Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0751295 (memory loss)
 3,619 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD, OMIM 167320) has recently been attributed to eight missense mutations in valosin-containing protein (VCP). We report novel VCP mutations N387H and L198W in six individuals from two families who presented with proximal muscle weakness at a mean age of diagnosis of 40 years, most losing the ability to walk within a few years of onset. Electromyographic studies in four individuals were suggestive of 'myopathic' changes, and neuropathic pattern was identified in one individual in family 1. Muscle biopsy in four individuals showed myopathic changes characterized by variable fiber size, two individuals showing rimmed vacuoles and IBM-type cytoplasmic inclusions in muscle fibers, and electron microscopy in one individual revealing abundant intranuclear inclusions. Frontotemporal dementia associated with characteristic behavioral changes including short-term memory loss, language difficulty, and antisocial behavior was observed in three individuals at a mean age of 47 years. Detailed brain pathology in one individual showed cortical degenerative changes, most severe in the temporal lobe and hippocampus. Abundant ubiquitin-positive tau-, alpha-synuclein-, polyglutamine repeat-negative neuronal intranuclear inclusions and only rare intracytoplasmic VCP positive inclusions were seen. These new mutations may cause structural changes in VCP and provide some insight into the functional effects of pathogenic mutations.
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PMID:Novel VCP mutations in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia. 1793 6

Frontotemporal dementias (FTD) are the second most common type of presenile dementias, considered to be clinically and pathologically different from Alzheimer's dementia (AD). FTD differs clinically from AD because memory loss is rarely an early symptom. Instead, FTD is usually denoted by behavioural and language difficulties, and may co-occur with motor neuron disease (MND). Frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) is the most common underlying pathology with and without MND. TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the major pathological protein of FTLD-U with or without MND, demonstrating that abnormal TDP-43 alone is sufficient to cause neurodegeneration. FTLD is a genetically complex disorder. A proportion of cases of FTLD-U have various pathogenic mutations in the progranulin (GRN) gene. Other FTLD-U entities with TDP-43 proteinopathy include FTLD-U with valosin-containing protein (VCP) gene mutation and FTLD with MND linked to chromosome 9p. In contrast, chromosome 3-linked dementia, a FTLD-U with chromatic modifying protein 2B (CHMP2B) mutation, has TDP-43 negative inclusions. Thus, TDP-43 defines a novel class of neurodegenerative diseases called TDP-43 proteinopathies. These recent discoveries will contribute to an accurate diagnosis, and facilitate the development of diagnosis and therapy.
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PMID:Frontotemporal dementias: update on recent developments in molecular genetics and neuropathology. 1932 83

Introduction. The valosin-containing protein (VCP) regulates several distinct cellular processes. Consistent with this, VCP mutations manifest variable clinical phenotypes among and within families and are a diagnostic challenge. Methods. A 60-year-old man who played ice hockey into his 50's was evaluated by electrodiagnostics, muscle biopsy, and molecular genetics. Results. With long-standing pes cavus and toe walking, our patient developed progressive weakness, cramps, memory loss, and paresthesias at age 52. An axonal sensorimotor neuropathy was found upon repeated testing at age 58. Neuropathic histopathology was present in the quadriceps, and exome sequencing revealed the VCP mutation c.290 C>T, p.Gly97Glu. Conclusions. Our patient reflects the clinical heterogeneity of VCP mutations, as his neurological localization is a spectrum between a lower motor neuron disorder and a hereditary axonal peripheral neuropathy such as CMT2. Our case demonstrates a rare manifestation of the c.290 C>T, pGly97Glu VCP mutation.
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PMID:Rare Manifestation of a c.290 C>T, p.Gly97Glu VCP Mutation. 2587 7