Atypical juvenile parkinsonism in a consanguineous SPG15 family

Mancozeb is a ethylene-bis-dithiocarbamate (EBDC) fungicide that contains zinc and manganese. In humans, chronic EBDC inhalation has been associated with neurocognitive impairment and parkinsonism while acute intoxication elicit reversible headache, dizziness, and seizures in a few cases, all of which were rapidly reversible. We report a case of severe and reversible parkinsonism in a man after the accidental oral ingestion of mancozeb. A 55-year-old man with history of alcohol abuse was admitted with a 4 days alcohol withdrawal. At examination, he was found to be alert, oriented, and showed postural tremor and diaphoresis. Treatment with tiapride (300 mg/day during 4 days) and thiamine was started. On the fourth day of hospitalization, he was diagnosed of acute cholecystitis and was surgically treated. Seven days later, he was found to be confused. At physical examination, the patient was alert, slow minded, and disoriented. He had a masked facies (video, segment 2) dysarthria and hypophonia resulting in his speech being unintelligible. He was noted to have poverty and slowness of movements (video, segment 2) and generalized cogwheel rigidity (video, segment 1), particularly in the jaw. His posture was stooped and he was unable to walk without assistance (video, segment 3). Bilateral resting tremor and isolated reflex myoclonus were observed. Startle reflex was pathologic. All deep tendon reflexes were brisk. He recognized having intake accidentally 5 g of a vegetable fungicide containing mancozeb. Laboratory test showed normal concentrations of blood glucose, creatinine, alkaline phosphatise, total bilirrubin, aspartate aminotransferase, and alanine aminotransferase level. c-Glutamyl transferase was 112 U/L (normal range 6– 38). Hepatitis B and C serologies were negative. Serum ammonium was within normal range but serum or urine manganese was not assessed. Cerebral magnetic resonance (MR) showed moderate generalized atrophy. Electroencephalogram was normal. SPECT examination using [I]FP-CIT showed a normal dopamine transporter (DAT) uptake in both putamen. Levodopa–carbidopa therapy was initiated with no motor improvement and was interrupted few weeks later. During the following 8 months, the neurological symptoms spontaneously remitted and 16 months later, he was still abstinent and without signs of parkinsonism. This patient manifested clinical features of subacute parkinsonism during a period of alcohol withdrawal and after the accidental oral intake of the EBDC fungicide mancozeb, which contains manganese. Accordingly, our patient showed the typical clinical features of manganese intoxication, particularly myoclonus, speech dysfunction, and postural instability. Exposure to the manganese-containing EBDC fungicide maneb has been found to produce parkinsonian-like symptoms in agricultural workers. In mesencephalic dopaminergic and gabaergic neuronal cell cultures, mancozeb has been proved to be neurotoxic and both the organic component and the manganese ion were found to contribute to the toxicity. Besides the toxic effect of mancozeb, two other potential mechanisms of parkinsonism should be considered in this patient. The influence of tiapride on the appearance of parkinsonism was ruled out as it was administered during a short period of time. As he had a history of alcohol abuse, a liver failure could have contributed to the development of the symptoms. Hepatic dysfunction has been associated with increased signal intensity in the pallidum on T1-weighed MR images, presumable related to elevated blood manganese levels and this fact has been proposed as the main mechanism in the pathogenesis of acquired hepatolenticular degeneration. Nevertheless, the normal hepatic function and plasma ammonium levels and the absence of T1-weighed MR hyperintensities in the pallidum rule out this possibility. The second possible pathogenic mechanism could be alcohol withdrawal. Parkinsonism due to ethanol withdrawal has been previously reported although its intrinsic mechanisms remain unclear and some authors have suggested that could be the result of an acute but reversible abnormality of nigrostriatal dopamine transmission due to either presynaptic dopamine deficiency or a reduction of postsynaptic dopamine receptor sensitivity. We speculate that on the ground of the possible effect of ethanol withdrawal on dopamine turnover, the toxic action of mancozeb on the nigrostriatal system could have been potentiated leading to the development of parkinsonian symptoms. Therefore, mancozeb could have exerted either a functional blockade of postsynaptic receptors or a functional inhibition of the nigrostriatal dopaminergic system as the MR and striatal uptake of DAT did not show structural alterations in the basal ganglia. In addition, the reversibility of symptoms supports the hypothesis of a dysfunction of the nigrostriatal pathway in the origin of parkinsonism. The possibility that mancozeb would have induced the same dysfunction in the absence of alcohol withdrawal cannot be elucidated from this observation. To our best knowledge, an acute parkinsonism as a consequence of accidental oral intake of mancozeb has not been previously reported.