疾患詳細
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| #221820 Leukoencephalopathy, diffuse hereditary, with spheroids (HDLS) (Leukoencephalopathy with neuroaxonal spheroids, autosomal dominant) (Gliosis, familial progressive subcortical; GPSC) (Dementia, familial, Neumann type) (Subcortical gliosis of Neumann) 白質脳症, びまん性遺伝性-回転楕円体 (白質脳症-神経軸索回転楕円体, 常染色体優性) (グリオーシス, 家族性進行性皮質下) (認知症, 家族性, Neumann 型) (皮質下グリオーシス, Neumann) 指定難病125 神経軸索スフェロイド形成を伴う遺伝性びまん性白質脳症 責任遺伝子：164770 Colony-stimulating factor 1 receptor (CSF1R) <5q32> 遺伝形式：常染色体優性 (要約) 成人発症性白質ジストロフィー-軸索楕円体と色素沈着性グリア (ALSP) ●成人発症性白質ジストロフィー-軸索楕円体と色素沈着性グリア (ALSP)は, 遺伝性びまん性白質脳症, 楕円体を伴う (HDLS) と色素沈着性性色素性白質ジストロフィー (POLD) の両方を含む 高度の機能障害, 記憶低下, 性格変化, 運動障害およびけいれんが特徴である 通常, 前頭葉症候群 (判断喪失, 社会的抑制欠損, 洞察力欠損, 運動持続など) が疾患早期に出現する 平均発症年齢は通常30歳代である 患者はその後痙性と拘縮のため寝たきりとなる 疾患経過は2〜30年以上(平均8年) である ●診断：特徴的臨床および脳 MRI 所見による CSF1R のヘテロ接合病的バリアントの証明で確定する ~13%で証明 ●遺伝：常染色体優性で通常患者の親をもつ (新生も生じうる) ●臨床診断 1）進行性神経学的低下 性格変化, 認知障害, 記憶低下, うつ 運動障害：不全麻痺, 歩行障害, 動作緩慢, 関節拘縮, 振戦 けいれん (まれ) (疾患後半のサイン) 認知症, けいれん, 錐体路サイン (痙性, 反射亢進, 開扇反射, 片不全麻痺, 四肢不全麻痺)および錐体外路サイン 2）常染色体優性の家族歴 3）脳MRI所見 白質病変：Ｔ2および FLAIRで高輝度, T1で低輝度 →深部, 皮質下および脳室周囲での両側前頭葉または両側前頭頭頂葉でのl T2/FLAIR 高輝度 大脳萎縮→大きな脳室 灰白質異常, 脳幹萎縮, 実質のコントラスト uptakeなし 小脳異常は最小限 (脳生検) 軸索楕円体を伴う白質病変の証明→遺伝子解析でOK ●頻度：不明 (知られているよりまれではない) (症状) 【神経】認知低下 記憶喪失 認知症 前頭葉認知症 失行症 硬直 動作緩慢 姿勢不安定 引きずり歩行 唖 痙性 反射亢進 深部白質病変 (特に前頭葉と頭頂葉) 髄鞘喪失 深部白質病変 (特に前頭葉と頭頂葉) 髄鞘喪失 ニューロン喪失 軸索回転楕円体 回転楕円体は神経線維を含む 星状膠細胞 グリオーシス 膨大化したニューロン マイクログリアとマクロファージの自己蛍光色素 うつ 平たい情動 実行能障害 行動変化 【その他】成人発症 多様な症状と症状の進化 急速進行性 発症後6年内死亡 ＜指定難病＞ 神経軸索スフェロイド形成を伴う遺伝性びまん性白質脳症 １．概要 神経軸索スフェロイド形成を伴う遺伝性びまん性白質脳症（hereditary diffuse leukoencephalopathy with spheroid：HDLS）は, 大脳白質を病変の主座とする神経変性疾患である。常染色体優性遺伝形式をとるが, 孤発例が数多く存在する。1984年にスウェーデン家系で最初に報告されたが, 世界各地に発症を認める。HDLSは, 脳生検又は剖検による神経病理学的検査により従来診断されていたが, 2012年にHDLSの原因遺伝子が同定されて以降は, 遺伝子検査により確定診断が可能になっている。 ２．原因 HDLSの原因遺伝子としてcolony stimulating factor-1 receptor（CSF-1R）が同定されている。HDLS患者に同定された既報の遺伝子変異は, 全てチロシンキナーゼ領域に位置している。変異の種類はミスセンス変異, スプライスサイト変異, 微小欠失, ナンセンス変異, フレームシフト変異がある。ナンセンス変異, フレームシフト変異例では片側のアレルのCSF-1Rが発現しないことから, HDLSの原因の１つはCSF-1Rのハプロ不全と考えられる。CSF-1Rは中枢神経ではミクログリアに強く発現しており, HDLSの病態にミクログリアの機能不全が関与していることが想定されている。しかし, CSF-1R変異がミクログリアの機能異常を介してHDLSを引き起こす詳細な機序は不明である。 ３．症状 発症年齢は平均45歳（18～78歳に分布）であり, 40歳～50歳台の発症が多い。発症前の社会生活は正常であることが多い。初発症状は認知機能障害が最も多いが, うつ, 性格変化や歩行障害, 失語と思われる言語障害で発症する例もある。主症状である認知機能障害は, 前頭葉機能を反映した意思発動性の低下, 注意障害, 無関心, 遂行機能障害などの性格変化や行動異常を特徴とする。動作緩慢や姿勢反射障害を主体とするパーキンソン症状, 錐体路徴候などの運動徴候も頻度が高い。けいれん発作も約半数の症例で認める。 ４．治療法 発症の機序や病態が不明であり, 根本的な治療法はない。症状に応じた対症療法が行われる。 ５．予後 進行性の経過であり, 発症後の進行は速い。通常５年以内に臥床状態となる。発症から死亡までの年数は平均６年（２～29年に分布）, 死亡時年齢は平均52歳（36から84歳に分布）である。 〈診断基準〉 Definite, Probable基準を満たす患者を対象とする。 神経軸索スフェロイド形成を伴う遺伝性びまん性白質脳症（HDLS）の診断基準 主要項目 １．60歳以下の発症（大脳白質病変又は２．の臨床症状）注１ ２．下記のうち２つ以上の臨床症状注２ a．進行性認知機能障害, 又は性格変化・行動異常 b．錐体路徴候 c．パーキンソン症状 d．けいれん発作 ３．常染色体優性遺伝形式又は孤発例注３ ４．頭部CT/MRIで下記の所見を認める注４ a．両側性の大脳白質病変 b．脳梁の菲薄化 ５．血管性認知症, 多発性硬化症, 白質ジストロフィー（副腎白質ジストロフィー（ALD）, 異染性白質ジストロフィー（MLD）等）など他疾患を除外できる 支持項目 １．臨床徴候やFrontal Assessment Battery (FAB) 検査等で前頭葉機能障害を示唆する所見を認める。 ２．進行が早く, 発症後５年以内に臥床状態となることが多い。 ３．頭部CTで大脳白質に点状の石灰化病変を認める。注４ 除外項目 １．10歳未満の発症 ２．高度な末梢神経障害の合併 ３．２回以上のstroke-like episodes（脳血管障害様エピソード）。ただし, けいれん発作は除く。 診断のカテゴリー 【Definite】主要項目２, ３, ４aを満たし, CSF-1R遺伝子の変異又はHDLSに特徴的な神経病理学的所見を認める。注５ 【Probable】主要項目５項目全てを満たすが, CSF-1R遺伝子変異の検索及び神経病理学的検索が行われていない。 【Possible】主要項目２-a, ３及び４aを満たすが, CSF-1R遺伝変異の検索及び神経病理学的検索が行われていない。 補足事項 注１．発症年齢に関連して 30歳代から50歳代の発症が多い。ただし, 遺伝子変異が確認された例では18～78歳と幅が広い。発症前は通常の社会生活が可能であることが多い。 注２．