Older-onset levodopa-responsive parkinsonism with normal DAT-SPECT and pterin hypometabolism

Background

Levodopa-responsive parkinsonism is specified in the diagnostic criteria of Parkinson’s disease (PD); patients with symptomatic parkinsonism other than PD respond poorly to dopamine replacement therapy.1–3 Another key feature for PD diagnosis is decreased striatal uptake in dopamine transporter single-photon emission computed tomography (DAT-SPECT), which reflects dopaminergic neuronal loss in the striatum.1 In clinically suspected cases of PD, normal DAT-SPECT results are known as scans without evidence for dopaminergic deficit (SWEDD). Possible explanations for SWEDD include vascular or drug-induced parkinsonism, psychogenic conditions and GTP cyclohydrolase 1 (GCH-1)-deficient dopa-responsive dystonia (DRD).4 5

Pterin is involved in the process of dopamine biosynthesis,6–9 and patients with abnormalities in pterin metabolism respond well to levodopa therapy.3 6 8–10 However, this condition is not accompanied by dopaminergic neuronal degeneration or Lewy body pathology; therefore, it does not meet the diagnostic criteria for PD. Pathogenic mutations or deletions in the GCH-1 gene are known to cause GCH-1-deficient DRD, which mediates pteridine hypometabolism. In addition, reduced cerebrospinal fluid (CSF) concentrations of total biopterin (BP) and total neopterin (NP), which are both by-products of the GCH-1 reaction, can be used as diagnostic biomarkers of GCH-1-deficient DRD even in individuals without identifiable pathogenic GCH-1 mutations or deletions.6–9 GCH-1-deficient DRD usually develops dystonia at 4–8 years of age, and often presents pediatric dystonia-parkinsonism.11 In contrast, there have been recent reports of adult-onset DRD cases with pathogenic GCH-1 variants and normal DAT-SPECT imaging who presented predominantly extrapyramidal symptoms (similar to those observed in PD) and were clinically diagnosed with PD before detailed biological examinations, including pterin metabolism.10 These findings indicate that abnormally low pteridine metabolism is one of the differential diagnoses for adult-onset atypical parkinsonism, including SWEDD.

Here, we report a unique case of older-onset extrapyramidal symptoms, who showed an excellent response to levodopa but had normal DAT-SPECT results. It is noteworthy that a characteristic pattern of pterin hypometabolism, similar to that of GCH-1-deficient DRD, was identified in this case, even though the patient had no dystonia. This case highlights the importance of pterin analysis in the diagnosis of older-onset levodopa-responsive parkinsonism.

Case presentation

An 81-year-old woman was admitted to our hospital because of the gradual onset of a festinating gait and tremor of the right hand. At the age of 79, her walking speed became slower. Her right hand began trembling intermittently 6 months before hospitalisation, and 4 months prior to admission, she noticed the development of forward flexion and a festinating gait. She was then admitted to our hospital. During the course of the disease, the patient was not aware of any olfactory deficit or hallucinations, and she had no stroke episodes. No similar symptoms were reported in any family members. The patient had no history of cognitive and behavioural deficits.

On her admission examination, the patient was diagnosed with bilateral knee osteoarthritis. A neurological examination revealed normal consciousness, and there was no obvious cognitive and behavioural deficits, such as memory, attention, executive functioning and social behavioural disorders. The patient’s Mini-Mental State Examination score was 28/30, and her Frontal Assessment Battery score was 14/18. The patient exhibited hypophonic speech and a mask-like face, but had no other abnormalities in the cranial nerves, including ocular movement. Lead-pipe rigidity (predominantly on the right side) and axial rigidity were observed. There were no symptoms of dystonia, and no obvious pathological reflexes were noted. However, a mild postural tremor in the right hand and an amplitude decrement in finger tapping in both hands were confirmed. The patient was observed to have decreased arm swing on her right side, a small-stepped gait and a mildly disturbed postural reflex. The patient’s sensory, coordination and autonomic nervous systems were all intact except for mild constipation, and her Unified Parkinson’s Disease Rating Scale Part 3 (UPDRS-III) score was 24.

