A Chinese case of fragile X-associated tremor/ataxia syndrome (FXTAS) with orthostatic tremor:case report and literature review on tremor in FXTAS

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset X-linked genetic neurodegenerative disorder caused by a “premutation (PM)” 55–200 CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. The normal number of CGG of FMR1 is less than 45 CGG repeats in the 5′ UTR region,gray zone contains 46–54 repeats (carriers with either movement disorders or memory complaints), premutation contains 55–200 repeats (causes FXTAS or FXPOI) and full mutation > 200(causes Fragile X syndrome). FXTAS mostly affects middle-aged and elderly men of 50–70 years old. The main motor features include tremor and cerebellar ataxia but there is high phenotypic variability with some carriers demonstrating parkinsonism, peripheral neuropathy, executive function deficits, dementia, and neuropsychiatric problems. The syndrome can mimic many common neurodegenerative disorders such as Parkinson’s disease (PD),multiple system atrophy (MSA), Alzheimer disorders (AD), essential tremor (ET), and pure ataxia. Tremor is seen in 48–80% patients and variable in different studies and intention tremor is the most common pattern [1, 2]. But it’s very rare that FXTAS patients present with orthostatic tremor (OT). Here we report an old man with FXTAS from mainland of China who had OT as initial manifestation for 8 years. We also review more than 64 cases in the literature to find out the spectrum of tremor and other phenotype.

A 67-year-old right-handed farmer from the mainland of China was admitted to neurology department with slowly progressive tremor in limbs for 8 years. The tremor started from both lower limbs. It was only present while standing but absent when sitting,lying or walking. He had no problem in initiating the gait and no fall. The patient was diagnosed with essential tremor for long time and he was still functional in daily life without any medical therapy. Tremor became worse one and a half year ago and he felt unsteady. Tremor started in both arms 8 months ago which was remarkable when working with hands. Family history showed that his younger daughter stopped the menstruation at her 30s and the son of his youngest daughter had autism and attention deficit hyperactivity disorder (ADHD) (Fig. 1 C). Neurological examination revealed remarkable and visible tremor in both legs when standing still, intention tremor in both hands, mild postural tremor in both arms and rest tremor in left hand. He swayed on Romberg’s test and had difficulty with tandem gait. He hadn’t finger-nose and heel-shin incoordination,rigidity of limbs or nystagmus in eyes. The finger tapping was slow and clumsy bilaterally. His cognitive evaluations with Mini-mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were 28/30(education state: primary school) and 20/30 respectively. There was no muscle weakness, sensory disturbance or orthostatic hypotension. Laboratory tests including blood cell counts, liver function, kidney function,thyroid function, ceruloplasmin and homocysteine were within the normal range. We found no abnormalities in the cerebrospinal fluid. Nerve conduction study values were within the normal range. The T2-weighted and fluid-attenuated inversion recovery (FLAIR) brain MRI indicated high intensity signals in the bilateral middle cerebellar peduncles (MCP),multiple sporadic high intensity signals in the cerebral white matter and atrophy of the cerebral cortex and cerebellum (Fig. 1a,b). FXTAS were considered and test for permutation of FMR1 gene was performed and showed positive with 101 CGG repeats (Fig. 1d,e). The patient met the the diagnosis criteria [3] with definite FXTAS. Because the heart beat was very low (50–60/min) β-receptor blocker was not used. Clonazepam (0.5 mg–1 mg qn) and topiramate (primidone was not available) were administered and the tremor was relieved a little.

In total, we searched 552 articles with term Fragile X-associated Tremor Ataxia Syndrome, we got 95 articles when limited to case report. We identified 33 articles reporting 64 patients fulfilling our inclusion criteria (Fig. 2). Reference 4 reported 19 patients with clinical information summarized in Tables but only 4 cases described in details so we included these 4 cases. The main findings of the review are summarized in Table 1 . We analyzed the clinical character and outlined in Table 2.

Here we report a rare case of FXTAS that OT was as initial manifestation for a long time. Studies have showed tremor in approximately 77% of men with FXTAS [36]. The tremor in FXTAS is typically bilateral intentional, postural or kinetic tremor in upper limbs, and although rest tremor may be seen in some patients it is often accompanied by intention tremor. Apartis et al. [37] reported that total of 86% of patients had tremor,action tremor resembling the tremor of ET in 35% of the patients, cerebellar intention tremor and postural tremor in 29%, and unilateral upper limb rest tremor in 12% in a study of 17 FXTAS patients using tremor recordings from a neuropack device.

