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Keywords:

  • autosomal recessive inheritance;
  • early-onset parkinsonism;
  • PARK2;
  • Parkinson's disease;
  • substantia nigra

Abstract

  1. Top of page
  2. Abstract
  3. PREFACE
  4. CLINICAL STUDY
  5. DEADLOCK AND RESTART
  6. PATHOLOGICAL STUDY
  7. EPDF FOUND WORLDWIDE
  8. GENE STUDY
  9. EPILOGUE
  10. REFERENCES

Research into familial Parkinson's disease (PD) remained at a virtual standstill in Europe and the US for several decades until a re-challenge by Japanese neurologists regarding an autosomal recessive form of PD. In 1965, our research group at Nagoya University examined familial cases of early-onset parkinsonism characterized by autosomal recessive inheritance, diurnal fluctuation of symptoms (alleviation after sleep), foot dystonia, good response to medication, and benign course without dementia. An inborn error of metabolism in some dopamine-related pathway was suspected. The clinical study of four families with the disease, named as “early-onset parkinsonism with diurnal fluctuation (EPDF)”, was published in Neurology in 1973. The pathological study of a case in 1993 revealed neuronal loss without Lewy bodies in the substantia nigra. Based on these clinical and pathological evidences, EPDF was defined as a distinct disease entity. Screening for the EPDF gene was started in 1994 in collaboration with Juntendo University. With the discovery of parkin gene in 1998, EPDF was designated as PARK2. Of our 16 families examined for gene analysis, 15 proved to be PARK2, and the remaining one, PARK6.


PREFACE

  1. Top of page
  2. Abstract
  3. PREFACE
  4. CLINICAL STUDY
  5. DEADLOCK AND RESTART
  6. PATHOLOGICAL STUDY
  7. EPDF FOUND WORLDWIDE
  8. GENE STUDY
  9. EPILOGUE
  10. REFERENCES

It was acknowledged long ago that Parkinson's disease (PD) occurs rarely in familial aggregations. Willige1 collected 12 cases of early-onset parkinsonism and noted a history of familial occurrence in half of them. He proposed regarding the familial cases as a separate nosological entity under the name of “paralysis agitans juvenilis familialis”, although he failed to find essential symptomatic differences from presenile PD. Mjones,2 through a large epidemiological study, indicated a family aggregation. However, in his report there was no mention of clinical manifestations. Research into this sphere remained at a virtual standstill in Europe and the US for several decades thereafter. The re-challenge to familial PD was the discovery by Japanese neurologists of an autosomal recessive form of PD.

CLINICAL STUDY

  1. Top of page
  2. Abstract
  3. PREFACE
  4. CLINICAL STUDY
  5. DEADLOCK AND RESTART
  6. PATHOLOGICAL STUDY
  7. EPDF FOUND WORLDWIDE
  8. GENE STUDY
  9. EPILOGUE
  10. REFERENCES

In 1964, I joined the Neurology Section (Director, Professor I. Sobue), Nagoya University School of Medicine, Nagoya, Japan. In this section, prominent physicians were all working actively and it was full of creative energy. In October 1965, sisters with parkinsonism were admitted to Nagoya University Hospital. I was appointed to these sisters. This was my first and shocking encounter with a novel disease, later known as PARK2. We were interested in their unusual symptoms: diurnal fluctuation or alleviation of difficulties in moving after sleep. We published the cases in Rinsho Shinkeigaku (Tokyo) in 1968.3 But that was not the end of it. 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 the dramatic effect of levodopa.

Extensive 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

DEADLOCK AND RESTART

  1. Top of page
  2. Abstract
  3. PREFACE
  4. CLINICAL STUDY
  5. DEADLOCK AND RESTART
  6. PATHOLOGICAL STUDY
  7. EPDF FOUND WORLDWIDE
  8. GENE STUDY
  9. EPILOGUE
  10. REFERENCES

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 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.13 Both HPD and EPDF were focused on hereditary extrapyramidal disease with diurnal fluctuation. Dr Segawa clarified the differences between both diseases14 and encouraged me to pursue my study on EPDF.

Following the Segawa Symposium, I proceeded with a clinical survey covering 43 cases of EPDF from 22 families.15–17 Sixteen of the 22 families had a positive family history, and 10 of them had parental consanguinity. There were 10 multiplex families, 11 simplex families and one uniplex family. No patients had a history of parkinsonism in their antecedent or descendant relatives. There was no gender preponderance. We conducted a study to compare patients with diurnal fluctuation (sleep benefit) versus those without, and found the difference in terms of age at onset, initial symptom, progression of the disease, as well as incidence of dystonia, hyperreflexia, and of dopa-induced dyskinesia (Table 1).15,16 This supports the idea that diurnal fluctuation is cardinal in characterizing EPDF, not merely seen by chance in early-onset PD. The magnitude of diurnal fluctuation varied among families and individuals. The phenomenon was marked in earlier stages of the disease, and became less so with increasing age and was masked with the initiation of antiparkinsonian drug therapy. Most patients experienced at least slight improvement after sleep even 30–40 years after the onset. Patients treated with levodopa frequently developed dyskinesia and motor fluctuation, which were alleviated by lowering the dose of levodopa and/or administering other drugs. Three patients developed delusions during levodopa treatment, which persisted even after reduction of levodopa with concomitant use of neuroleptics. The clinical manifestations of EPDF are relatively uniform, without any cognitive disorders or severe autonomic failures. Genetic analysis using the Weinberg's proband method confirmed that EPDF is of autosomal recessive form.17