Investigations

Laboratory data, including renal function, thyroid function and serum copper levels, were normal. Brain MRI demonstrated no obvious abnormalities. In ¹²³I-metaiodobenzylguanidine (MIBG) imaging of the epicardium sympathetic innervation, uptake was preserved; the heart-to-mediastinum (H/M) ratio was 3.40 in the early phase and 3.49 in the late phase. Brain ¹²³I-iodoamphetamine SPECT imaging revealed slight hypoperfusion in the bilateral frontal lobes. DAT-SPECT imaging revealed that dopamine transporters were well preserved in the striatum (figure 1A). The patient showed a clear improvement on levodopa administration (described in the Treatment section) and was diagnosed with SWEDD, raising the possibility that dopamine deficits in preserved striatal nerve terminals may be caused by disturbances in pteridine metabolic pathways.

To narrow the differential diagnosis, a spinal fluid examination was performed after several days of levodopa withdrawal, revealing that CSF homovanillic acid (HVA, a dopamine metabolite) was 50.4 nmol/L and CSF 5-hydroxyindoleacetic acid (5-HIAA, a serotonin metabolite) was 16.5 nmol/L. These values were both lower than the normal reference ranges (HVA 115–488 nmol/L; 5-HIAA 66–141 nmol/L),12 indicating reduced dopamine and serotonin levels in the brain. Blood and CSF pterin were therefore measured (table 1). In the CSF pterin analysis, both NP and BP were below the normal reference ranges (see table 1).6–8 13–16 In particular, the CSF concentration of BH4 (tetrahydrobiopterin, the active type of BP) was markedly decreased (0.41 nmol/L) compared with that of normal adult controls (17.7±1.69 nmol/L13, 16.1±3.5nmol/L7) and patients with PD (8.9±0.95 nmol/L13). The ratio of BH4 to BP in the CSF was reduced to 8%, which is a marked reduction considering that most BP in the brain exists as BH4 (normally more than 70%).6–8 Blood phenylalanine and tyrosine were normal (table 1). GCH-1 gene analysis detected no mutations or deletions using either the direct sequencing method or the multiplex ligation-dependent probe amplification method.

Differential diagnosis

The patient gradually developed extrapyramidal signs, such as bradykinesia, tremor, limb rigidity, a forward-bent posture and mild postural instability, over 2 years. Pyramidal tract signs, cerebellar ataxia, gaze palsy, cognitive decline, psychosis, sensory disturbance and severe autonomic failure were absent, thus ruling out the possibility of atypical parkinsonism, such as progressive supranuclear palsy, corticobasal degeneration or multiple system atrophy. The patient had no history of medication causing extrapyramidal symptoms, and none of her relatives had similar symptoms. She showed a clear improvement on levodopa administration without a reduction in striatal uptake in DAT-SPECT. We therefore considered that the patient had SWEDD, which excludes the possibility of PD and suggests the involvement of the dopamine biosynthesis pathway.1

The low HVA and 5-HIAA levels in the CSF indicated that both dopamine and serotonin concentrations were reduced in the patient’s brain. Reduced NP in the CSF excluded the possibility of sepiapterin reductase deficiency, tyrosine hydroxylase deficiency and 6-pyruvoyl tetrahydropterin synthase deficiency. The low levels of CSF NP and BP, the markedly low levels of CSF BH4 and the normal blood phenylalanine and tyrosine levels (table 1) excluded the possibility of hyperphenylalaninaemia or BH4 deficiency. These findings indicate that the patient had GCH-1-related pterin hypometabolism (figure 2), although no mutation or deletion was detected by conventional GCH-1 gene screening. Low pterin hypometabolism reported in the patients with neurodegenerative diseases such as sporadic PD or Alzherimer’s disease is less severe than this case,13–17 which further indicates the involvement of pterin hypometabosim for parkinsonism of this patient.

Treatment

Low-dose levodopa/carbidopa administration, of 150 mg/day, produced a marked improvement in rigidity, postural tremor, bradykinesia, gait disturbance and postural reflex in the patient. Her UPDRS-III score decreased from 24 to 11.

Outcome and follow-up

After being discharged from the hospital, the patient’s parkinsonism gradually progressed, and her levodopa/carbidopa dose was increased to 400 mg/day. At 1 year and 4 months after discharge, she retained a postural reflex, normal eye movement, normal cognition and the beneficial effects of levodopa. Her UPDRS-III score was 19. Her striatal uptake in DAT-SPECT (figure 1B) and MIBG cardiac sympathetic nerve uptake were still preserved at 2 years after the first scan. The 2-year follow-up MRI of the brain exhibited no obvious change. Given normal imaging studies, PD and atypical parkinsonism should be ruled out as the cause of her levodopa-responsive parkinsonism.