author Roles
1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.
S.O.M.: 3A
K.M.: 3B
H.J.B.: 3B
Disclosures
Ethical Compliance Statement: 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 Conflict of Interest: The authors report no conflicts of interest relevant to this work.
Financial Disclosures for the previous 12 months: The authors report no sources of funding and no conflicts of interest.
Supporting information
A video accompanying this article is available in the supporting information here.
Video S1. The video was taken at age 26 years. She demonstrates a moderate‐to‐severe kinetic and intention tremor in both upper extremities. There is mild heel‐to‐shin dysmetria, which is worse on the left. She walks with a mild‐to‐moderate, wide base, and she is unable to tandem walk.
Relevant disclosures and conflicts of interest are listed at the end of this article.
Supporting information may be found in the online version of this article.
References
- 1. Hagerman RJ, Hagerman P. Fragile X‐associated tremor/ataxia syndrome features, mechanisms and management. Nat Review Neurol 2016;12:403–412. [DOI] [PubMed] [Google Scholar]
- 2. Hagerman RJ, Leehey M, Heinrichs W, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 2001;57:127–130. [DOI] [PubMed] [Google Scholar]
- 3. Jacquemont S, Hagerman RJ, Leehey M, et al. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 2003;72:869–878. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Bailey DB Jr, Raspa M, Olmsted M, Holiday DB. Co‐occurring conditions associated with FMR1 gene variations: findings from a national parent survey. Am J Med Genet A 2008;146A:2060–2069. [DOI] [PubMed] [Google Scholar]
- 5. Chonchaiya W, Au J, Schneider A, et al. Increased prevalence of seizures in boys who were probands with the FMR1 premutation and co‐morbid autism spectrum disorder. Hum Genet 2012;131:581–589. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Farzin F, Perry H, Hessl D, et al. Autism spectrum disorders and attention‐deficit/hyperactivity disorder in boys with the fragile X premutation. J Dev Behav Pediatr 2006;27(2 Suppl):S137–S144. [DOI] [PubMed] [Google Scholar]
- 7. Wheeler AC, Sideris J, Hagerman R, Berry‐Kravis E, Tassone F, Bailey DB Jr. Developmental profiles of infants with an FMR1 premutation [serial online]. J Neurodev Disord 2016;8:40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Sarac H, Henigsberg N, Markeljevic J, Pavlisa G, Hof PR, Simic G. Fragile X‐premutation tremor/ataxia syndrome (FXTAS) in a young woman: clinical, genetics, MRI and 1H‐MR spectroscopy correlates. Coll Antropol 2011;35(Suppl 1):327–332. [PubMed] [Google Scholar]
- 9. Jacquemont S, Hagerman RJ, Leehey MA, et al. Penetrance of the fragile X‐associated tremor/ataxia syndrome in a premutation carrier population. JAMA 2004;291:460–469. [DOI] [PubMed] [Google Scholar]
- 10. Hall D, Todorova‐Koteva K, Pandya S, et al. Neurological and endocrine phenotypes of fragile X carrier women. Clin Genet 2016;89:60–67. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Hall DA, Robertson‐Dick EE, O'Keefe JA, Hadd AG, Zhou L, Berry‐Kravis E. X‐inactivation in the clinical phenotype of fragile X premutation carrier sisters [serial online]. Neurol Genet 2016;2:e45. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Hagerman RJ, Leavitt BR, Farzin F, et al. Fragile‐X‐associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet 2004;74:1051–1056. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
A video accompanying this article is available in the supporting information here.
Video S1. The video was taken at age 26 years. She demonstrates a moderate‐to‐severe kinetic and intention tremor in both upper extremities. There is mild heel‐to‐shin dysmetria, which is worse on the left. She walks with a mild‐to‐moderate, wide base, and she is unable to tandem walk.