Fragile X-associated tremor ataxia syndrome

Rachael C. Cvejic, Julian N. Trollor and Darren R. Hocking

Introduction

Fragile X-associated disorders are a family of X-linked disorders caused by expansions of a CGG repetitive sequence in the Fragile X Mental Retardation 1 (FMR1) gene (Verkerk et al., 1991), which codes for the Fragile X Mental Retardation Protein (FMRP). The Fragile X Mental Retardation Protein (FMRP) has been found to have an important role in the regulation of a number of neuronal processes associated with healthy brain development, including synaptic development and neuroplasticity (Huber, Gallagher, Warren & Bear, 2002; Zalfa & Bagni, 2004). Perhaps the most widely known abnormal phenotype associated with the FMR1 gene is fragile X syndrome (FXS), the most common form of inherited intellectual disability. However, less marked expansions within this same gene produce other clinical phenotypes distinct from FXS. These include the neurodegenerative phenotype of fragile X-associated tremor ataxia syndrome (FXTAS), and clinical signs of ovarian dysfunction (fragile X-associated primary ovarian insufficiency; FXPOI).

The FMR1 gene and it expansions can be classified according to CGG repeat sizes. These can be within the normal (6-44 CGG repeats), grey zone (45-54 CGG repeats), premutation (PM; 55-200 CGG repeats), or full mutation range (>200 CGG repeats) (Human Genetics Society of Australasia, 2012). Normal repeats are typically stable when transmitted from parent to offspring, with 29-30 repeats being the most commonly found alleles (as reviewed in Peprah, 2012). Grey zone alleles are also common in the general population, found in approximately 1 in 66 females and 1 in 112 males (Tassone et al., 2012). The phenotypic impact of grey zone alleles is unclear; while a number of studies have reported no difference in the number of grey zone alleles identified in target populations compared to control population rates (Reis et al., 2008; Kurz et al., 2007; Biancalana et al., 2005), some studies have indicated that grey zone FMRi repeat expansions may be over-represented in people with idiopathic Parkinson’s disease and other causes of Parkinsonism (Hall et al., 2011; Loesch et al., 2009; Zhang et al., 2012). Approximately 1 in 209 females and 1 in 430 males (Tassone et al., 2012) carry PM expansions of the FMRi gene; unstable alleles that during maternal transmission may expand into the full mutation range in subsequent generations (Nolin et al., 2003). Although it was previously thought that PM alleles were not associated with any specific clinical phenotype, PM alleles are now known to be associated with both FXTAS and FXPOI. Unlike the full mutation, PM expansions are associated with increased transcription and elevated levels of FMR1 messenger ribonucleic acid (mRNA), and normal or slightly reduced levels of FMRP (Tassone et al., 2000). Full mutation of the FMRi gene results in aberrant methylation and transcriptional silencing of the gene (Verkerk et al., 1991), disrupting the production of FMRP, and causing FXS.

Preliminary considerations

The FMRi PM confers health risks that are distinct from FXS. Approximately 10-30% of women who earn' the PM develop FXPOI (Cronister et al., 1991; Rodriguez-Revenga et al., 2009; Schwartz et al., 1994). This term encompasses a range of clinical signs of ovarian dysfunction, including irregular menses, increased follicle stimulating hormone, fertility problems, and cessation of menstruation prior to 40 years of age (Schwartz et al., 1994; Allingham-Hawkins et al., 1999). While this phenotype has been known to be associated with the PM in women since the early 1990s, early investigations failed to identify a distinct clinical phenotype in men. However, in 2001, Hagerman et al. (2001) described a case series of five elderly PM males all of whom showed a distinct profile of motor and cognitive features. These individuals presented with cerebellar and parkinsonian features including intention and resting tremor, bradvkinesia, wide based gait and inability to tandem walk. Neuropsychological evaluation indicated impairments on the Wisconsin Card Sorting Task, a measure of executive function tapping abstract reasoning and set-shifting ability. Cognitive deficits were described as progressive and two cases met diagnostic criteria for dementia. It was proposed that this progressive neurological syndrome, termed FXTAS, represented a previously unrecognised phenotype associated with the PM caused by elevated production of FMRI mRNA (Hagerman et al., 2001).

