Clinical manifestations

Presentation and course

Fragile X syndrome A is the most common form of X-linked mental retardation. Males are typically more affected than females, with IQs in the moderate to severe mental retardation range (25 to 70). One third to one half of females also has some intellectual deficit with IQs of 55 to 90. Males tend to have more severe behavioral problems. Often they have attention deficit hyperactive disorder; females may be slightly hyperactive. Anxiety and depression may be present. Some 30% of boys meet full criteria for autism, others have an abortive form (19). Inappropriate jocularity, echolalia, and perseveration occur. Ten percent to 20% of fragile X syndrome A patients have epilepsy. Seizures are commonly complex partial, less frequently partial motor, and generalized (36). Distinctive physical features of fragile X syndrome A typically appear around puberty, including connective tissue problems and macroorchidism. Patients may have long facies, prominent jaw, long widened ears, and increased head circumference. Females may have a high and arched palate. Double jointedness, ear infections secondary to floppy Eustachian tubes prior to puberty, mitral valve prolapse, aortic root dilatation, and flat feet result from connective tissue involvement.

Grandparents with fragile X-associated tremor/ataxia syndrome of children with fragile X syndrome A can present with impaired gait and fine motor skills, fluctuating weakness, numbness, neuropathic pain, erectile dysfunction, and bladder or bowel incontinence.

In males, neurologic evaluation reveals gait difficulties (95%), impaired fine motors skill (90%), cerebellar ataxia (78% to 93%), kinetic tremor (70%), parkinsonism (57%), proximal leg weakness (30%), lower extremity neuropathy (60%), autonomic dysfunction (30% to 80%) (29), and dementia (20%) (21). Impairment of executive functioning with relative preservation of language and visuospatial skills is the hallmark of dementia; this resembles frontotemporal dementia (FTD) and some of the marked and early loss of memory and language in Alzheimer disease (29; 03; 17; 05). Commonly reported neuropsychiatric symptoms include apathy, irritability, depression, disinhibition, anxiety, and delusions (05; 06). Atypical symptoms at onset include spastic paraparesis (09). There is an increased risk of sleep apnea and hypertension (25; 26). Onset, progression, and severity may be sensitive to environmental toxins including methadone (37), phenobarbital (42), and others.

Fragile X-associated tremor/ataxia syndrome affects 8% to 16% of female premutation carriers over 50 years of age with milder symptoms and fewer motor anomalies (30; 21; 04; 32). Women with the premutation may have neurocognitive dysfunction, specifically in visual attention testing (50), as well as premature ovarian failure with early menopause and infertility, and a propensity for autoimmune conditions (27; 47; 55). Executive dysfunction in premutation carriers was worse in women with fragile X-associated tremor/ataxia syndrome than those without (56). Conversion disorder has been described (45).

Prognosis and complications

The available information on fragile X-associated tremor/ataxia syndrome, being a recently described progressive neurodegenerative condition, is derived from single case reports and case series. In a retrospective longitudinal analysis of disease progression and survival in 55 men, the average age of onset was 60 years, with tremor being the first symptom. Patients began suffering falls 6 years, using a walking device 12 years, and dying 21 years after onset, respectively. Most were confined to bed with severe parkinsonian features before death (33).

Clinical vignette

At his first visit with a referral for parkinsonism, a 78-year-old man with well-controlled diabetes (HgA1c 5.5) arrived in a wheelchair. Progressive gait abnormality had started 2 years earlier, initially with difficulty standing and walking and several falls. Around that time he developed urinary incontinence and over the next year tremor and mental decline. Relatives noted that he often looked as if he were about to cry, yet he would laugh. Frequently he was unable to express himself due to word-finding difficulties. His short-term memory had significantly declined. Three months before the visit he stopped driving after he was pulled over by the police several times for swerving. Levodopa/carbidopa for his tremor and gait difficulties was of no benefit.

His mini-mental status exam score was 22/30 with deficits in recall, attention, and construction. He had mild ptosis of the left eye, a diminished left nasolabial fold, and mask-like facies. Jaw jerk and snout reflexes were present. He had a prominent action tremor and cogwheeling. Power was 4/5 diffusely. Ankle jerks were absent, and plantar responses were extensor. Sensation was impaired distally. His gait was ataxic, and a Romberg sign was present.

His daughter remarked that the mental status testing resembled the exam her 11-year-old son had undergone during an evaluation, which led to a genetically confirmed diagnosis of fragile X syndrome A. Her sister also had a son with fragile X syndrome A.

