Dopamine transporter imaging study in parkinsonism occurring in fragile X premutation carriers

The fragile X premutation is caused by an expansion of 55 to 200 repeats of the trinucleotide element (CGG)_n located in the 5′ UTR of the fragile X mental retardation 1 (FMR1) gene. A syndrome characterized by tremor, parkinsonism, and ataxia (FXTAS) has been described in association with the fragile X premutation.^1,2 The prevalence of such a premutation in groups of patients affected by movement disorders needs to be clarified.^3–8 In this study, we investigated nigrostriatal dopaminergic function in vivo using dopamine transporter (DAT) imaging in four patients who were carriers of the fragile X premutation with clinical parkinsonism.

Methods.

Patient 1 was a 75-year-old married man with no children with a 5-year history of progressive action tremor and dysmetria (more in the right arm), ataxia, and mild parkinsonism. A computerized analysis of the eye movements showed cerebellar impairment, autonomic tests (Valsalva test and tilt test) were abnormal, motor evoked potentials and somatosensory evoked potentials suggested pyramidal and coronal impairment, cranial MRI showed a symmetrically increased T2 signal in the middle cerebellar peduncles with expansion to the white matter of the cerebellar hemispheres, and genetic assays for spinocerebellar ataxia (SCA) were negative. The genetic assay for the FMR1 allele showed an expansion of 105 CGG. The score of the clinical rating scale for tremor was 14, the score on the Unified Parkinson’s Disease Rating Scale (UPDRS) motor section was 10, and the score on the International Cooperative Ataxia Rating Scale (ICARS) was 14.

Patient 2 was a 76-year-old married man with two children with a 2-year history of mild progressive action tremor and postural instability. Genetic testing revealed an expansion of 73 CGG triplets in the FMR1 gene. He also had two grandsons with mental retardation and fragile X syndrome. His neurologic examination showed mild postural and action tremor (more on the left side), mild bradykinesia of the upper limbs (left > right), no rigidity, and no resting tremor. His gait was normal, but he could not walk in tandem and the pull test was altered. Neuropsychological testing revealed normal cognitive status. The score on the clinical rating scale for tremor was 17, the score of the UPDRS motor section was 12, and the score on the ICARS was 15. Brain MRI showed no signal abnormalities in the middle cerebellar peduncles or in the cerebellar hemispheres; however, very mild cortical atrophy was present.

Patient 3 was a 52-year-old man with a 2-year history of gait disorder, irregularity of steps, lateral veering, inability to walk without assistance, dysarthria, nystagmus evoked in lateral gaze in both directions, mild dysmetria, urge incontinence, orthostatic hypotension, and mild cognitive impairment. Cranial MRI showed olivopontocerebellar atrophy and mild cortical atrophy; genetic assays for different SCAs were negative. Tilt testing confirmed orthostatic hypotension, and neuropsychological tests showed alterations in attention and short-term memory tasks. Motor response to the l-Dopa acute challenge test (200 mg orally) was negative. The score on the UPDRS motor section was 14. The genetic assay for the FMR1 allele showed an expansion of 85 CGG.

Patient 4 was a 71-year-old man with a grandchild with fragile X syndrome with a 10-year history of intentional tremor of the right arm, complicated by resting tremor in the past 3 years. He had had mood disorders for the previous 20 years and memory problems for 5 years. He was diagnosed with Parkinson disease (PD), but the acute or chronic response to levodopa was poor (the score on the UPDRS motor section was 16). Brain CT scan showed cortical atrophy and diffuse white matter lesions. The genetic assay for the FMR1 allele showed an expansion of 97 CGG.

In addition to routine clinical examination, all patients were videotaped and blindly evaluated by two neurologists who are experts in movement disorders (A.A., U.B.) who graded the presence and severity of parkinsonism.

Results.

In our patients with FXTAS, parkinsonism was mild to moderate (the score on the UPDRS motor section ranging from 10 to 16) and the response to dopaminergic therapy was poor or absent (table).

The uptake of [¹²³I]FP-CIT (semiquantitative measure as specific/nonspecific binding ratio) in patients with FXTAS was similar to that reported in healthy subjects in the putamen (FXTAS: right [mean ± SD] 2.52 ± 0.19; left 2.47 ± 0.13; controls: right 2.30 ± 0.26, left 2.36 ± 0.24) and in the caudate nucleus (FXTAS: right 2.63 ± 0.13, left 2.69 ± 0.12; controls: 2.60 ± 0.21, left 2.58 ± 0.35). Because the motor impairment as assessed by UPDRS was mild to moderate in our patients, seven patients with PD with mild parkinsonism were chosen as pathologic controls (UPDRS 10.6 ± 1.5). In this mild PD group, the uptake measures were 1.43 ± 0.39 for the right putamen, 1.35 ± 0.25 for the left putamen, 1.95 ± 0.15 for the right caudate, and 1.88 ± 0.20 for the left caudate. These values were lower in all striatal areas vs the results obtained in the FXTAS group and in the healthy controls (p < 0.005) (figure).

• Download figure
• Open in new tab
• Download powerpoint

Figure. [¹²³I]FP-CIT SPECT images obtained in a fragile X premutation carrier with parkinsonism (tremor, parkinsonism, and ataxia), a patient with PD at Hoehn and Yahr stage 2 (maximum 5), and a healthy control.

Discussion.

The pathophysiology of parkinsonism occurring in FXTAS is not well known. Neuroimaging studies carried out on fragile X premutation carriers have shown a reduction in volume of cerebellar and cerebral cortex and an increase in the hippocampal volume.⁹ Interestingly, a decrease in the volume of the bilateral caudate nuclei in a group of fragile X premutation female carriers was also reported.¹⁰ This evidence supporting the involvement of basal ganglia could contribute to the explanation of the occurrence of parkinsonism in FXTAS. In our FXTAS patients with parkinsonism, a normal striatal [¹²³I]FP-CIT uptake was observed, suggesting the preservation of presynaptic nigrostriatal dopaminergic nerve terminals in these subjects. Our findings indicate that parkinsonism in FXTAS patients could be caused by dysfunction involving the nigrostriatal pathway at the postsynaptic level or different neurotransmitter systems. This hypothesis is consistent with the poor or absent response to dopaminergic therapy reported in our patients, although some degree of levodopa response, moderate or transient, has been reported in a minority of FXTAS patients.¹

Patients with tremor, ataxia, or parkinsonism have been screened for the fragile X premutation in other studies.^3–8 Whereas 4 to 5% premutation has been reported in ataxia patients, indicating the utility of this analysis in the molecular investigation of ataxia,^7,8 only a few studies have been performed on subjects with movement disorders. Our findings suggest that genetic screening for the fragile X premutation should be carried out on those patients with parkinsonism otherwise unexplained with a negative DAT imaging study. Our study population was small; thus, no definitive conclusion regarding the molecular basis of parkinsonism in the fragile X premutation can be made; our observations warrant further study in larger populations.