Searching patients with familial and/or early-onset parkinsonism, we found similar cases within 3 years. We called the disorder “early-onset parkinsonism with diurnal fluctuation (EPDF)”.

Clinical features of EPDF included: (i) four families, consanguineous marriage in two, with sibling affection; (ii) onset of disease from the ages 17 to 24; (iii) parkinsonism as the main symptom; (iv) diurnal fluctuation of symptoms (alleviation after sleep); (v) mild dystonia, mainly of feet; (vi) hyperactive tendon reflex; (vii) mild autonomic symptoms; (viii) neither dementia nor depression; (ix) good response to antiparkinsonian drugs; and (x) slow progression of the disease. Regarding therapy, anticholinergic drugs were the only thing available at that time. It was several years later that we were amazed at VX-770 nmr the dramatic

effect of levodopa. Extensive 3-MA clinical trial literature study on case records of familial and/or early-onset parkinsonism revealed that Nasu et al.4 alone paid particular attention to alleviation of symptoms after sleep. I came to the view that among early-onset parkinsonism cases reported in the literature, in addition to early-onset cases of idiopathic PD, there would be heterogeneous groups including cases by Siehr,5 Bury,6 Hunt,7 van Bogaert,8 and of Davison9; EPDF could be one of them. What is diurnal fluctuation? Alleviation after sleep is a reversible process of consumption and restoration of some dopamine-related substance. Heredity and early-onset indicate inborn error in the metabolism, and progression of the disease reflects degeneration and neuronal loss of the substantia nigra. I was convinced that EPDF was a new disease. From autumn 1969, I moved to the Department of Neuropathology (Professors Oyake and Ikuta), the Niigata University Brain Research Institute. While training in Niigata, I drew up a manuscript based on my acquired pathological data. The paper “Paralysis agitans of early onset with marked diurnal

fluctuation” appeared in Neurology in 1973.10 I had been abroad to study at the Department of Neuropathology (Professor Krucke), Max-Planck Institute for Brain Research, Frankfurt-am-Main, from 1974 to 1976, and after that, via the Kyoto Prefectural University of Medicine, I was assigned to the Department of Internal Medicine, Hiroshima University Succinyl-CoA in 1978. During the next 12 years, I kept on with my study in Hiroshima and its neighborhood, adding families to my EPDF file. Two decades had past from the initial report without finding any substantial evidence to establish disease entity, while several papers on EPDF were published by Japanese researchers.11,12 My turning point for breaking this deadlock was the Symposium on Hereditary Progressive Dystonia with Marked Diurnal Fluctuation (HPD, Segawa disease) held in Tokyo, 1990. Invited to the Symposium, I presented the results of a follow-up study of EPDF patients in Nagoya.