A CT showed enlarged ventricles and cortical atrophy, but MR imaging was not possible due to a pacemaker. Nerve conduction studies revealed a generalized sensorimotor polyneuropathy. The following blood tests were normal: rheumatoid factor, ANA, hepatitis B and C, syphilis serology, TSH, folate, and B12 (579). Fragile X testing revealed a 112 CGG repeat expansion in the fragile X syndrome A gene.

With donepezil, the mini-mental status exam score improved slightly to 25/30.

Biological basis

Etiology and pathogenesis

In fragile X syndrome A and fragile X-associated tremor/ataxia syndrome, there is a CGG expansion in the 5’ promoter region of the FMR1 gene on chromosome Xq27.3. Normal individuals have 6 to 50 CGG repeats, carriers of the premutation have 55 to 200 repeats, and fragile X syndrome A patients have 200 to 1500 repeats with methylation at the cytosine within the CGG repeat leading to silencing of the gene. Normal individuals and carriers do not have methylation of their CGG expansions (38). Rare patients have 45 to 54 repeats or an unmethylated full mutation (18). In analogy to other triplet repeat disorders, fragile X syndrome A may also result from a point mutation in FMR1 or an FMR1 deletion. Maternal transmission is more likely to result in a greater CGG triplet repeat expansion and a more severe and earlier form of the disease.

In fragile X syndrome A, the long stretch of methylated DNA repeat sequences in the promoter leads to reduced gene expression of the FMR1 gene and its protein product, fragile X mental retardation protein. This is an RNA binding protein that affects splicing, stability, transport, and translation, and, thus, may affect activity of multiple genes expressed in different organs, resulting in age-dependent abnormalities in several organ systems (see above), ie, facial, skeletal and cardiovascular, central nervous system, peripheral nervous system, and endocrine abnormalities. Its role in RNA translation in the brain remains controversial; however, fragile X mental retardation protein forms complexes with cortical brain polyribosomes (49). Fragile X mental retardation protein may also function as a DNA-binding protein and transcription factor.

In fragile X-associated tremor/ataxia syndrome, fragile X mental retardation protein blood levels are near normal or mildly reduced. FMR1 mRNA levels are elevated 2 to 4 times in men with alleles in the low mutation range of 55 to 100 CGG repeats, and 4 to 10 times in men with 100 to 200 CGG repeats. Elevated mRNA levels also occur in women with premutation alleles (53). This may represent a reduced translational efficiency of the FMR1 gene; the elevated level may have a cumulative cytotoxic effect leading to inclusion body formation discussed below (16).

As women have two X chromosomes, lyonization, the random inactivation of the normal versus abnormal X chromosome, results in phenotypic variability: Thus, some female carriers may have normal fragile X mental retardation protein (47; 28). The presence and severity of ataxia correlates with increasing CGG repeat length when the percentage of normal alleles that are active is considered (32).

Histological and molecular autopsy studies of the brains of patients with the premutation reveal accumulations of abnormal cellular material as nuclear cortical, brainstem neuronal, and astroglial inclusion bodies and marked spongiosis of the deep cerebellar white matter (16). Inclusion bodies were found in all autopsied female carriers, even in two without fragile X-associated tremor/ataxia syndrome (52). Spongiosis was seen in the middle cerebellar peduncle (MCP) in seven of eight cases, which correlates with the characteristic T2 signal change (MCP sign) seen in many patients (15; 03). Inclusion bodies are concentrated in the hippocampus and frontal cortical regions, areas that control movement and are important in learning, memory, and emotions. Their location has been correlated with clinical symptoms and MRI findings (29). Inclusion bodies are also specifically concentrated in the hypoglossal nucleus and in spinal cord autonomic neurons, which may explain the dysphagia and autonomic involvement (15). The authors found a correlation between the repeat number and intranuclear astroglial and neuronal inclusions. Interestingly, fragile X syndrome A patients with the full mutation do not have inclusion body formation (40). Binding of ubiquitin antibodies to these inclusions suggests that they are somehow related to degradation of as yet unknown proteins; neurodegeneration may result from the inability of affected cells to degrade abnormal proteins (16). Intranuclear inclusions also occur in the ganglion cells of adrenal medulla, dorsal root ganglia, paraspinal sympathetic ganglia, myenteric ganglia, and subepicardial autonomic ganglion (14). In vitro studies reveal mitochondrial dysfunction that may sensitize carriers to environmental stressors that, in turn, trigger the clinical features (41). Furthermore, there is evidence of an RNA gain-of-function mechanism (43). A mouse model displayed embryonic neocortical migration defects and altered neuronal marker expression, consistent with neurodevelopmental abnormalities (10).

