Fragile X Tremor Ataxia Syndrome Research Articles

Fragile X Premutation in a Woman With Cognitive Impairment, Tremor, and History of Premature Ovarian Failure

Few women with Fragile X tremor ataxia syndrome (FXTAS) have been reported. They have milder manifestations at a later age than men. This gender difference may be related to the X inactivation pattern in women. We describe a woman who presented to her geriatrician with poor memory and was found to have ataxia and tremor. Additional queries yielded history of premature ovarian failure. Genetic testing showed heterozygous fragile X mental retardation gene premutation with 103 CGG repeats in the abnormal allele and 31 CGG repeats in the normal allele. Also, the X inactivation pattern was skewed with the active X chromosome predominantly having the premutation allele. We believe that FXTAS is more common in women than is generally thought and that many such patients masquerade as dementia of old age. Action tremor and ataxia associated with a history suggestive of premature ovarian failure should raise suspicions for FXTAS.

MEDICAL AND NEUROLOGIC PROBLEMS IN FEMALES WITH THE FRAGILE X PREMUTATION.

Purpose of Study Women with the fragile X premutation were originally thought to be unaffected by the CGG repeat (55-200). Recent research shows that women with the premutation have a higher rate of premature ovarian failure and osteoporosis than the general population and are also affected with the fragile X tremor ataxia syndrome (FXTAS). The purpose of this study is to evaluate the medical problems and neurologic examination in a large group of women with the fragile X premutation compared with controls to identify other medical problems that may be related to the carrier state. Methods All females seen in the Fragile X Research and Treatment Center at UC-Davis with the premutation were included in this study (n = 139). Control subjects (n = 68) included family members of fragile X families and females recruited from the Sacramento area without the premutation age-matched to the premutation group. All subjects underwent a standardized detailed medical history, review of systems, and examination including comprehensive neurologic testing. Prevalence of medical and neurologic problems were compared between the premutation group and the control group. Results The study groups included 139 women with the fragile X premutation (18 FXTAS, 121 non-FXTAS) and 68 controls. In the premutation group, 16% had premature ovarian failure, consistent with previous reports in the literature in this population. Results also showed many other medical problems and physical examination findings in the premutation group with significantly higher prevalence than the typical population and controls, including hypothyroidism (22.5%), lupus (3%), optic neuritis (3.7%), multiple sclerosis (2%) fibromyalgia (12.4%), muscle pain (33%), and peripheral sensory deficits (12%) (p Conclusions Women with the fragile X premutation are more likely to have thyroid disease, MS symptoms, fibromyalgia, and neurologic findings such as peripheral sensory deficits, even if they do not meet the diagnostic criteria for FXTAS. Women with FXTAS have the characteristic symptoms of FXTAS (tremor, ataxia), in addition to higher rates of thyroid disease and cardiovascular problems. Thyroid screening and close neurologic follow-up are recommended for all women with the fragile X premutation.

RNA-MEDIATED NEUROMUSCULAR DISORDERS

Myotonic dystrophy type 1 (DM1) is caused by a CTG expansion mutation located in the 3' untranslated portion of the dystrophica myotonin protein kinase gene. The identification and characterization of RNA-binding proteins that interact with expanded CUG repeats and the discovery that a similar transcribed but untranslated CCTG expansion in an intron causes myotonic dystrophy type 2 (DM2) have uncovered a new type of mechanism in which microsatellite expansion mutations cause disease through an RNA gain-of-function mechanism. This review discusses RNA pathogenesis in DM1 and DM2 and evidence that similar mechanisms may play a role in a growing number of dominant noncoding expansion disorders, including fragile X tremor ataxia syndrome (FXTAS), spinocerebellar ataxia type 8 (SCA8), SCA10, SCA12, and Huntington's disease-like 2 (HDL2).

Fragile X and company: Finding the right diagnosis

Fragile X syndrome (FXS) is a common cause of inherited mental retardation in boys. (More information about FXS can be found on the next page.) It is caused by a defect in a gene located on the X chromosome that is inherited from the mother. The gene in the mother carries a “premutation” which, when passed on to her son, expands to a “full” mutation that produces the signs of fragile X syndrome. The mother who carries the “premutation” does not have mental retardation because she also carries a normal X chromosome. She may have inherited the premutation from her father. This grandfather does not have mental retardation either because the gene only carries a “premutation.” However, some of these grandfathers develop a progressive tremor (shaking) and gait ataxia (unsteadiness) later in life, known as fragile X tremor-ataxia syndrome (FXTAS). Even more rarely, the mother with the premutation may develop FXTAS. This issue of Neurology has two papers that further describe FXTAS, as well as an editorial on the subject. One of the papers, by Hall et al.,1 is from the same group of researchers who originally reported this syndrome in 2001. In the clinics where the boys with FXS were treated, the mothers indicated that their fathers (the boys’ maternal grandfathers) were having neurologic problems. Sixty-two family members were found to have the fragile X premutation by genetic testing. “Definite” FXTAS was diagnosed if the patients had a tremor with movement (intention tremor) or ataxia when walking with either 1) a very typical abnormality on brain MRI scan or 2) the disease was confirmed on autopsy. Twenty of the 62 met this …

FMR1 gene premutation is a frequent genetic cause of late-onset sporadic cerebellar ataxia

In an Italian population of 275 unrelated men affected by adult-onset sporadic progressive cerebellar ataxia, the authors found six patients carrying an FMR1 gene premutation. Age at onset (range, 53 to 69 years) and clinical-neuropathologic findings were consistent with the fragile-X tremor ataxia syndrome (FXTAS), although tremor was not as common as previously described. FXTAS accounted for 4.2% of the cases diagnosed at >50 years, suggesting that it is a frequent genetic cause of late-onset sporadic ataxia.

Fragile X–associated tremor/ataxia syndrome in sisters related to X‐inactivation

Fragile X tremor/ataxia syndrome (FXTAS) is a recently described condition consisting of tremor, ataxia, parkinsonism, and executive dysfunction, presenting predominantly in male carriers of a fragile X mental retardation 1 premutation. In this report, we present premutation carrier sisters in whom severity of clinical signs correlated with a molecular pattern of X-inactivation favoring higher expression of the premutation allele. In these women with a common genetic background, we suggest that symptom severity may be dictated by X-inactivation, and thus a higher percentage of cells producing the premutation-containing mRNA result in increased toxicity and disease.

Something lost in the translation: ‘premutations’ in the FMR1 gene cause Fragile X tremor/ataxia syndrome (FXTAS)

Something lost in the translation: ‘premutations’ in the <i>FMR1</i> gene cause Fragile X tremor/ataxia syndrome (FXTAS)