The orthostatic tremor, also known as “shaky legs syndrome” was first coined in 1984 by Heilman and is an intriguing and rare condition, characterized by unsteadiness and tremor when standing that is relieved when sitting or walking which primarily affects the legs and trunk. As there are no published population-based epidemiological data, the prevalence and incidence of OT are unknown. In the Neurological Disorders of Central Spain (NEDICES) study [38], one group detected one OT patient in a cohort of approximately 4000 elderly subjects (data not published) [39]. Only recently there was a study reported othostatic tremor in their FXTAS cohort [35]. There is a broad spectrum in differential diagnosis of symptomatic OT, including non-tumoral aqueduct stenosis,chronic relapsing polyradiculoneuropathy, pontine lesions (such as Cavernoma, Tuberculoma), spinocerebellar ataxia type 2, small cell lung cancer, stiff-person syndrome, Graves’ disease and etc. [39] but rarely considering FXTAS. The tremor in both legs in our patient was orthostatic tremor according to the definition [40]. Idiopathic OT manifests with a high-frequency tremor (13–18 Hz). Fast (high frequency) OT may not be visible on routine examination, sometimes be palpable as a fine- amplitude rippling of leg muscles and might be heard noise using a stethoscope on the muscles of the legs but the patients rarely report tremor sensation as a presenting symptom. Slow OT(< 13 Hz) is usually sensed and reported by patients and visible on examination. In our patient it looked like low frequency though we didn’t perform tremor anyalysis with tremorgram. There were other similar condition should be considered to differentiate from OT. Orthostatic myoclonus (OM) could be confused with OT, which also causes unsteadiness on standing and improves with walking or sitting but OM patients usually have non-rhythmic, synchronous and have difficulty in initiate gait. OM patients usually can’t stand for long time because of jerk movement and orthostatic intolerance. Making the distinction between OM and OT requires electrophysiological studies. Unlike OT, the bursts are shorter in duration, non-rhythmic, and irregular. Our patient more likely had OT than OM because of other clinical aspects including the long history of the tremor with function, no fall and without problem of initiating gait.

In our review we found out that 85.2% patients reported tremor,42.6% with intention tremor,36.1% with kinetic tremor,32.8% with rest tremor,29.5% with posture tremor. 37.7% of patients with tremor showed at least two types of tremor. It was interesting that there were 6 patients with isolated rest tremor which was different from previous study [36, 37, 41]. There were 2 patients with voice tremor and 6 with head tremor which hasn’t been addressed before. Orthostatic tremor in associated with FXTAS and our findings in the review will make us better understand the spectrum of tremors in FXTAS.

The premutation is also associated with fragile X-associated primary ovarian insufficiency (FXPOI) in female and full-mutation carriers with over 200 repeats is associated with the Fragile X Syndrome (FXS), which is characterized by childhood-onset intellectual disability, seizures and autism. In western countries the FMR1 premutation occurs in 1/800 males and 1/250 females, with FXTAS affecting 40–45% of male and 8–16% of female premutation carriers over the age of 50 [42]. It is estimated that there are many FXTAS patients in China because of the huge baseline population. From our review of the literature FXTAS was always misdiagnosed with PD,ET,MSA and other types of cerebellar ataxia. That is similar with the conclusion described in previous reports [43]. In mainland of China there were some studies which tried to find out FXTAS patients in many movement disorder cohorts. But there was negative result in screening FMR1 gene within premutaion range in 201 PD,36 ET, 68 sporadic spinocerebellar ataxia, 32 MSA patients and healthy control. But if we select subjects in the individuals with high risk we will find more FXTAS patients. In our review we found out that 74.6% (44/59) FXTAS patients had family history of FXS, FXTAS and/or FXPOI. If we do family investigation in FXS children and FXPOI females we will find more FXTAS patients or premutation carriers.

In summary, we demonstrated orthostatic tremor as a rare potential clinical feature of FXTAS. Our review about the tremor in FXTAS and presentaion with OT in our patient might expand the spectrum of tremor associated with FXTAS. Our study also highlight that family history of FXS, FXTAS and FXPOI can be an important clue to the diagnosis.