Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085632 (apathy)
 4,089 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the progranulin gene (GRN) are a major cause of frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) but the distinguishing clinical and anatomical features of this subgroup remain unclear. In a large UK cohort we found five different frameshift and premature termination mutations likely to be causative of FTLD in 25 affected family members. A previously described 4-bp insertion mutation in GRN exon 2 comprised the majority of cases in our cohort (20/25), with four novel mutations being identified in the other five affected members. Additional novel missense changes were discovered, of uncertain pathogenicity, but deletion of the entire gene was not detected. The patient collection was investigated by a single tertiary referral centre and is enriched for familial early onset FTLD with a high proportion of patients undergoing neuropsychological testing, MRI and eventual neuropathological diagnosis. Age at onset was variable, but four mutation carriers presented in their 40s and when analysed as a group, the mean age at onset of disease in GRN mutation carriers was later than tau gene (MAPT) mutation carriers and duration of disease was shorter when compared with both MAPT and FTLD-U without mutation. The most common clinical presentation seen in GRN mutation carriers was behavioural variant FTLD with apathy as the dominant feature. However, many patients had language output impairment that was either a progressive non-fluent aphasia or decreased speech output consistent with a dynamic aphasia. Neurological and neuropsychological examination also suggests that parietal lobe dysfunction is a characteristic feature of GRN mutation and differentiates this group from other patients with FTLD. MR imaging showed evidence of strikingly asymmetrical atrophy with the frontal, temporal and parietal lobes all affected. Both right- and left-sided predominant atrophy was seen even within the same family. As a group, the GRN carriers showed more asymmetry than in other FTLD groups. All pathologically investigated cases showed extensive type 3 TDP-43-positive pathology, including frequent neuronal cytoplasmic inclusions, dystrophic neurites in both grey and white matter and also neuronal intranuclear inclusions. Finally, we confirmed a modifying effect of APOE-E4 genotype on clinical phenotype with a later onset in the GRN carriers suggesting that this gene has distinct phenotypic effects in different neurodegenerative diseases.
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PMID:A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series. 1823 97

Frontotemporal dementia is a disorder of paralimbic prefrontal-insular circuitry. The disorder is often sporadic but can be caused by genetic mutations in tau, progranulin, valosin, TDP-43 and CHMP2b. The major clinical manifestations of FTD include addictive behaviors, disinhibition, apathy, overeating and loss of sympathy and empathy for others. Treatment is currently focused around symptoms but disease-modifying therapies seem feasible.
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PMID:Early features in frontotemporal dementia. 1968 32

Primary progressive aphasia (PPA) is a group of disorders with progressive language impairment. Abnormal behaviour may develop in PPA as the disease evolves, but the clinical features and brain basis of behavioural change in PPA have not been fully defined. 33 PPA patients (9 semantic dementia, SD, 14 progressive nonfluent aphasia, PNFA, 7 logopenic/phonological aphasia, LPA and 3 patients with a PPA syndrome in association with progranulin mutations, GRN-PPA) were assessed using the Neuropsychiatric Inventory to record behavioural changes, as well as volumetric MR imaging. The most common abnormal behaviours in SD were irritability, disinhibition, depression and abnormal appetite, in PNFA apathy, agitation and depression, in LPA anxiety, irritability, agitation and apathy, and in GRN-PPA apathy and irritability. Voxel-based morphometry analysis revealed greater atrophy of right lateral orbitofrontal cortex (OFC) in PPA patients with anxiety, apathy, irritability/lability and abnormal appetite/eating disorders, and greater atrophy of left OFC in those with disinhibition. Areas involved beyond OFC included right dorsolateral prefrontal cortex (apathy), right cingulate (irritability/lability) and left anterior superior and medial temporal lobe (disinhibition). Behavioural abnormalities may be clinically significant in PPA, and these abnormalities are underpinned by atrophy of overlapping frontotemporal networks centred on OFC.
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PMID:Phenomenology and anatomy of abnormal behaviours in primary progressive aphasia. 2040 Jan 20

Frontotemporal dementia (FTD) is one of the commonest forms of early-onset dementia, accounting for up to 20% of all dementia patients. Recently, it has been shown that mutations in progranulin gene (PGRN) cause many familial cases of FTD. Members of a family affected by FTD spectrum disorders were ascertained in Poland and Canada. Clinical, radiological, molecular, genetic, and pathological studies were performed. A sequencing analysis of PGRN exons 1-13 was performed in the proband. Genotyping of the identified PGRN mutation and pathological analysis was carried out in the proband's brother. The onset of symptoms of FTD in the proband included bradykinesia, apathy, and somnolence followed by changes in personality, cognitive deficits, and psychotic features. The proband's clinical diagnosis was FTD and parkinsonism (FTDP). DNA sequence analysis of PGRN revealed a novel, heterozygous mutation in exon 11 (g.2988_2989delCA, P439_R440fsX6). The mutation introduced a premature stop codon at position 444. The proband's brother with the same mutation had a different course first presenting as progressive non-fluent aphasia, and later evolving symptoms of behavioral variant of FTD. He also developed parkinsonism late in the disease course evolving into corticobasal syndrome. Pathological analysis in the brother revealed Frontotemporal Lobar Degeneration-Ubiquitin (FTLD-U)/TDP-43 positive pathology. The novel PGRN mutation is a disease-causing mutation and is associated with substantial intra-familial clinical heterogeneity. Although presenting features were different, rapid and substantial deterioration in the disease course was observed in both family members.
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PMID:Intra-familial clinical heterogeneity due to FTLD-U with TDP-43 proteinopathy caused by a novel deletion in progranulin gene (PGRN). 2093 Feb 69