神経内科CPCがMGHのCPCと同じようなスタイルで進められた。しかし、新しいことを学んでいこうと思っていた僕としては、CPCのdiscussantとして新潟大学の河内先生がスライドを使用せずに口頭で説明したことに対して大いなる不満を感じた。MGHのCPCはNEJMに掲載され、レベルの高い鑑別診断が展開され、Clinical Diagnosisが提示される。今回のCPCが臨床神経学に掲載されるなら、納得できるが、そのようなアナウンスメントはなかった。

2009年の日本神経感染症学会で初めての試みで、neuro-CPCが開催されたが、僕がdiscussantに選出された。16歳時に複視とふらつきで発症後,急速に進行した症例で、google scholarにkey wordを入力し、入手可能な必要文献をとりよせた。最終診断は正解したので、ほっとした。日本で初の10歳台発症の遺伝性プリオン病であった。自治医科大学の症例であり、詳細に検査が行われていた。当時には記載されていない遺伝性プリオン病ではないかと推定し、その後の文献を集め、レビューを行った。

日本神経学会の症例は40歳台の女性で家族に同様疾患があり。パーキンソン病症状とうつ症状を呈し、約2年間の経過で中枢性低換気による呼吸不全にて死亡した。あまりにも経過が早いので、何の病気かなと思ったが、河内先生がまず第1にPerry症候群を鑑別にあげた。Perry syndromeか!以前に福岡大学の坪井先生が講演されたことを思い出した。急速に進行するパーキンソン症候群と中枢性低換気の2つのキーワードを入れると、この疾患が出てくる。でも、これなら、それほど難しい診断ではなさそうだ。錐体路症状がみられることや、SPECTで前頭側頭部(記憶不確か)の血流低下があり、河内先生は、FTDを鑑別にあげ、また、遺伝性PDも鑑別にあがった。以前にパーキンソン症候群で初発したPML例を経験したときに、パーキンソン病の診断についての総説を読んだことを思い出した(この症例は英語で症例報告を行った。Efficacy of mefloquine to progressive multifocal leukoencephalopathy initially presented with parkinsonism. Clinical neurology and neurosurgery, 2012, 114: 728-731.日本でのPML治療ガイドラインが最近発表されているが、何故かはわからないが、僕の論文は引用されていなかった )。i-PADのGoodReaderに文献をたくさんPDFとして入れてあるので、早速開いた。Tolosaの総説でsecondary Parkinsonismとして、下記の疾患が記載されていた。この総説の唯一の欠点は、Perry症候群を鑑別診断の中に入れていなかったことである。

Tolosa E, Wenning G, Poewe W. (2006). The diagnosis of Parkinson’s disease. The Lancet Neurology 5: 75-86.

Panel 1: Secondary parkinsonism



Encephalitis lethargica and other viral infections (eg, AIDS, PML)

Prion disease




Carbon monoxide


Carbon disulphide




Drug induced

Dopamine-receptor blockers

Classic neuroleptics (eg, phenothiazines, butyrophenones)

Atypical antipsychotics (eg, risperidone, olanzapine)

Dopamine-depleting drugs (eg, tetrabenazine)

Other drugs (eg, valproic acid, calcium channel blockers)

Brain tumours

Supratentorial and brainstem tumours

Arteriovenous malformations

Cranial trauma

Striatal variant of dementia pugilistica

Chronic subdural haematoma

Mid-brain trauma

Vascular lesions




Familial basal ganglia calcification

Extrapontine myelinolysis

Chronic liver failure

Wilson’s disease


Huntington’s disease

SCA mutations



Dentatorubropallidal-luysian atrophy

Normal pressure hydrocephalus

Haemiatrophy–hemiparkinson syndrome



PML=progressive multifocal leucoencephalopathy; MPTP=1-methyl-4-pnenyl- 4-propionoxypiperidine; FTDP-17=frontotemporal dementia with parkinsonism linked to chromosome 17


Perry syndrome


Farrer MJ et al. “DCTN1 mutations in Perry syndrome.” Nature genetics 41: 163-165,


SCHWARZACHER SW et al. Neuroanatomical characteristics of the human pre-Bötzinger complex and its involvement in neurodegenerative brainstem diseases. Brain, 2011, 134: 24-35.


Tada M et al. Depletion of medullary serotonergic neurons in patients with multiple system atrophy who succumbed to sudden death. Brain 132: 1810-1819, 2009.


Wider, Christian, et al. Elucidating the genetics and pathology of Perry syndrome. Journal of the neurological sciences 289: 149-154, 2010.




Localization of the Gene for Rapidly Progressive Autosomal Dominant Parkinsonism and Dementia with Pallido-Ponto-Nigral Degeneration to Chromosome 17q21


The tauopathy associated with mutation +3 in intron 10 of Tau: characterization of the MSTD family


文献検索していたら、CPC症例は2012年にNeurologyですでに発表されていた! 何たることか!?何もこのことについて言及しなかったのは、discussantの河内先生がこの症例報告をご存じなかったのか、わざと言及しななかったのかどうかは不明である。

Autosomal dominant tauopathy with parkinsonism and central hypoventilation

Omoto M et al. (2012). Autosomal dominant tauopathy with parkinsonism and central hypoventilation. Neurology, 78, 762-764.


Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T) can show various clinical phenotypes.1 We describe Japanese siblings with the intronic 10 + 14 splice site mutation of the microtubule-associated protein tau (MAPT) gene, showing parkinsonism, depression, weight loss, and central hypoventilation with reduced serotonin concentration suggested by low 5-hydroxyindole acetic acid (5-HIAA) in CSF. These clinical and biochemical features are just shared by Perry syndrome,2–4 although neither DCTN1 gene mutation nor TDP-43 proteinopathy was found.

Case reports.

A Japanese woman (III-5) (figure, A) developed clumsiness, tremor of the upper limbs, appetite loss, and apathy at age 44. She had lost 14 kilograms of body weight during 10 months. Mask-like face, hypophonic voice, bradykinesia, and muscle rigidity with predominance on the right side were observed. Deep tendon reflexes were hyperactive, especially in the right extremities with the Babinski sign. Despite levodopa treatment, her parkinsonism progressed and memory loss, disorientation, and cyanosis became apparent. Blood tests, EKG, and chest X-ray were not remarkable. Arterial blood gases showed reduced oxygen (60.3 Torr) and increased carbon dioxide (55.5 Torr). CSF analysis showed reduced 5-HIAA (5.6 ng/mL [normal 28.5 ± 7.2 ng/mL]). Brain MRI demonstrated mild atrophy in the brainstem tegmentum. Polysomnography revealed central hypoventilation with hypoxia. Although memory loss, disorientation, and apathy improved under ventilation assistance, she died due to sudden apnea, 22 months after the onset. Autopsy examination showed severe neuronal loss with gliosis in the globus pallidus, dentate nucleus, subthalamic nucleus, substantia nigra, locus ceruleus, and brainstem tegmentum including the dorsal raphe. Phosphorylated-tau-positive globose-type neurofibrillary tangles, neuropil threads, and oligodendroglial inclusions were seen in the above lesions. These structures were positive for 4 repeat (4R) tau, but negative for TDP-43. In addition to these typical progressive supranuclear palsy (PSP) pathologies, she also showed severe gliosis, rarefaction, and 4R tau deposition in widespread areas of ventrolateral medulla oblongata including the pre-Bötzinger complex (figure, B–M). Sequencing of all coding exons of tau gene revealed a heterozygous C-to-T substitution at + 14th downstream of exon 10. Immunoblot analysis of dephosphorylated samples using phosphorylation-independent anti-tau antibody revealed 2 major bands that aligned with the recombinant 4R tau isoforms, equivalent to PSP and corticobasal degeneration cases (figure, N). Further, by immunoblot using sarkosyl-insoluble brain extracts, a tau fragment of 33 kDa similar to PSP was observed (figure, O). These findings suggest that she shares both histopathologic and biochemical features of tauopathy with PSP.

The younger sister of the proband (III-6) presented with delusion and hallucination at age 19. Neurologic examination at age 43 showed slight spasticity of lower limbs. Like her sister, CSF analysis revealed reduced 5-HIAA (13.8 ng/mL), and the same MAPT gene mutation was detected. The proband’s mother (II-8) showed parkinsonism at age 48, and despite levodopa treatment, became bedridden and almost mute 1 year later, and died at age 54.


An English consanguineous kindred with central hypoventilation and parkinsonism was reported to have the MAPT gene mutation, in which extensive tauopathy in the tegmental medullary neurons and a novel homozygous S352L mutation in exon 12 of the MAPT gene were found.5 In comparison with this family, in which occasional tau deposition in medullary white matter was seen, the proband showed severer tau deposition in the widespread areas of ventrolateral medulla oblongata. This family showed a recessive mode of inheritance and further details of the neuropathology and serotonin/5-HIAA concentration in the CSF were not available.

In addition to PSP pathology, the proband also showed severe degeneration in widespread areas including the dorsal raphe, an area containing serotonergic neurons and known to be chemosensitive to hypercapnia, and the ventrolateral medulla including the pre-Bötzinger complex, a part of the ventral respiratory group shown to be critical for generation of the normal respiratory rhythm.6 These pathologic changes as well as reduction in CSF serotonin metabolite suggest that central hypoventilation might have been caused by mechanisms similar to those of Perry syndrome.7 Clinical and laboratory features of Perry syndrome, parkinsonism, depression, weight loss, and central hypoventilation with reduced 5-HIAA concentration in CSF, are also caused by mutations of MAPT, especially the intronic 10 + 14 mutation, which develops 4R tauopathy.



Foster NL et al. Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Annals of neurology 41: 706-715.1997

Wszolek, Z. K., Tsuboi, Y., Ghetti, B., Pickering-Brown, S., Baba, Y., & Cheshire, W. P. (2006). Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Orphanet J Rare Dis, 1(30).

Tsuboi, Y., et al. Clinical and genetic studies of families with the tau N279K mutation (FTDP-17). Neurology 59: 1791-1793, 2002.

Tsuboi, Yoshio, Virgilio H. Evidente, and Zbigniew K. Wszolek. “Clinical Diagnosis of Familial Atypical Parkinsonian Disorders.” Atypical Parkinsonian Disorders. Humana Press, 2005. 375-392.(Google Scholarで検索すると、無料でPDFが入手できる。なんと


http://blog.with2.net/link.php/36571 ブログランキングに登録しています。




marugametorao について

神経内科専門医 neurologist
カテゴリー: 神経内科医, 神経学, 健康, 医学, 医学教育, 挑戦 パーマリンク



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