臨床症状に関連して a（進行性認知症又は病初期における性格変化・行動異常）は中核症状であり, ほぼ必発である。認知症は皮質性が目立つ場合も少なくない。前頭葉機能障害を反映して, 意思発動性低下, 注意障害, 無関心・無頓着, 遂行機能障害などの性格変化や行動異常が前景に立つ。パーキンソン症状は発語・思考・動作の緩慢さが目立つ。 注３．家族歴に関連して de novo変異による孤発例が存在する。また, 家系内でも症状が多彩で家族歴を見落とす可能性がある。 注４．頭部画像に関連して (a)白質病変は初期には散在性のことがあるが, やがて融合性, びまん性となる．前頭葉・頭頂葉優位で, かつ脳室周囲の深部白質に目立つ。(b)MRIでは, 病初期から脳梁の菲薄化と信号異常を認めることが多く, 検出には矢状断像を推奨する。内包などの投射線維に信号異常を認めることがある。MRI拡散強調画像で白質病変の一部に, 持続する高信号病変を呈する例が存在する。ガドリニウム増強効果は通常認めない。脳小血管病で認められる側頭極病変や穿通枝領域の多発性ラクナ梗塞, 多発性の微小出血は認めない。石灰化病変は, 側脳室前角近傍や頭頂葉皮質下白質に両側性に認めることが多い。微小なものも少なくないため, 検出にはthin-slice CTを推奨する。 注５．神経病理所見に関連して 広範な白質変性（髄鞘・軸索の崩壊）, 軸索腫大（スフェロイド）, マクロファージの浸潤を特徴とする。 (Responsible gene) *164770 Colony-stimulating factor 1 receptor (CSF1R) <5q32> .0001 Leukoencephalopathy, diffuse hereditary, with spheroids (221820) [CSF1R, MET875THR] (Rademakers et al. 2011) .0002 Leukoencephalopathy, diffuse hereditary, with spheroids [CSF1R, GLU633LYS] (Rademakers et al. 2011) .0003 Leukoencephalopathy, diffuse hereditary, with spheroids [CSF1R, IVS12AS, A-G, -2] (Rademakers et al. 2011) .0004 Leukoencephalopathy, diffuse hereditary, with spheroids [CSF1R, ILE794THR] (Rademakers et al. 2011; Konno et al. 2014) .0005 Leukoencephalopathy, diffuse hereditary, with spheroids [CSF1R, ASP837TYR] (Rademakers et al. 2011) .0006 Leukoencephalopathy, diffuse hereditary, with spheroids [CSF1R, 1-BP INS, 2060T [dbSNP:rs587777245] (Konno et al. 2014) .0007 Leukoencephalopathy, diffuse hereditary, with spheroids [CSF1R, IVS18DS, G-T, +1 [dbSNP:rs587777246] (Konno et al. 2014) .0008 Leukoencephalopathy, diffuse hereditary, with spheroids [CSF1R, ALA781GLU [dbSNP:rs587777247] (Konno et al. 2014) .0009 Leukoencephalopathy, diffuse hereditary, with spheroids [CSF1R, ARG782HIS] (Nicholson et al. 2013) (Other causes of presenile dementia) Pick disease (172700), Alzheimer disease (104300), Huntington disease (143100), Creutzfeldt-Jakob disease (123400), Wilson disease (277900), amyloid cerebral angiopathy (105150) (Note) A number sign (#) is used with this entry because hereditary diffuse leukoencephalopathy with spheroids (HDLS) is caused by heterozygous mutation in the CSF1R gene (164770) on chromosome 5q32. Hereditary diffuse leukoencephalopathy with spheroids is an autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes (summary by Rademakers et al., 2012). Clinical Features Lanska et al. (1994) presented clinical and pathologic information on 2 large multigenerational families with a form of autosomal dominant adult-onset dementia termed progressive subcortical gliosis. Affected individuals presented in the fifth or sixth decade of life with personality change and degeneration of social ability which later developed into a profound dementia with mutism, dysphagia, and extrapyramidal signs. The presentation was similar to that of Pick disease. Autopsies were done on 7 affected individuals. These showed moderately severe atrophy with preferential involvement of the frontal and temporal lobes but without the knife edge pattern characteristic of Pick disease. The most striking microscopic finding was a marked fibrillary astrocytosis, particularly in the area of the short cortical association tracts (U fibers) at the junction of cortical lamina VI and the subcortical white matter, and in the subpial cerebral cortex (lamina I). There was also laminar spongiosis, particularly in laminae II and III similar to that observed in Pick disease and Alzheimer disease, but different from the pancortical