Table 1.  Clinical features compared between parkinsonism cases with symptomatic diurnal fluctuation (DF) and those without
 Cases with DF (early-onset parkinsonism with diurnal fluctuation)Cases without DFStastistics
n = 43n = 34
  • Chi-square test;

  • ** 

    ** One-way ANOVA;

  • *** 

    *** Two-way ANOVA.

Family history (+)86.0%17.6%*P < 0.001
Age at onset (years)26.1 ± 7.832.7 ± 6.8**P < 0.001
Initial symptom   
 Dystonic gait41.9%5.9%*P < 0.001
 Parkinsonian gait18.6%52.9%*P < 0.001
 Resting tremor30.2%38.2% 
Foot dystonia77.5%38.2%*P < 0.001
Hyperreflexia92.5%55.9%*P < 0.001
Dopa dyskinesia96.9%61.8%*P < 0.001
Hoehn-Yahr stage in duration (years)  ***P < 0.001
 <10 years2.5 ± 0.72.0 
 10–20 years2.2 ± 0.43.0 ± 1.1 
 20–30 years2.6 ± 0.73.3 ± 0.5 
 ≥30 years3.2 ± 0.94.3 ± 0.6 

PATHOLOGICAL STUDY

  1. Top of page
  2. Abstract
  3. PREFACE
  4. CLINICAL STUDY
  5. DEADLOCK AND RESTART
  6. PATHOLOGICAL STUDY
  7. EPDF FOUND WORLDWIDE
  8. GENE STUDY
  9. EPILOGUE
  10. REFERENCES

Pathology is an essential qualification in building disease entities. Prior to our presentation, there were only a few reports on the neuropathology of autosomal recessive parkinsonism. One patient reported by Ota et al.18 was likely the first based on the age of onset, occurrence of the disease in siblings, and consanguineous marriage. However, the authors did not refer to diurnal fluctuation, nor to presence or absence of Lewy bodies in the substantia nigra pars compacta (SNPC). Another case was reported by Mizutani et al.19 with a few Lewy bodies in the SNPC in addition to decreased neuronal melanin. However, this case later proved to be Segawa disease (Yokochi, pers. comm., 2008).

In 1992 one of my EPDF patients died. The patient was a 52-year-old woman from a family with parental consanguinity and two other sisters affected from the same disease. Her disease started at the age of 20. From the initial stage, she noticed symptomatic alleviation after sleep (sleep benefit) which allowed her to do housework for 2–3 h after sleep. Subsequently diurnal fluctuation became less remarkable. Examination at age 37 revealed Hoehn-Yahr stage 4 parkinsonism, foot dystonia and hyperreflexia. She had constipation and hyperidrosis. She was intelligent, enjoying flower arrangement and poetry. She developed no drug-induced psychotic manifestations, and dyskinesia and on–off phenomenon were controlled by reducing levodopa and combination of other drugs. Her parkinsonism had been kept at stage 3 until age 48, and progressed to stage 4 at age 50 accompanied by dysphagia. She died 33 years after the onset.

At autopsy the substantia nigra was markedly discolored (Fig. 1). There was marked neuronal loss in the SNPC, but no Lewy bodies (Fig. 2). The ventral tegmental area (Fig. 3), locus caeruleus, and raphe nuclei were unremarkable, and there were no age-related changes in the neocortex, hippocampus, nor in the nucleus basalis of Meynert. The findings were compatible with absence of depression or dementia. The same was true of mild autonomic manifestations. The dorsal-vagal nucleus and sympathetic ganglia were well preserved. Pathological change was limited almost exclusively to SNPC. I had anticipated these results; however, they were impressive. I published a report to the Rinsho Shinkeigaku (Tokyo) in 1993,20 proposing EPDF as a clinicopathologic disease entity. The following year, Takahashi et al.21 showed identical pathologic changes as ours.

image

Figure 1. The midbrain showing advanced depigmentation of the substantia nigra.

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image

Figure 2. The substantia nigra pars compacta. Except for a few normally pigmented neurons of the nucleus parabrachialis pigmentosus in the right upper area, most of remaining ones of the substantia nigra pars compacta have reduced amounts of melanin pigments and are smaller than normal in size. Hematoxylin-eosin stain, ×160.

