A case of membranous lipodystrophy (Nasu-Hakola disease) with unique MRI findings

Motohashi, Norihisa; Shinohara, M.; Shioe, K.; Fukuzawa, Hiroaki; Akiyama, Yukinori; Kariya, Taro

doi:10.1007/bf00593716

Cited by 9 publications

(4 citation statements)

References 5 publications

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“…The present study includes five NHD patients, composed of a 42-year-old man (NHD1), a 48-year-old woman (NHD2), a 44-year-old man (NHD3), a 32-year-old woman (NHD4), and a 38-year-old man (NHD5), four neuropsychiatric disease controls affected with myotonic dystrophy (MD), composed of a 68-year-old man (MD1), a 61-year-old man (MD2), a 60-year-old man (MD3), and a 53-year-old woman (MD4), four demyelinating disease controls affected with chronic progressive multiple sclerosis (MS), composed of a 29-year-old woman (MS1), a 40-year-old woman (MS2), a 43-year-old woman (MS3), and a 33-year-old man (MS4), and four subjects who died of non-neurological causes (NC), composed of a 63-year-old man who died of prostate cancer and acute myocardial infarction (NC1), a 67-year-old man who died of dissecting aortic aneurysm (NC2), a 57-year-old man who died of alcoholic liver cirrhosis (NC3), and a 61-year-old man who died of rheumatoid arthritis with interstitial pneumonia (NC4). The homozygous mutation of a single base deletion of 141G (141delG) in exon 3 of DAP12 was identified in NHD1, NHD2, and NHD5 [19,26], while the genetic analysis was not performed in NHD3 [27] or NHD4 [28]. …”

Section: Methodsmentioning

confidence: 99%

LC3, an autophagosome marker, is expressed on oligodendrocytes in Nasu-Hakola disease brains

Satoh

Motohashi

Kino

et al. 2014

Orphanet J Rare Dis

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BackgroundNasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by sclerosing leukoencephalopathy and multifocal bone cysts, caused by a loss-of-function mutation of either DAP12 or TREM2. TREM2 and DAP12 constitute a receptor/adaptor signaling complex expressed exclusively on osteoclasts, dendritic cells, macrophages, and microglia. Neuropathologically, NHD exhibits profound loss of myelin and accumulation of axonal spheroids, accompanied by intense gliosis accentuated in the white matter of the frontal and temporal lobes. At present, the molecular mechanism responsible for development of leukoencephalopathy in NHD brains remains totally unknown.MethodsBy immunohistochemistry, we studied the expression of microtubule-associated protein 1 light chain 3 (LC3), an autophagosome marker, in 5 NHD and 12 control brains.ResultsIn all NHD brains, Nogo-A-positive, CNPase-positive oligodendrocytes surviving in the non-demyelinated white matter intensely expressed LC3. They also expressed ubiquitin, ubiquilin-1, and histone deacetylase 6 (HDAC6) but did not express Beclin 1 or sequestosome 1 (p62). Substantial numbers of axonal spheroids were also labeled with LC3 in NHD brains. In contrast, none of oligodendrocytes expressed LC3 in control brains. Furthermore, surviving oligodendrocytes located at the demyelinated lesion edge of multiple sclerosis (MS) did not express LC3, whereas infiltrating Iba1-positive macrophages and microglia intensely expressed LC3 in MS lesions.ConclusionsThese results propose a novel hypothesis that aberrant regulation of autophagy might induce oligodendrogliopathy causative of leukoencephalopathy in NHD brains.