spongiform change in Creutzfeldt-Jakob disease which is usually most prominent in deeper layers. Neuronal inclusions and amyloid deposits, which are pathologic hallmarks of Alzheimer disease and Pick disease, were uniformly absent. One of the families reported by Lanska et al. (1994) was found by Goedert et al. (1999) to have a mutation in the MAPT gene (157140.0006), thus confirming a diagnosis of MAPT-related frontotemporal dementia (FTD; 600274). Knopman et al. (1996) reported 3 sisters who developed progressive frontotemporal dementia between 40 and 70 years of age. Two presented with depression, abnormal behavior, and mild memory difficulties, ultimately resulting in an inability to function. None had prominent motor dysfunction. Neuropathologic examination of 2 sisters who died showed atrophy of the frontal and temporal lobes as well as white matter degeneration affecting the subcortical white matter and deep white matter without neuronal loss. There was extensive demyelination, loss of white matter axons, and gliosis. Abundant lipofuscin granules in microglia, macrophages, and astrocytes were also noted. Neurofibrillary tangles and senile plaques were not found in either case. The clinical and pathologic findings were consistent with a diagnosis of orthochromatic leukodystrophy. Nicholson et al. (2013) reported another affected member of the family described by Knopman et al. (1996), a daughter of 1 of the affected sisters. This patient developed symptoms of frontotemporal dementia at age 51. Brain imaging showed frontal atrophy and white matter hyperintensities throughout the frontal lobes, which worsened over time. Reevaluation of the neuropathology from the deceased affected family members showed the presence of axonal spheroids in areas with early white matter changes, consistent with HDLS. Van der Knaap et al. (2000) reported a father and daughter with adult-onset deterioration of frontal lobe function, spasticity, ataxia, and mild extrapyramidal signs. MRI showed cerebral atrophy and patchy white matter changes. Postmortem examination showed leukoencephalopathy with numerous neuroaxonal spheroids. The frontal and frontoparietal lobes were most affected. Baba et al. (2006) reported a kindred in which 6 individuals had dementia, depression, and frontal lobe signs variably associated with parkinsonism, apraxia, and seizures. The mean age at onset was 54 years. Postmortem examination of the brains showed loss of myelinated fibers, bizarre astrocytosis, white matter gliosis, and axonal spheroids. Inheritance was autosomal dominant. Molecular analysis excluded mutations in the MAPT gene and in several genes involved in leukoencephalopathy with white matter disease (603896). Swerdlow et al. (2009) reported a multigenerational family with frontotemporal dementia associated with subcortical gliosis inherited in an autosomal dominant pattern. Age at onset ranged from the forties to sixties in affected individuals. The phenotype was characterized mainly by progressive behavioral changes, disorientation, frontal release signs, and memory loss. Later symptoms and signs included dementia, mutism, and incontinence. Some individuals developed parkinsonism. Neuropathologic studies showed frontotemporal cortical atrophy, ventriculomegaly, neuronal loss, hypertrophic astrogliosis in the superficial and deep white matter, loss of axons, dystrophic axons, and axonal spheroids containing neurofilaments. Immunohistochemical