Symmetrical Corticobasal Syndrome Caused by a Novel c.314dup Progranulin Mutation

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.

Pathology and sensitivity of current clinical criteria in corticobasal syndrome

“…Myoclonus and memory impairment, especially when they appear at an early stage of the disease, may predict CBS‐AD according to a previous report . However, symmetric CBS might not predict CBS‐AD, because symmetric CBS is also observed in CBS‐CBD and in CBS caused by progranulin mutation . Early diagnosis of CBS‐CBD is still difficult, because, to date, no characteristic features have been identified that can predict CBD pathology.…”

Visual signs and symptoms of corticobasal degeneration

“…47 In addition, a rare mutation of the tau gene has been reported in a single case of CBD. 48 Research also suggests a possible association between CBD and mutations of the progranulin 49 and fused in sarcoma 50 genes, which have also been implicated in FTLD. 5…”

Corticobasal Degeneration and Dementia

“…In addition, there is no evidence that it is caused by a virus or other infectious agent. Recent research also suggests associations between CBD and mutations of the progranulin (GRN) [41], and fused in sarcoma (FUS) [42] genes emphasizing further the relationship between CBD and FTD [13]. Mutations affecting the alternate spliced exon 10 or the 5' regulatory region of the tau gene do result in the type of filamentous inclusions observed in various tauopathies including CBD [39], and hence, it is possible that tau mutations could be identified in CBD.…”