Intrafamilial variable phenotype including corticobasal syndrome in a family with p.P301L mutation in the MAPT gene: first report in South America

Abstract

Frontotemporal lobar degeneration (FTLD) is a neuropathological disorder that causes a variety of clinical syndromes including fronto-temporal dementia (FTD), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). FTD associated with parkinsonism occurs frequently as a result of mutations in the C9orf72 gene and also in the genes coding for the protein associated with microtubule tau (MAPT) and progranulin (GRN) on chromosome 17 (FTDP-17). Herein we report an Argentinean family, of Basque ancestry, with an extensive family history of behavioral variant of FTD (bvFTD). Twenty one members over 6 generations composed the pedigree. An extensive neurological and neurocognitive examination was performed on 2 symptomatic individuals and 3 non-symptomatic individuals. Two different phenotypes were identified among affected members, CBS in the proband and FTD in his brother. DNA was extracted from blood for these five individuals and whole-exome sequencing (WES) was performed on 3 of them followed by Sanger sequencing of candidate genes on the other 2. In both affected individuals a missense mutation (p.P301L; rs63751273) in exon 10 of the MAPT gene (chr17q21.3) was identified. Among MAPT mutations, p.P301L is the most frequently associated to different phenotypes: a) aggressive, symmetrical and early-onset Parkinsonism; b) late parkinsonism associated with FTD and c) PSP but only exceptionally it is reported associated to CBS. This is the first report of the occurrence of the p.P301L-MAPT mutation in South America and supports the marked phenotypic heterogeneity among members of the same family as previously reported.

Genetics of dementia: insights from Latin America

“…During the follow-up, the CBS proband developed gait disturbance, high risk of fall, worsening of motor symptoms in her right arm (focal dystonia and alien limb syndrome), myoclonus, hyperreflexia, apraxia, and frontal release signs. 16 Attention and executive function worsened, and she developed problems with memory and language. 16 The second case (FTD) involved a man with symptoms such as logorrhea, tangentiality, disinhibition, inappropriate behavior such as waking his son up at night just to talk (the authors of the report considered it a lack of empathy), isolation, compulsions (alcoholism), repetitive behaviors (eating the same meals every day), emotional apathy (he seemed not to care about his difficult financial situation), and grooming neglect.…”

“…16 Attention and executive function worsened, and she developed problems with memory and language. 16 The second case (FTD) involved a man with symptoms such as logorrhea, tangentiality, disinhibition, inappropriate behavior such as waking his son up at night just to talk (the authors of the report considered it a lack of empathy), isolation, compulsions (alcoholism), repetitive behaviors (eating the same meals every day), emotional apathy (he seemed not to care about his difficult financial situation), and grooming neglect. 16 Neuropsychological tests led to the conclusion that he had attention problems and executive impairment (as in the proband's case).…”

“…In 2017, Gatto et al reported an intrafamilial variable phenotype in a family with a missense mutation (p.P301L; rs63751273) in exon 10 of the MAPT gene. 16 This family of Basque ancestry had 26 members over 6 generations and 9 affected individuals. The two living subjects analyzed had different phenotypes: CBS (1 female) and FTD (1 male), while the 7 deceased family members over 4 generations, whose cases were described as early-onset dementia, presented with apathy and disinhibition as the main symptoms.…”

“…During the follow-up, the CBS proband developed gait disturbance, high risk of fall, worsening of motor symptoms in her right arm (focal dystonia and alien limb syndrome), myoclonus, hyperreflexia, apraxia, and frontal release signs. 16 Attention and executive function worsened, and she developed problems with memory and language. 16 …”

Unravelling Genetic Factors Underlying Corticobasal Syndrome: A Systematic Review

“…They are an established cause of FTD with parkinsonism-17 (FTDP-17) [ 47 ] and, less frequently, of PSP [ 48 ]. In rare cases, certain MAPT mutations can lead to a CBS presentation [ 49 , 50 , 51 , 52 , 53 , 54 , 55 ].…”