studies did not identify tau, ubiquitin, or prion (PRNP; 176640) inclusions. Swerdlow et al. (2009) noted that the disorder shared some characteristics with leukoencephalopathy with neuroaxonal spheroids, as described by van der Knaap et al. (2000) and Baba et al. (2006). Rademakers et al. (2012) reported 14 families with HDLS, including those reported previously by Swerdlow et al. (2009) and Baba et al. (2006). Clinical features of 24 affected individuals showed that the mean age at onset was 47.2 years (range, 18-78 years), with a mean age of death at 57.2 years (range, 40-84 years). One patient was described in detail. He developed mild depression and forgetfulness at age 50 years. Two years later, he had a flat affect, inappropriate behavior, poor concentration, executive dysfunction, restless legs syndrome, and insomnia. There was psychomotor slowing, and ideomotor and constructional apraxia. He had a slow, shuffling gait, postural instability, rigidity, and bradykinesia. Brain imaging showed hyperintense foci in both the frontal and parietal lobes, involving the periventricular, deep and subcortical white matter, but sparing the subcortical U fibers. At the end of his illness, he was mute and in a vegetative state; death occurred at age 55 years. Neuropathologic examination showed myelin loss, axonal spheroids containing neurofilaments, astrocytes, gliosis, and ballooned neurons. There was inter- and intrafamilial variability, with different ages at onset and death, as well as variable clinical features. Antemortem clinical diagnoses in mutation carriers included frontotemporal dementia (FTD; 600275), corticobasal syndrome, Alzheimer disease (AD; 104300), multiple sclerosis (MS; 126200), atypical cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; 125310), and Parkinson disease (PD; 168600). Konno et al. (2014) reported 7 Japanese patients with HDLS. The age at onset ranged from 36 to 55 years (mean of 44 years), and all patients presented with cognitive impairment followed by behavioral and personality changes. Later features included parkinsonism, including bradykinesia and gait disturbance, pyramidal signs, and seizures (2 patients). Six of the 7 patients progressed to being wheelchair-bound and having severe dementia with communication problems within 5 years after onset. Three patients had a family history of a similar disorder, consistent with autosomal dominant inheritance. Neuropathologic studies of several patients showed diffuse loss of myelin sheaths and axons in the white matter, as well as severe gliosis prominent in the frontal lobe. Scattered axonal spheroids that were immunoreactive for phosphorylated neurofilaments were present in the white matter lesions. In addition, there was abnormal appearance of activated microglia. Neuroradiologic Findings Sundal et al. (2012) reviewed 20 brain MRI scans of 15 patients from 9 HDLS families, all of Caucasian descent with genetically confirmed disease, and assigned a severity score based on the lesion load. The mean age at onset was 44.3 years and the mean age at death was 53.2 years. All patients had a progressive clinical course, except 1, who had mild disease burden on initial MRI. At onset, 14 of 15 patients had localized white matter lesions (WML) with deep, subcortical, and periventricular involvement, whereas 1 more severely affected patient had generalized WML. All lesions were bilateral, but asymmetric, and