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

Inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD) is a progressive, fatal genetic disorder with variable penetrance, predominantly affecting three main tissue types: muscle (IBM), bone (PDB), and brain (FTD). IBMPFD is caused by mutations in the ubiquitously expressed valosin-containing protein (VCP) gene, a member of the AAA-ATPase superfamily. The majority of individuals who develop IBM have progressive proximal muscle weakness. Muscle biopsies reveal rimmed vacuoles and inclusions that are ubiquitin- and TAR DNA binding protein-43 (TDP-43)-positive using immunohistochemistry. PDB, seen in half the individuals, is caused by overactive osteoclasts and is associated clinically with pain, elevated serum alkaline phosphatase, and X-ray findings of coarse trabeculation and sclerotic lesions. FTD diagnosed at a mean age of 55 years in a third of individuals is characterized clinically by comprehension deficits, dysnomia, dyscalculia, and social unawareness. Ubiquitin- and TDP-43-positive neuronal inclusions are also found in the brain. Genotype-phenotype correlations are difficult with marked intra-familial and inter-familial variations being seen. Varied phenotypes within families include frontotemporal dementia, amyotrophic lateral sclerosis, Parkinsonism, myotonia, cataracts, and anal incompetence, among others. Cellular and animal models indicate pathogenetic disturbances in IBMPFD tissues including altered protein degradation, autophagy pathway alterations, apoptosis, and mitochondrial dysfunction. Currently, mouse and drosophila models carrying VCP mutations provide insights into the human IBMPFD pathology and are useful as tools for preclinical studies and testing of therapeutic strategies. In this review, we will explore the pathogenesis and clinical phenotype of IBMPFD caused by VCP mutations.
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PMID:The multiple faces of valosin-containing protein-associated diseases: inclusion body myopathy with Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis. 2189 20

Frontotemporal lobar degeneration (FTLD) describes a spectrum of clinically, pathologically and genetically heterogeneous neurodegenerative disorders of unknown aetiology. FTLD spectrum disorders collectively represent a leading cause of early-onset dementia, with most cases presenting between 45 and 64 years of age. FTLD is characterized by progressive changes in behaviour, executive dysfunction and/or language impairment and can be differentiated clinically into three frontotemporal dementia (FTD) syndromes as follows: (i) behavioural variant (bvFTD); (ii) semantic dementia (SD); and (iii) progressive nonfluent aphasia (PNFA). Additionally, there is a significant clinical, pathological and genetic overlap between FTD and motor neuron disease/amyotrophic lateral sclerosis (FTD-ALS) and the atypical parkinsonian syndromes, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). bvFTD is characterized by progressive behavioural impairment and a decline in executive function with frontal lobe-predominant atrophy, SD by a loss of object knowledge with prominent anomia and asymmetrical atrophy of the anterior temporal lobes and PNFA by expressive or motor speech deficits with predominantly left peri-sylvian atrophy. Recent advances in molecular biology and immunohistochemical staining techniques have further classified the FTLD spectrum disorders based upon the predominant neuropathological protein into three main categories: (i) microtubule-associated protein tau (FTLD-TAU); (ii) TAR DNA-binding protein-43 (FTLD-TDP); and (iii) fused in sarcoma protein (FTLD-FUS). Up to 40% of FTD patients report a family history of neurodegenerative illness, and one-third to one-half of familial cases of FTD follow an autosomal dominant inheritance pattern. Mutations in MAPT, PGRN, TARDBP, VCP and CHMP2B have been described, along with a recently identified C9ORF72 hexanucleotide repeat expansion. To date, there are no US FDA-approved treatments or disease-modifying therapies for FTD. Pharmacological strategies have focused on neurotransmitter replacement and modulation for the treatment of behavioural, motor and cognitive symptoms of FTD, and include selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics, acetylcholinesterase inhibitors and glutamate NMDA receptor antagonists. At present, adequate management of FTD symptoms involves a combination of pharmacological therapy with behavioural, physical and environmental modification techniques.
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PMID:Frontotemporal lobar degeneration: epidemiology, pathology, diagnosis and management. 2295 Apr 90