Epidemiology

Some 1 in 450 to 800 men and 1 in 150 to 300 women carry the fragile X syndrome A premutation. The prevalence of fragile X-associated tremor/ataxia syndrome in men above 50 years of age may approach 1 in 3000 (30). Among late-onset ataxia, the positivity rate for FMR1 is 0.6% to 5.1% (08; 23). On the other hand, a study of 167 patients with essential tremor, sporadic progressive cerebellar ataxia, multiple system atrophy, and atypical parkinsonism with no family history of fragile X syndrome A found no instance of the FMR1 premutation with abnormal CGG triplet expansion (51). Likewise, no CGG premutation was detected in any of the 412 X-chromosomes of patients with Parkinson disease and essential tremor (31; 11).

However, Park and colleagues found a 2.7% prevalence of FXTAS among 74 patients with presumed essential tremor and additional cerebellar or extrapyramidal signs (39).

Of 77 patients diagnosed with multiple system atrophy or related phenotypes, one man and one woman had an FMR1 premutation expansion (04). Case reports of orthostatic tremor are found in the literature (57).

Differential diagnosis

The differential diagnosis includes: Alzheimer disease, ataxia, multiple system atrophy, Parkinson disease, progressive supranuclear palsy, peripheral neuropathy, and tremor.

Diagnostic workup

Recommendations for definite, probable, or possible fragile X-associated tremor/ataxia syndrome based on clinical appearance and radiographical findings have been suggested (29). Typical findings of brain MRI include ventricular enlargement, severe frontoparietal volume loss, and cerebellar hyperintensities and atrophy. The changes on neuroimaging are milder in females compared to males. Middle cerebellar peduncle T2 hyperintensity (the characteristic MCP sign) is seen in 13% of females compared to 58% males with fragile X-associated tremor/ataxia syndrome (01). MRI changes may precede the neurologic deterioration, and there may be significant discrepancy (34).

Decreased middle cerebellar peduncle (MCP) width may be one of the earliest signs in FXTAS. In a study involving 53 male patients with FXTAS and 61 controls with an average follow-up for 1.96 years, MCP width was initially reduced in a subset of premutation carriers who developed FXTAS and also decreased over time during follow-up (46).

Hall and colleagues recommended FMR1 testing for unexplained late-onset cerebellar ataxia in men over 50 years of age or for patients with Parkinson disease or fragile X-associated tremor/ataxia syndrome phenotype with either the MCP sign on MRI or with a family history of developmental delay, autism, mental retardation, or premature ovarian failure (23; 24). Neuropsychological evaluation can document the degree of cognitive involvement and characterize it as dysexecutive (07). Neurophysiological abnormalities of peripheral neuropathy, if present, include reduced tibial nerve conduction velocities and prolonged F-wave latencies (48). Histological changes include dystrophic white matter and astrocytic and neuronal intranuclear inclusions with increased putaminal iron deposits (02). These inclusions may result from a triplet repeat-triggered cryptic polyglycine-containing protein (54). Other coexisting causes of peripheral neuropathies must be addressed, including infectious, endocrinological, and immunological abnormalities, vitamin deficiencies, and nerve compression. The same tests may reveal additional causes for mental decline.

Longitudinal development over 4 to 5 years of deficits in executive and motor function were described in 64 male premutation carriers (12).

Management

In addition to conservative therapy, balance training, and anti-dementia medications, it is important to look for, treat, and prevent acquired causes of mental decline and neuropathies. Neuropsychological testing can be the basis of cognitive retraining. Otherwise, the various features associated with fragile X-associated tremor/ataxia syndrome are treated symptomatically (20). Thalamic deep brain stimulation was found to effectively relieve disabling action tremor in a patient with fragile X-associated tremor/ataxia syndrome who failed to improve with conventional anti-tremor treatments (Jankovic J, personal communication). Memantine did not ameliorate the neurologic, cognitive, or behavioral features (44). As with other progressive neurologic conditions, emotional, logistical, and educational support of patients and caregivers can promote successful coping (13).

Special considerations

Pregnancy

Prenatal counseling, including of the risk of allele expansion; education regarding fragile X syndrome and fragile X-associated tremor/ataxia syndrome; and carrier testing are important steps toward enabling affected families to plan for the future and make informed decisions (35).