predominantly in the frontal/parietal regions. There was cortical atrophy and involvement of the corpus callosum, but gray matter pathology and brainstem atrophy were absent; corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology. Indicators of rapid disease progression included onset before age 45 years, female sex, WML extending beyond the frontal regions, an MRI severity score greater than 15 points, and deletion mutations. Sundal et al. (2012) concluded that recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments. Konno et al. (2014) reported the neuroradiologic features of 7 Japanese patients with HDLS. Brain MRI showed T2-weighted bilateral hyperintensities in the white matter with frontal predominance, as well as thinning of the corpus callosum. The changes were progressive, and included brain atrophy. CT scans of 5 patients showed spotty calcifications in the affected white matter, which were confirmed by histology in 1 patient. Inheritance The transmission pattern in the families with HDLS reported by Rademakers et al. (2012) was consistent with autosomal dominant inheritance. Molecular Genetics By linkage analysis followed by whole-exome sequencing of the family with HDLS reported by Swerdlow et al. (2009), Rademakers et al. (2012) identified a heterozygous mutation in the CSF1R gene (164770.0001). Sequencing of this gene in 13 additional probands with HDLS identified a different heterozygous mutation in each (see, e.g., 164770.0002-164770.0005). The mutations cosegregated with the disorder in all families for which DNA from multiple affected individuals was available, including the family reported by Baba et al. (2006). In vitro functional expression studies of some of the missense mutations indicated that the mutant proteins did not show autophosphorylation, suggesting a defect in kinase activity that likely also affects downstream targets. The mutant proteins probably also act in a dominant-negative manner, since CSF1R assembles into homodimers. Overall, the findings indicated that a defect in microglial signaling and function resulting from CSF1R mutations can cause central nervous system degeneration. In 7 Japanese probands with HDLS, Konno et al. (2014) identified 6 different heterozygous mutations in the CSF1R gene (see, e.g., 164770.0004; 164770.0006-164770.0008). Two of the mutations resulted in truncated proteins, indicating that haploinsufficiency is sufficient to cause the disorder. In vitro functional expression studies in HEK293 cells showed that none of the mutant CSF1R proteins, including those caused by missense mutations, were able to autophosphorylate. However, coexpression of the mutants with wildtype did not suppress wildtype autophosphorylation, indicating that the mutations do not act in a dominant-negative manner. In affected members of a family (FTD368) with a clinicopathologic diagnosis of pigmented orthochromatic leukodystrophy (POLD), originally reported by Knopman et al. (1996), Nicholson et al. (2013) identified a heterozygous missense mutation in the CSF1R gene (R728H; 164770.0009). In vitro functional expression studies in HeLa cells showed that the mutation abrogated CSF1R autophosphorylation, which would inhibit downstream signaling. The findings indicated that POLD and HDLS are a single disease entity, and Nicholson et al. (2013) suggested the term 'adult-onset leukodystrophy with axonal spheroids and pigmented glia' (ALSP). History Khoubesserian