FMR1 Premutation and Demyelinating Syndromes: Case or Causality? A Case Report

Methods: A 51-year-old woman, with a carrier status for Fragile X Syndrome with 68 CGG expansions, was referred to the neurological unit for suspected MS. At the age of 47 years patient rapidly developed motor symptoms with walking impairment and personality alterations. The first Magnetic Resonance Imaging showed white matter lesions consistent with demyelinating disorders; the cerebrospinal fluid analysis was negative for oligoclonal bands. Neurological disorders worsened a few years after diagnosis with onset of ataxia.


Introduction
Background Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder that involves individuals with permutation alleles of the fragile X mental retardation (FMR1) gene [1]. Premutation alleles (from 55 to 200 CGG repeats) of the FMR1 gene are common, occurring approximately in 1/100-300 females and in 1/300-800 males [2]. The full mutation is much rarer: 1/2500-4000 [3,4]. FXTAS penetrance varies within males and females: it is approximately 40% in males and 5%-10% in females [5,6]. The phenotype includes intention tremor, parkinsonism, ataxia, peripheral neuropathy, autonomic disfunction and cognitive impairment [7]. Demyelinating diseases of the central nervous system (CNS) are a heterogeneous group of diseases of the nervous system in which the myelin sheath of neurons is damaged [8].
Multiple sclerosis (MS) is the most common demyelinating disease of the CNS with an estimated prevalence worldwide of 2.3 million people [9]. In this report we describe a woman with FXTAS and a clinical and radiological presentation partially consistent with a demyelinating disease. MS is a typical young adults disorder, more common in women [10]. Penetrance is approximately 40% in males and 5%-10% in females [5,6]. MRI of FXTAS patients can show moderate to severe generalized brain atrophy with ventricular enlargement, specific cerebellar atrophy, and subcortical and/or pontocerebellar white matter lesions [14][15][16]. Approximately 60% of males with FXTAS have white matter lesions or hyperintensities on T2-weighted MRI in the middle cerebellar peduncles (MCP), termed the ''MCP sign'', which is a major radiologic feature of FXTAS, but it has also been reported in other neurological conditions such as multiple system atrophy [17,18], recessive ataxia [18] and acquired hepatocerebral degeneration [19]. Since the initial FXTAS description, the literature has been enriched by numerous case reports and studies that lead to more awareness about the disease characteristics describing phenotypes that vary from the original diagnostic criteria. Although FXTAS was originally described in male patients, females with FXTAS have now been reported. Recent case reports described female carriers with typical FXTAS [20], with FXTAS and spasmodic dysphonia [21] and with FXTAS and MS [2,22]. The hypothesised mechanism leading to FXTAS, involves a direct toxic gain-of-function of the FMR1 mRNA, likely through altered regulation of some protein that interact with the high levels of altered FMR1 mRNA [7].

Case Report
In neurons and astrocytes throughout the brain and brainstem of FXTAS patients there are intranuclear inclusions, astrocyte activation, axonal retraction bulbs, axonal loss, and myelin loss [23,24]. The inclusions contain αβ-crystallin, MBP, lamin A/C isoforms, and numerous other proteins [24]. According to this finding the toxic effects of FMR1 mRNA should result in the disruption of nuclear lamin A/C architecture and formation of perinuclear αβ-crystallin aggregates in cultured neural cells [25]. αB-crystallin is a small heat shock protein, likely involved both in the normal dynamics of cytoskeletal proteins [26] and in maintenance of cell survival during cellular stress [27]. According to recent knowledge, it seems that the αB-crystallin is a protein also related to the pathogenesis of MS. It is, in fact, a key antigen in the development of MS [28]; the up regulation of αB-crystallin in patients with FXTAS could result in loss of immunologic tolerance, leading to predisposition or exacerbation of MS. Firthermore αB-crystallin is highly expressed during the early phases of MS relapses [28], and autoantibodies to αB-crystallin are found in the cerebrospinal fluid of patients with MS. It is postulated that they could potentially interfere with the protective role in reducing brain inflammation and brain cell death [29]. Finally, carrier women seems to be particularly susceptible to develop autoimmune disorders, including autoimmune thyroiditis and fibromyalgia [22].

Conclusion
Our patient had clinical and radiological features partially consistent with MS, but not enough to meet the revised Mc Donalds diagnostic criteria [12]. According to the diagnostic criteria for FXTAS [14] the patient appears to have a degree of probability to a demyelinating disease such as MS. First of all both conditions are very common and, therefore, it would not be rare to observe the two conditions in the same patients, expecially a female, simply by chance. Regarding the molecular biological point of view, the two conditions appear to be linked by the increase of a small heat shock protein, the αB-crystallin, which elevation observed in FXTAS may lead to enhanced predisposition to autoimmune diseases, by predisposing or exacerbating a picture of demyelination.
In the approach to the patients is also important to consider the clinical features of presentation and development of the disease.
Our patient, in fact, in addition to a clinical picture characterized by motor deficit compatible with both situations, experienced also a rapid onset of psychiatric disorders requiring specific antipsychotic therapy. Therefore, in the diagnostic process, especially if the patient is a female with POF, in presence of alterations on MRI consistent with a demyelinating process and with also atypical symptoms we recommend to screen the patient for FXTAS. In conclusion, all the findings described in this report, shows the need for further clinical, radiological and molecular studies, able to establish the relations between the fragile X premutation carrier status and demyelinating disorders.