Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Seventy-one Japanese cases of presenile dementia with motor neuron disease were reviewed. The clinico-pathological features were: (1) progressive dementia with insidious onset, mostly in the presenile period: (2) neurogenic muscular wasting in the course of illness (ALS- or SPMA-like symptoms); (3) duration from the onset of the illness to death: 2-5 years (average 30.6 months); (4) extrapyramidal symptoms and definite sensory deficits are less commonly present; (5) no characteristic abnormalities in the CSF or EEG; (6) no known consanguinity or familial occurrence; (7) non-specific mild to moderate degenerative changes in the fronto-temporal cerebral cortex, hypoglossal nuclei and spinal cord, and frequently in the substantia nigra. The author was interested in discovering whether the frequency and topology of lesions in the brain of patients with presenile dementia and motor neuron disease differed characteristically from the distribution found in cases of Alzheimer's disease, Pick's disease, Creutzfeldt-Jakob disease or progressive subcortical gliosis. Presenile dementia with motor neuron disease might be a new disease entity.
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PMID:Presenile dementia with motor neuron disease. 840 81

This is the report of a case of a 41-year-old male patient with a rapidly progressing amyotrophic lateral sclerosis (ALS) combined with a severe presenile dementia. Screening for antibody binding on fresh-frozen human brain sections, we found that the patient's cerebrospinal fluid contained antibodies against microglia, the dominant and potentially cytotoxic immuneffector cell of the brain. This finding extends previous observations of CSF autoantibodies against microglia in neurodegenerative diseases. It demonstrates that in addition to antigens of neuronal origin (e.g. anti-Purkinje cell antibodies in paraneoplastic cerebellar dysfunction), glial antigens also appear to be under the surveillance of the CNS and/or the peripheral immune system. Our data provide evidence for a close link between neurodegeneration and the activation of microglia; a possible local antigen production against microglia/brain macrophages, which might regulate the concomitant glial activation in neurodegenerative diseases; and the presence of microglia-binding cerebrospinal antibodies as a marker for the acuity of the disease process underlying the acute deterioration of the neurological and cognitive performance in patients with, e.g., ALS. Future therapeutic strategies could therefore include the modulation of the possibly disease-promoting activation of microglia/brain macrophages.
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PMID:Antibodies against microglia/brain macrophages in the cerebrospinal fluid of a patient with acute amyotrophic lateral sclerosis and presenile dementia. 852 21

Two patients with the Kennedy's disease (KD) mutation have been identified in the Newcastle Brain Tissue Bank. One of these patients had presenile dementia as a prominent clinical feature, previously undescribed in KD. The pathologic substrate underlying the cognitive changes in this patient included neuronal depletion and gliosis in the hippocampus and subcortical gliosis in the prefrontal region. Immunostaining for macrophage markers showed evidence for subtle corticospinal tract pathology in both cases. In contrast to the molecular pathologic features found in ALS, surviving motor neurons in the two KD cases showed no evidence of ubiquitinated inclusions or alterations in neurofilament phosphorylation.
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PMID:Kennedy's disease: unusual molecular pathologic and clinical features. 967 12

We first reported ubiquitin-positive tau-negative intraneuronal inclusions in the hippocampal granular cell layer and entorhinal cortices in patients with amyotrophic lateral sclerosis (ALS). We then found that those inclusions occur frequently in patients with presenile dementia and motor neuron disease. The ultrastructure of the inclusions consists mainly of granules with a few filaments. In 2006, TDP-43 was identified as a major component of the inclusions specific for frontotemporal lobar degeneration and ALS. Here, we review the current knowledge regarding ubiquitin-positive tau-negative intraneuronal inclusions.
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PMID:Ubiquitin-positive tau-negative intraneuronal inclusions in dementia with motor neuron disease: The 50th Anniversary of Japanese Society of Neuropathology. 2050 Apr 51