et al. (1985) reported a 70-year-old man with dementia who had 2 brothers who died at age 59 with dementia. Pick disease (172700) and Alzheimer disease (AD; 104300) were ruled out by cerebral biopsy and normal levels of neurotransmitters in the biopsy tissue and CSF. These and histologic changes suggested that this may be the disorder reported by Neumann (1949) and designated 'subcortical gliosis' (Neumann and Cohn, 1967). This was the first familial observation. (文献) (1) Neumann, M. A. Pick's disease. J. Neuropath. Exp. Neurol. 8: 255-282, 1949 (2) Neumann, M. A., Cohn, R. Progressive subcortical gliosis: a rare form of presenile dementia. Brain 90: 405-418, 1967 (3) Khoubesserian, P., Davous, P., Bianco, C., Puymirat, J., Fontaine, C., de Recondo, J., Rondot, P. Demence familiale de type Neumann (gliose sous corticale). Rev. Neurol. 141: 706-712, 1985 (4) Lanska, D. J., Currier, R. D., Cohen, M., Gambetti, P., Smith, E. E., Bebin, J., Jackson, J. F., Whitehouse, P. J., Markesbery, W. R. Familial progressive subcortical gliosis. Neurology 44: 1633-1643, 1994 (5) Knopman, D., Sung, J. H., Davis, D. Progressive familial leukodystrophy of late onset. Neurology 46: 429-434, 1996 (6) Goedert, M., Spillantini, M. G., Crowther, R. A., Chen, S. G., Parchi, P., Tabaton, M., Lanska, D. J., Markesbery, W. R., Wilhelmsen, K. C., Dickson, D. W., Petersen, R. B., Gambetti, P. Tau gene mutation in familial progressive subcortical gliosis. Nature Med. 5: 454-457, 1999 (7) van der Knaap, M. S., Naidu, S., Kleinschmidt-DeMasters, B. K., Kamphorst, W., Weinstein, H. C. Autosomal dominant diffuse leukoencephalopathy with neuroaxonal spheroids. Neurology 54: 463-468, 2000 (8) Baba, Y., Ghetti, B., Baker, M. C., Uitti, R. J., Hutton, M. L., Yamaguchi, K., Bird, T., Lin, W., DeLucia, M. W., Dickson, D. W., Wszolek, Z. K. Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred. Acta Neuropath. 111: 300-311, 2006 (9) Swerdlow, R. H., Miller, B. B., Lopes, M. B. S., Mandell, J. W., Wooten, G. F., Damgaard, P., Manning, C., Fowler, M., Brashear, H. R. Autosomal dominant subcortical gliosis presenting as frontotemporal dementia. Neurology 72: 260-267, 2009 (10) Rademakers, R., Baker, M., Nicholson, A. M., Rutherford, N. J., Finch, N., Soto-Ortolaza, A., Lash, J., Wider, C., Wojtas, A., DeJesus-Hernandez, M., Adamson, J., Kouri, N., and 26 others. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nature Genet. 44: 200-205, 2012 (11) Sundal, C., Van Gerpen, J. A., Nicholson, A. M., Wider, C., Shuster, E. A., Aasly, J., Spina, S., Ghetti, B., Roeber, S., Garbern, J., Borjesson-Hanson, A., Tselis, A., and 12 others. MRI characteristics and scoring in HDLS due to CSF1R gene mutations. Neurology 79: 566-574, 2012 (12) Nicholson, A. M., Baker, M. C, Finch, N. A., Rutherford, N. J., Wider, C., Graff-Radford, N. R., Nelson, P. T., Clark, H. B., Wszolek, Z. K., Dickson, D. W., Knopman, D. S., Rademakers, R. CSF1R mutations link POLD and HDLS as a single disease entity. Neurology 80: 1033-1040, 2013 (13) Konno, T., Tada, M., Tada, M., Koyama, A., Nozaki, H., Harigaya, Y., Nishimiya, J., Matsunaga, A., Yoshikura, N., Ishihara, K., Arakawa, M., Isami, A., and 11 others. Haploinsufficiency of CSF-1R and clinicopathologic characterization in patients with HDLS. Neurology 82: 139-148, 2014 2010/10/05 2012/02/08 2012/03/13 2012/11/08 2014/03/28 2014/11/14 変異追加 2014/11/16 症状追加 2016/03/26 ノート/文献追加 2016/04/04 遺伝形式入力訂正 要約 2017/04/21 ノート改訂 |