Clinical vignette

A 66-year-old man presented with a history of tremor and balance problems. He reported that he first noticed the tremor beginning in his dominant hand at the age of 56 and that this progressed bilaterally, followed by the onset of a postural head tremor and mild balance problems by 63 years of age. He also described sensor)' loss in both lower limbs developing over the last 12 months. His medical history included diagnoses of major depressive disorder, generalised anxiety disorder, high blood pressure, and high cholesterol. There was no history of other significant health conditions such as diabetes, epilepsy, thyroid disorder, transient ischemic attack, stroke, or heart attack. He was an ex-smoker with a 9-year pack-a-day history and reported consuming three to six alcoholic beverages per week. There was no history of illicit substance use.

Genetic testing for an FMR1 premutation was undertaken at the age of 60 years when his grandson was diagnosed with fragile X syndrome. Prior to her death, his mother was diagnosed with an unspecified type of dementia. There was no other remarkable family history in terms of risk for neurological or psychiatric disorder.

A neurological examination revealed multiple cerebellar and parkinsonian signs. He walked with a normal posture, stride, and speed, but showed a loss of arm swing. His handwriting was moderately abnormal with considerable tremor (Figure 6.1). He exhibited moderate intention tremor bilaterally in the upper extremities; bilateral action tremor in the lower extremities; intermittent bilateral resting tremor in the upper extremities; and infrequent resting tremor in the right leg. Difficulties with tandem walking (>3 deviations) were also observed.

Cognitive testing revealed deficits in executive function, speed of information processing, and visuospatial processing. His wife denied noticing any cognitive

Abnormal handwriting demonstrated on a drawing task

FIGURE 6.1 Abnormal handwriting demonstrated on a drawing task.

changes but reported psychiatric symptoms including moderate depression, moderate anxiety, and mild irritability and agitation. Diagnoses of current and lifetime history of major depression and generalised anxiety disorder were confirmed during a formal psychiatric interview.

On the brain MRI, T1 -weighted and T2 FLAIR sequences showed moderate diffuse cerebral hemispheric and cerebellar volume loss (Figure 6.2A); white matter hyperintensities in the middle cerebellar peduncles (Figure 6.2B).

Onset and prevalence

FXTAS affects approximately 45% of PM males over 50 years of age and 8-16% of PM females over 40 years of age (Rodriguez-Revenga et al., 2009). The penetrance increases with age, such that approximately 17% of PM males in their 50s will have FXTAS, but this number rises to 38% in their 60s, 47% in their 70s and 75% of PM males in their 80s (Jacquemont et al., 2004).

Clinical signs and symptoms

Motor signs of FXTAS include intention tremor (increasing in amplitude toward the end point of a movement), and cerebellar ataxia (wide-based, unsteady gait), with less pronounced signs of parkinsonism (rigidity, bradvkinesia, hypomimia, resting tremor) (Jacquemont et al., 2003; Leehey et al., 2008). Although less common, dystonia, spasticity and muscle weakness may also be present (Jacquemont

Slices from brain magnetic resonance imaging

FIGURE 6.2 Slices from brain magnetic resonance imaging. (A) T-weighted image showing bilateral volume loss in the cerebral cortex and cerebellum. (B) T2-weighted fluid-attenuated inversion recovery image showing white matter hyperintensities in the middle cerebellar peduncles.

et al., 2003; Jacquemont et al., 2005; Zhang et al., 2014). Generally, neurological symptoms are more frequent and severe in males compared to females, possibly due to the random inactivation of the expanded X chromosome (Alvarez-Mora et al., 2016), a neuroprotective effect of oestrogen (Hagerman et al., 2004; Berry-Kravis, Potanos, Weinberg, Zhou & Goetz, 2005; Jacquemont et al., 2005; Horvath et al., 2007), or other, as yet unknown factors.

