Abstract
Juvenile-onset dystonia that improves after levodopa may occur in both dopa-responsive dystonia (DRD) and juvenile parkinsonism (JP), clinically similar conditions with different prognoses and management goals. The authors show normal striatal uptake of the dopamine transporter ligand FP-CIT with SPECT in a clinically atypical case of DRD, in contrast to the reduced uptake observed in JP.
Juvenile-onset dystonia usually leads to progressive disability with limited therapeutic options. Wilson’s disease and dopa-responsive dystonia (DRD) are important treatable exceptions. DRD has been linked to mutations in the genes for the enzymes guanosine triphosphate cyclohydrolase (GTP-CH) and tyrosine hydroxylase (TH) in the dopamine synthetic pathway. It is typically characterized by childhood-onset gait disturbance with diurnal variation in symptoms and dramatic, sustained response to low doses of levodopa.1
Lower limb dystonia that improves with levodopa is also common in juvenile parkinsonism (JP) resulting from depletion of nigrostriatal dopaminergic neurones. Although sometimes difficult, early clinical differentiation between DRD and JP has important prognostic and therapeutic implications because, in contrast to DRD, JP is usually progressive, requires increasing levodopa doses, and is often associated with disabling motor response fluctuations and drug-induced involuntary movements. [123I]-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)- nortropane (FP-CIT) is a new SPECT ligand that binds to the presynaptic dopamine transporter (DAT).2 We report an atypical presentation of DRD in which normal FP-CIT SPECT provided strong support for the diagnosis.
Case report.
At age 17, the patient experienced mild involuntary inversion of the right foot after prolonged walking, which resolved completely when she avoided excessive exercise. Three years later, she developed rest and action tremor in all limbs, particularly the arms, with a right-sided predominance, and mild cramping of the right hand during writing. She had no other neurologic symptoms or diurnal variation in her symptoms.
One sister developed postural and rest tremor of both arms at age 12 years, associated with cervical dystonia that subsequently generalized. Her mother had experienced the onset of irregular, sometimes rhythmic jerks of both lower limbs from the age of 17. Both sister and mother improved considerably with relatively low doses of levodopa. Another sister developed irregular jerks of one arm at age 19 years, then a fine resting tremor of the same arm and mild cramps in the ipsilateral foot 10 months later. A maternal uncle had a mild dystonic head tremor, particularly on exertion, and occasional dystonic posturing of one foot developing in his late teens. Her maternal grandmother experienced isolated postural arm tremor in her teens and mild tremor-dominant parkinsonism in later life that responded well to levodopa. 18F-dopa PET was performed on both sisters, and striatal uptake was within the normal range.
Examination at age 22 years showed bilateral arm tremor at approximately 6 Hz, more marked at rest than with posture, without other features of parkinsonism or dystonia. Serum phenylalanine but not tyrosine increased after an oral phenylalanine load (100 mg/kg) with a serum phenylalanine/tyrosine ratio at 1 hour of 14.8 (normal range, 2.8 to 6.4).3 Levodopa/benserazide 100/25 mg three times daily was started, and within 2 days she experienced marked tremor reduction.
Twelve months later, she remained completely free of symptoms while taking levodopa/carbidopa 150/37.5 mg daily in two divided doses. A SPECT scan was performed with a single-slice brain-dedicated tomograph (SME 810) 3.5 hours after IV FP-CIT (178 MBq). Radioactivity uptake for the caudate and the anterior and posterior putamen compared with nonspecific uptake in occipital cortex was expressed as a ratio and compared with nine normal volunteers between the ages of 22 and 35 years, and with a 39-year-old woman with a 20-year history of progressive levodopa-responsive JP with early foot dystonia, and subsequent motor response fluctuations and dyskinesias (figures 1 and 2). The uptake ratios for each striatal region were within the normal range for the patient with DRD. In contrast, the patient with JP had depressed putaminal uptake ratios, typical of the pattern in adult-onset PD.
Figure 1. Radioactivity ratios for the patient with dopa-responsive dystonia (22-year-old woman; filled circles), a patient with juvenile parkinsonism (39-year-old woman; gray circles), and normal volunteers (mean ± SD; white circles). CN = caudate nucleus; AP = anterior putamen; PP = posterior putamen.
Figure 2. Axial FP-CIT brain images of (A) a normal volunteer (27-year-old woman), (B) the patient with dopa-responsive dystonia (22-year-old woman), and (C) a patient with juvenile parkinsonism (39-year-old woman) (subject’s right is on reader’s left).
Discussion.
The clinical presentation in this patient highlights difficulties in differentiating DRD from JP. The onset of mild and transient dystonia at the age of 17 years is atypical for DRD, which usually starts before the age of 12 years, with lower limb dystonia that is worse in the evening and progressively involves other body parts.1 Postural tremor is unusual early in the course of the DRD, and rest tremor is rare, except in occasional family members presenting with relatively pure adult-onset parkinsonism.
A diagnosis of DRD can be confidently made in this patient in view of her family history and the results of the phenylalanine loading test.3 Family history or detectable mutations of the GTP-CH or TH genes are absent in half the cases of DRD, and false-negative phenylalanine loading tests results have been reported.1 Measuring CSF neopterin and tetrahydrobiopterin may prove to be a more sensitive, although not widely available, diagnostic test.
Striatal binding of 18F-Dopa by using PET is normal in DRD but reduced in JP4; however, the expense and limited availability of PET precludes widespread clinical application. Normal DAT binding also has been reported in a few cases of typical childhood-onset DRD by using SPECT and FP-CIT5 or [123I]-2β-carbomethoxy-3β-(4-iodophenyl)-tropane (β-CIT), a related ligand with a longer half-life, necessitating imaging the day after injection.6,7⇓ The current case supports these studies and suggests that clinically atypical DRD also can be distinguished from JP by using SPECT. Although the disease duration was longer in our patient with JP, significantly reduced striatal uptake of FP-CIT has been shown bilaterally in patients with very early PD, including those with hemi-parkinsonism.2 Imaging of DAT binding with SPECT has not, to our knowledge, been compared in patients with early JP and DRD. Because scanning can be performed within 4 hours of FP-CIT injection, this technique provides a practical noninvasive tool to assess the nigrostriatal dopaminergic pathway. In addition to differentiating DRD from JP, it may be useful in other cases with diagnostic uncertainty, including atypical tremor and neuroleptic-induced or psychogenic parkinsonism.8
Acknowledgments
Acknowledgment
FP-CIT was provided free of charge by Nycomed–Amersham, plc.
- Received June 1, 2000.
- Accepted September 28, 2000.
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