Nasu-hakola disease (NHD) is a rare disease characterized by bone cysts and fractures, frontal lobe syndrome, and progressive presenile dementia. NHD may be the prototype of primary microglial disorders of the CNS or, as they have been coined, "microgliopathies". Mutations in TREM2 and TYROBP genes are known to cause NHD. Interestingly, recent evidence-associated rare genetic variants of TREM2 gene with increased risk of Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Parkinson's disease. Here, we report a 33-year-old Greek female with phenotype suggestive of NHD. Full gene sequencing of the TREM2 and TYROBP genes revealed a novel mutation in exon 2 of TREM2 gene, namely c.244G>T (p.W50C) and heterozygosity in the parents and her brother. This report extends the range of TREM2 mutations that cause NHD phenotype. In addition, we provide a comprehensive review of all reported in the literature TREM2 gene mutations and the respective wide spectrum of clinical manifestations that highlights the importance of considering TREM2 gene mutations in a variety of neurodegenerative phenotypes.
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PMID:A novel mutation in TREM2 gene causing Nasu-Hakola disease and review of the literature. 2821 9

A large GGGGCC hexanucleotide repeat expansion in the first intron or promoter region of the C9orf72 gene is the most common genetic cause of familial and sporadic Amyotrophic lateral sclerosis (ALS), a devastating degenerative disease of motor neurons, and of Frontotemporal Dementia (FTD), the second most common form of presenile dementia after Alzheimer's disease. C9orf72-associated ALS/FTD is a multifaceted disease both in terms of its clinical presentation and the misregulated cellular pathways contributing to disease progression. Among the numerous pathways misregulated in C9orf72-associated ALS/FTD, altered RNA processing has consistently appeared at the forefront of C9orf72 research. This includes bidirectional transcription of the repeat sequence, accumulation of repeat RNA into nuclear foci sequestering specific RNA-binding proteins (RBPs) and translation of RNA repeats into dipeptide repeat proteins (DPRs) by repeat-associated non-AUG (RAN)-initiated translation. Over the past few years the true extent of RNA misprocessing in C9orf72-associated ALS/FTD has begun to emerge and disruptions have been identified in almost all aspects of the life of an RNA molecule, including release from RNA polymerase II, translation in the cytoplasm and degradation. Furthermore, several alterations have been identified in the processing of the C9orf72 RNA itself, in terms of its transcription, splicing and localization. This review article aims to consolidate our current knowledge on the consequence of the C9orf72 repeat expansion on RNA processing and draws attention to the mechanisms by which several aspects of C9orf72 molecular pathology converge to perturb every stage of RNA metabolism.
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PMID:RNA Misprocessing in C9orf72-Linked Neurodegeneration. 2874 2

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a type I transmembrane glycoprotein first identified in low-metastatic human melanoma cell lines as a regulator of tumor growth. GPNMB is widely expressed in various tissues, where it is involved in cell differentiation, migration, inflammation/anti-inflammation, tissue regeneration, and neuroprotection. GPNMB is identified in microglia of adult rat brains, neurons and astrocytes of GPNMB transgenic (Tg) mouse brains, and motor neurons of amyotrophic lateral sclerosis (ALS) patients. Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by genetic mutations of either TYROBP (DAP12) or TREM2. TREM2 and DAP12 constitute a receptor/adaptor signaling complex expressed exclusively on osteoclasts, dendritic cells, macrophages, and microglia. Pathologically, the brains of NHD patients exhibit leukoencephalopathy, astrogliosis, accumulation of axonal spheroids, and remarkable activation of microglia predominantly in the white matter of frontal and temporal lobes and the basal ganglia. At present, molecular mechanisms responsible for development of leukoencephaolpathy in NHD brains remain totally unknown. Recent evidence indicates that disease-associated microglia (DAM) that cluster around amyloid plaques express high levels of GPNMB in Alzheimer's disease (AD) brains. Because microglia act as a key regulator of leukoencephalopathy in NHD brains, it is proposed that GPNMB expressed on microglia might play a protective role in progression of leukoencephalopathy possibly via active phagocytosis of myelin debris. In the present study using immunohistochemistry, we have attempted to clarify the expression of GPNMB in NHD brains, compared with AD brains. We found that microglia accumulating in the white matter express an intense GPNMB immunoreactivity in both NHD and AD brains, suggesting that the accumulation of GPNMB-immunoreactive microglia is a general phenomenon in neurodegenerative brains.
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PMID:Microglia express GPNMB in the brains of Alzheimer's disease and Nasu-Hakola disease. 3121 62