Cognitive features of FXTAS include poorer performance on measures of executive function, working memory, information processing speed, and fine motor function relative to matched controls (as reviewed in Birch, Cornish, Hocking & Trollor, 2014). Psychiatric features may include depression, anxiety and obsessive-compulsive symptoms (Bourgeois et al., 2009, 2011; Bacalman et al., 2006; Adams et al., 2010), as well as agitation, aggression, irritability and disinhibition (Bacalman et al., 2006; Grigsby et al., 2016). This neuropsychiatric profile is similar to other neurodegenera- tive disorders with primary cognitive and motor features including Parkinson’s disease and dementia with Lew)' bodies, and is suggestive of dysfunction to fronto-subcortical neural circuits modulating affect and behaviour (Bacalman et al., 2006).

Diagnostic instruments and clinical rating scales

Diagnostic criteria for FXTAS (Table 6.1) describing core clinical and radiological features were formulated in 2003 based on a study of 20 PM males presenting with at least one clinical sign (intention tremor, gait ataxia) and white matter lesions

TABLE 6.1 Diagnostic criteria for FXTAS. Inclusion criteria = FMR1 grey zone, premutation or full mutation. MRI: magnetic resonance imaging.

Examination

Degree

Observation

Radiological

Major

Major

Minor

Minor

MRI white matter lesions in MCPs and or brain stem MRI white matter lesions in the splenium of the corpus callosum MRI white matter lesions in cerebral white matter Moderate-to-severe generalised atrophy

Clinical

Major

Major

Minor

Minor

Minor

Minor

Intention tremor Gait ataxia Parkinsonism Neuropathy

Moderate-to-severe short-term memory deficiency Executive function deficit

Diagnostic categories:

Definite:

  • a) One major clinical + one major radiological sign, or
  • b) One major clinical sign + presence of intranuclear neuronal and astrocytic inclusions on post-mortem examination of brain tissue

Probable:

  • a) One major radiological sign + one minor clinical symptom, or
  • b) Two major clinical symptoms

Possible:

a) One major clinical + one minor radiological sign

Sources: Jacquemont et al. (2003); Hall et al. (2014); Hagerman & Hagerman (2004) in the middle cerebellar peduncles (MCP) (Jacquemont et al., 2003). Using these criteria, individuals were classified as having ‘definite’, ‘probable’, or ‘possible’ FXTAS according to clinical and radiological signs. Neuropathological features were subsequently included and may be used to make diagnoses of FXTAS where post-mortem brain tissue was available (Hagerman & Hagerman, 2004). Most recently, diagnostic criteria were updated to include white matter lesions in the splenium of the corpus callosum as a major radiological criterion, and neuropathy was added as a minor clinical criterion (Flail et al., 2014; Apartis et al., 2012). Criteria were also extended to include not only carriers of the premutation, but also the rare situations in which FXTAS develops in individuals with grey zone and full mutation expansions (Hall et al., 2014).

A seven-point clinical staging scale for FXTAS has also been developed whereby individuals are assigned a score according to the severity of motor symptoms (Bacalman et al., 2006). These clinical stages are defined as follows:

  • 0 Normal.
  • 1 Subtle or questionable signs (i.e. subtle tremor and/or mild balance problems) but no interference with activities of daily living (ADLs).
  • 2 Minor, but clear tremor and/or balance problems producing minor interference with ADLs.
  • 3 Moderate tremor and/or balance problems and at least occasional falls.
  • 4 Severe tremor and/or balance problems requiring the use of cane or walker.
  • 5 Uses wheelchair on a daily basis.
  • 6 Bedridden.
 
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