Progressive supranuclear palsy and pawpaw

PRACTICAL IMPLICATIONS

Consider consumption of annonacin-containing plant products, including pawpaw, as a possible environmental risk factor for atypical parkinsonism.

Consumption of annonacin-containing plant products has been linked to increased prevalence of atypical parkinsonism in previous studies of tropical-dwelling populations. We describe a case of possible progressive supranuclear palsy-speech-language variant (PSP-SL) in a patient in the Northeast United States who habitually consumed annonacin-containing pawpaw fruit.

Case

An 80-year-old white man was initially evaluated for a complaint of effortful speech for 2 years prior to presentation. He also noted mild balance impairment without falls. Examination revealed halting but grammatical speech with paraphasic errors and decreased letter fluency, mild dysarthria, and speech and ideomotor limb apraxia. There were square-wave jerks, as well as partial upgaze restriction and vertical saccade slowing on optokinetic and gross testing. There was axial and symmetric limb rigidity and mild bradykinesia, decreased right arm swing with dystonic arm posturing, and no notable impairment of ambulation or postural instability. He reported no improvement in symptoms with levodopa. Brain MRI demonstrated midbrain atrophy (midbrain-to-pons ratio 0.41) and moderate generalized cortical atrophy (figure). He was diagnosed with nonfluent primary progressive aphasia, later reclassified as a subtype of progressive supranuclear palsy, meeting diagnostic criteria for possible PSP-SL.¹ In the years following his presentation, he experienced progressive language impairment and bulbar symptoms (dysphagia, anarthria) with a relative preservation of gross motor function as well as worsening supranuclear vertical gaze palsy. The patient died due to aspiration 5 years after symptom onset. Subsequently, his wife disclosed that he had habitually consumed pawpaw fruit from their family-owned nursery, starting 5 years prior to symptom onset and continuing until his death (10 years total). She estimated that he had consumed up to 13.6 kg of raw fruit annually over the five-year period prior to death.

Figure. MRI.

MR imaging of the brain, performed approximately 2 years after symptom onset. Midline sagittal T1-weighted image demonstrates midbrain atrophy. Diffuse cortical atrophy was also evident.

Discussion

Annonacin is a selective inhibitor of mitochondrial complex I, and potently induces neuronal death by adenosine triphosphate depletion.² Intravenous infusion of annonacin in rats induces degeneration of the nigrostriatal system and brainstem nuclei with more modest involvement of the cerebral cortex, hippocampus, and cerebellum, in a distribution pathologically similar to PSP.³

Annonacin is present in the fruit, leaves, and bark of plants belonging to the Annonaceae family, which includes Annona muricata (soursop) and Asimina triloba (pawpaw).⁴ Pawpaw is native to the eastern United States and southern Canada and is the only fruit-bearing annonaceous plant widely distributed in North America. A recent regional increase in pawpaw's popularity is concerning in light of studies demonstrating the neurotoxicity of annonacin as well as possible associations with the development of neurodegenerative disease. A 1999 case–control study in Guadeloupe described an association between regular consumption (at least monthly, for at least 2 years) of fruit and tea from annonaceous plants and diagnosis of an akinetic-rigid parkinsonian disorder resembling PSP, with the PSP-like patients more likely to have reported routine consumption of these plant products compared to patients with Parkinson's disease (odds ratio 5.98, 95% CI 1.05–34.22).⁵ This study also reported an unusual prevalence of atypical parkinsonism in this population: of 87 consecutive patients presenting with parkinsonism, only 25% presented as idiopathic Parkinson disease. A smaller 2004 study also described a high proportion of atypical parkinsonism in New Caledonia and noted a higher percentage of habitual Annonaceae consumers in the atypical parkinsonism group.⁶ This association has therefore been noted in 2 genetically distinct populations, making the possibility of a common environmental exposure more compelling. The authors report that the plant products consumed in these regions are derived from A. muricata, Annona squamosa, and Annona reticulata. Notably, annonacin represents 0.007% of pawpaw fruit pulp by weight, which is higher than other analyzed sources (soursop pulp contains only 0.002% annonacin).⁴

Although this case of possible PSP-SL presents an opportunity to highlight the possible association between pawpaw and atypical parkinsonism, this patient did not match the clinical syndromic presentation (akinetic-rigid, postural instability) of previously studied populations. While phenotypic diversity (including dystonia, motor neuron disease, and cerebellar ataxia) was present in the Guadeloupean patients, cortical-predominant syndromes have not previously been described in association with annonacin consumption.⁵ In addition to experimental evidence showing cortical neuronal toxicity with annonacin infusion in rats, a study of parkinsonian patients in Guadeloupe described radiographic cortical atrophy in most of the PSP-like patients, along with temporoparietal symptoms in several subjects (including aphasia in one individual).^3,7 This case potentially expands the phenotypic range of annonacin-associated parkinsonism. Further study is necessary to better understand the relationship between consumption of fruits such as the increasingly popular pawpaw and neurodegenerative presentations.

Appendix. Authors

Study funding

No targeted funding reported.

Disclosure

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