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image

Figure 3. The ventral tegemntal area showing no distinct histological changes. Hematoxylin- eosin stain, ×200.

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EPDF FOUND WORLDWIDE

  1. Top of page
  2. Abstract
  3. PREFACE
  4. CLINICAL STUDY
  5. DEADLOCK AND RESTART
  6. PATHOLOGICAL STUDY
  7. EPDF FOUND WORLDWIDE
  8. GENE STUDY
  9. EPILOGUE
  10. REFERENCES

After my initial paper, there had been no reports of EPDF in Western countries, although Gershanik and Leist22 briefly described a young-onset parkinsonian patient with motor fluctuations prior to the institution of levodopa treatment. Dominant inheritance diseases23–26 which had been published in Europe and the US were primarily different from EPDF. I had long harbored a question whether or not EPDF is limited to Japanese people. Fortunately, the answer came from Turkey. At the 4th International Congress of Movement Disorders in Vienna in 1996, I met Dr B. Elibol at my poster presentation site. He spoke to me that he had similar patients at Hacettepe University Hospital in Ankala. Three months later, when I saw Turkish families at his office, I realized that EPDF could have a worldwide distribution.

GENE STUDY

  1. Top of page
  2. Abstract
  3. PREFACE
  4. CLINICAL STUDY
  5. DEADLOCK AND RESTART
  6. PATHOLOGICAL STUDY
  7. EPDF FOUND WORLDWIDE
  8. GENE STUDY
  9. EPILOGUE
  10. REFERENCES

Since the beginning of the 1990s genetic studies have rapidly advanced in the field of neurological diseases. Screening for the EPDF gene was initiated in 1993 by the Department of Neurology, Juntendo University (Professors Hattori and Mizuno), and our collaborative study successfully identified the gene locus for EPDF on 6q25.2-27 in 1994.27 In this connection, one of my patients from Hirosima was found to have deletion of the specific marker D6S306, which led to acceleration of the research operation. After discovery of the novel gene parkin by Kitada et al.,28 EPDF was designated as PARK2. The PARK2 gene produces a protein parkin which functions as one of the E3 protein-ubiquitin ligases to degrade unwanted protein, and mutations of the PARK2 lead to a functional loss of parkin. Of our 16 families examined for gene analysis, 15 proved to be PARK2+,17,29,30 and the other, PARK6.31 Recent studies suggest that, unlike autosomal-dominant types of PD which are limited to specific pedigrees, EPDF is identified in many countries and many races.32–35 Although a number of atypical cases have been reported, the core phenotype of PARK2 appears essentially the same as we reported in 1973. As for the pathophysiologies of PARK2, there remain yet many problems to be elucidated.

EPILOGUE

  1. Top of page
  2. Abstract
  3. PREFACE
  4. CLINICAL STUDY
  5. DEADLOCK AND RESTART
  6. PATHOLOGICAL STUDY
  7. EPDF FOUND WORLDWIDE
  8. GENE STUDY
  9. EPILOGUE
  10. REFERENCES

In 2008, PARK2 is awarded as one of the “Diseases established in Japan” at The 50th Anniversary for the Japanese Society of Neuropathology. PARK2, one of the hereditary PDs, is widely known among neurologists and those who study neurology today. Devoting nearly 30 years to PARK2 before its acknowledgement, I am honored to write this essay for my junior fellows.

I have enjoyed various experiences as a neurologist, especially my close relationship with this difficult and fascinating disease, EPDF.

EPDF was in tune with of times. In the era from 1960s to early 1970s, when I first encountered EPDF, parkinsonism-dementia complex on Guam, striatonigral degeneration, progressive supranuclear palsy, congenital muscular dystrophy (Fukuyama), Segawa's disease, and subacute myelo-optico-neuropathy (clioquinol intoxication), significant diseases of today, were established as disease entities. The features of EPDF were conspicuous enough to move a young neurologist to the frontiers of neurology.

I had imagined EPDF to be a dopamine-related inborn error of metabolism, but never imagined the cause of the disease would be identified in the genes. Two decades later EPDF has become one of the hottest topics of the times again. Genes of neurological diseases were identified one after another in the 1990s. Close collaboration among multiple research groups in Japan could afford the speedy exploration of PARK2. Studies on the molecular mechanism of selective neuronal degeneration in PARK2 are opening up new strategies to investigate the pathogenesis of sporadic PD, as well as other neurodegenerative diseases.

The study of neurological diseases will further progress with gene studies and regenerative medicine. However, it begins with clinical neurology and neuropathology, and the notion that studies and research findings are for patients will never change.

REFERENCES

  1. Top of page
  2. Abstract
  3. PREFACE
  4. CLINICAL STUDY
  5. DEADLOCK AND RESTART
  6. PATHOLOGICAL STUDY
  7. EPDF FOUND WORLDWIDE
  8. GENE STUDY
  9. EPILOGUE
  10. REFERENCES
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