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Section: Methodsmentioning

confidence: 99%

LC3, an autophagosome marker, is expressed on oligodendrocytes in Nasu-Hakola disease brains

Satoh

Motohashi

Kino

et al. 2014

Orphanet J Rare Dis

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“…The ML-like changes found in the osteolytic lesions of these patients are non-specific and these changes of fat tissue have also been found in other diseases [14]. In fact, some authors have established ML diagnosis with unique MR findings, without cystic lesions in bones or histological features [21].…”

Section: Discussionmentioning

confidence: 81%

“…Magnetic resonance (MR) findings in T1-weighted images reveal dilatation of ventricles and cerebral cortical sulci in addition to decreased volume of the cerebral white matter. T2-weighted MR images show a signal intensity of the white matter that is equal to or greater than that of the cortex and a reduced signal density in the putamen and thalamus [21]. There are no prominent patchy or confluent hyperintense areas.…”

Section: Discussionmentioning

confidence: 97%

Membranous lipodystrophy

et al. 2003

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“…The present study includes four subjects who died of non‐neurological causes (NC), composed of a 63‐year‐old man who died of prostate cancer and acute myocardial infarction (NC1), a 67‐year‐old man who died of dissecting aortic aneurysm (NC2), a 57‐year‐old man who died of alcoholic liver cirrhosis (NC3), and a 61‐year‐old man who died of rheumatoid arthritis with interstitial pneumonia (NC4), four neuropsychiatric disease controls affected with myotonic dystrophy (MD), composed of a 68‐year‐old man (MD1), a 61‐year‐old man (MD2), a 60‐year‐old man (MD3) and a 53‐year‐old woman (MD4), three demyelinating disease controls affected with chronic progressive multiple sclerosis (MS), composed of a 29‐year‐old woman (MS1), a 40‐year‐old woman (MS2) and a 43‐year‐old woman (MS3), and five NHD patients, composed of a 42‐year‐old man (NHD1), a 48‐year‐old woman (NHD2), a 44‐year‐old man (NHD3), a 32‐year‐old woman (NHD4) and a 38‐year‐old man (NHD5). The homozygous mutation of a single base deletion of 141G (141delG) in exon 3 of DAP12 was identified in NHD1, NHD2 and NHD5, while the genetic analysis was not performed in NHD3 or NHD4, as previously described . In selected cases, additional tissues of the hippocampus and basal ganglia were processed for immunohistochemical studies.…”

Section: Methodsmentioning

confidence: 99%

Immunohistochemical characterization of CD33 expression on microglia in Nasu‐Hakola disease brains

et al. 2015

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Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by formation of multifocal bone cysts and development of leukoencephalopathy, caused by genetic mutations of either DNAX-activation protein 12 (DAP12) or triggering receptor expressed on myeloid cells 2 (TREM2). Although increasing evidence suggests a defect in microglial TREM2/DAP12 function in NHD, the molecular mechanism underlying leukoencephalopathy with relevance to microglial dysfunction remains unknown. TREM2, by transmitting signals via the immunoreceptor tyrosine-based activation motif (ITAM) of DAP12, stimulates phagocytic activity of microglia, and ITAM signaling is counterbalanced by sialic acid-binding immunoglobulin (Ig)-like lectins (Siglecs)-mediated immunoreceptor tyrosine-based inhibitory motif (ITIM) signaling. To investigate a role of CD33, a member of the Siglecs family acting as a negative regulator of microglia activation, in the pathology of NHD, we studied CD33 expression patterns in five NHD brains and 11 controls by immunohistochemistry. In NHD brains, CD33 was identified exclusively on ramified and amoeboid microglia accumulated in demyelinated white matter lesions but not expressed in astrocytes, oligodendrocytes, or neurons. However, the number of CD33-immunoreactive microglia showed great variability from case to case and from lesion to lesion without significant differences between NHD and control brains. These results do not support the view that CD33-expressing microglia play a central role in the development of leukoencephalopathy in NHD brains.

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A case of membranous lipodystrophy (Nasu-Hakola disease) with unique MRI findings

Cited by 9 publications

References 5 publications

LC3, an autophagosome marker, is expressed on oligodendrocytes in Nasu-Hakola disease brains

LC3, an autophagosome marker, is expressed on oligodendrocytes in Nasu-Hakola disease brains

Membranous lipodystrophy

Immunohistochemical characterization of CD33 expression on microglia in Nasu‐Hakola disease brains

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