Sporadic corticobasal syndrome due to FTLD-TDP

University of California Department of Neurology San Francisco USA
Acta Neuropathologica (Impact Factor: 10.76). 03/2010; 119(3):365-374. DOI: 10.1007/s00401-009-0605-1


Sporadic corticobasal syndrome (CBS) has been associated with diverse pathological substrates, but frontotemporal lobar degeneration
with TDP-43 immunoreactive inclusions (FTLD-TDP) has only been linked to CBS among progranulin mutation carriers. We report
the clinical, neuropsychological, imaging, genetic, and neuropathological features of GS, a patient with sporadic corticobasal
syndrome. Genetic testing revealed no mutations in the microtubule associated protein tau or progranulin (PGRN) genes, but GS proved homozygous for the T allele of the rs5848 PGRN variant. Autopsy showed ubiquitin and TDP-43 pathology most similar to a pattern previously associated with PGRN mutation carriers. These findings confirm that FTLD-TDP should be included in the pathological differential diagnosis for
sporadic CBS.

KeywordsCorticobasal degeneration-TDP-43-Frontotemporal lobar degeneration-Progranulin

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Available from: Eric Huang, Jul 17, 2014
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    • "Neuronal loss was judged by visual assessment as absent, mild, moderate or severe. The presence of other proteinopathies was assessed by antibodies for hyperphosphorylated tau (CP13, from Peter Davies), β-amyloid (mouse anti-β-amyloid monoclonal Ab (mAb), 4G8, catalog# NE1002, Millipore), α-synuclein (mouse mAb, catalog# ab27766, Abcam, Cambridge, MA), TDP43 (rabbit polyclonal, catalog # 10782-2-AP, Proteintech Group, Inc. Chicago, IL), and ubiquitin (rabbit polyclonal, catalog # Z0458, Dako), as previously described [25]. "
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    ABSTRACT: A novel point mutation resulting in a glutamate-to-glycine substitution in PRNP at codon 200, E200G with codon 129 MV polymorphism (cis valine) and type 2 PrPSc was identified in a patient with a prolonged disease course leading to pathology-proven Jakob-Creutzfeldt disease. Despite the same codon as the most common genetic form of human PRNP mutation, E200K, this novel mutation (E200G) presented with a different clinical and pathological phenotype, including prolonged duration, large vacuoles, no vacuolation in the hippocampus, severe neuronal loss in the thalamus, mild cerebellar involvement, and abundant punctate linear and curvilinear deposition of PrPSc in synaptic boutons and axonal terminals along the dendrites.
    12/2013; 1(1):80. DOI:10.1186/2051-5960-1-80
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    • "(CBD) is the most frequent underlying pathology of CBS, other neuropathological causes, including frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and Creutzfeldt–Jakob disease have been reported (Boeve et al. 1999; Wadia and Lang 2007; Tartaglia et al. 2010). Although family history is usually negative in CBS (Spina et al. 2007), a familial form has been described which can be caused by progranulin (GRN) mutations (Wadia and Lang 2007; van Swieten and Heutink 2008). "
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    ABSTRACT: Corticobasal syndrome (CBS) is characterised by asymmetrical parkinsonism and cognitive impairment. The underlying pathology varies between corticobasal degeneration, progressive supranuclear palsy, Alzheimer's disease, Creutzfeldt-Jakob disease and frontotemporal lobar degeneration sometimes in association with GRN mutations. A 61-year-old male underwent neurological examination, neuropsychological assessment, MRI, and HMPAO-SPECT at our medical centre. After his death at the age of 63, brain autopsy, genetic screening and mRNA expression analysis were performed. The patient presented with slow progressive walking disabilities, non-fluent language problems, behavioural changes and forgetfulness. His family history was negative. He had primitive reflexes, rigidity of his arms and postural instability. Later in the disease course he developed dystonia of his left leg, pathological crying, mutism and dysphagia. Neuropsychological assessment revealed prominent ideomotor and ideational apraxia, executive dysfunction, non-fluent aphasia and memory deficits. Neuroimaging showed symmetrical predominant frontoparietal atrophy and hypoperfusion. Frontotemporal lobar degeneration (FTLD)-TDP type 3 pathology was found at autopsy. GRN sequencing revealed a novel frameshift mutation c.314dup, p.Cys105fs and GRN mRNA levels showed a 50% decrease. We found a novel GRN mutation in a patient with an atypical (CBS) presentation with symmetric neuroimaging findings. GRN mutations are an important cause of CBS associated with FTLD-TDP type 3 pathology, sometimes in sporadic cases. Screening for GRN mutations should also be considered in CBS patients without a positive family history.
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    • "PSP is considered to be a tauopathy; however, a PSP-like syndrome has been associated with ubiquitin-only-immunoreactive neuronal changes [9], and thus could be part of the clinical picture of "ALS-plus syndrome" caused by TDP-43 proteinopathy [2,10]. Moreover, FTLD-TDP may have a presentation similar to corticobasal degeneration [11] indicating that these disorders can present with a spectrum of clinical phenotypes that also overlaps other neurodegenerative disorders. "
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    ABSTRACT: Frontotemporal lobar degeneration with ubiquitin and TDP-43 positive neuronal inclusions represents a novel entity (FTLD-TDP) that may be associated with motor neuron disease (FTLD-MND); involvement of extrapyramidal and other systems has also been reported. We present three cases with similar clinical symptoms, including Parkinsonism, supranuclear gaze palsy, visuospatial impairment and a behavioral variant of frontotemporal dementia, associated with either clinically possible or definite MND. Neuropathological examination revealed hallmarks of FTLD-TDP with major involvement of subcortical and, in particular, mesencephalic structures. These cases differed in onset and progression of clinical manifestations as well as distribution of histopathological changes in the brain and spinal cord. Two cases were sporadic, whereas the third case had a pathological variation in the progranulin gene 102 delC. Association of a "progressive supranuclear palsy-like" syndrome with marked visuospatial impairment, motor neuron disease and early behavioral disturbances may represent a clinically distinct phenotype of FTLD-TDP. Our observations further support the concept that TDP-43 proteinopathies represent a spectrum of disorders, where preferential localization of pathogenetic inclusions and neuronal cell loss defines clinical phenotypes ranging from frontotemporal dementia with or without motor neuron disease, to corticobasal syndrome and to a progressive supranuclear palsy-like syndrome.
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