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

Frontotemporal lobar degeneration is a neuropathological disorder that causes a variety of clinical syndromes including frontotemporal dementia (FTD), progressive supranuclear palsy, 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. Twenty-one members over 6 generations composed the pedigree. An extensive neurologic and neurocognitive examination was performed on 2 symptomatic individuals and 3 nonsymptomatic 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 5 individuals and whole-exome sequencing 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: (1) aggressive, symmetrical, and early-onset Parkinsonism; (2) late parkinsonism associated with FTD; and (3) progressive supranuclear palsy 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.

The PSP-associated MAPT H1 subhaplotype in Guadeloupean atypical parkinsonism.

The aim of this study was to determine whether the H1 subhaplotype in MAPT associated with progressive supranuclear palsy (PSP) in Caucasians confers risk for PSP-like atypical parkinsonism in Guadeloupe, a tauopathy. Guadeloupean controls and patients with atypical and idiopathic parkinsonism and ethnically and age-matched controls were genotyped for H1 and H2 alleles, then for the H1 subhaplotype associated with PSP in Caucasians, using previously described haplotype-tagging single nucleotide polymorphisms (Ht-SNPs) in linkage disequilibrium at the MAPT locus. Most Guadeloupean controls and patients were homozygous for the H1 allele; only 5% were heterozygous for the H2 allele, consistent with the European contribution to the racial admixture in Guadeloupe, but equivalent to the frequency found in Caucasian PSP patients. The frequencies of the Ht-SNPs used to determine the PSP-associated H1 subhaplotype in both Guadeloupean controls and parkinsonians were similar, indicating that the H1 subhaplotype associated with PSP in Caucasians was not a risk factor for PSP-like atypical parkinsonism in Guadeloupe. Interestingly, they were also similar to the frequencies in Caucasian PSP patients. The major H1 subhaplotype in Guadeloupe, determined by analysis of linkage desequibrium, differed from the major Caucasian subhaplotype, but corresponded to minor alleles previously described.

Steele-Richardson-Olszewski syndrome in a patient with a single C212Y mutation in the parkin protein.

Steele-Richardson-Olszewski syndrome (SROS) is a neurodegenerative disorder of unknown aetiology, most frequently sporadic. Familial cases of SROS have been described. An intronic polymorphism of the tau gene is associated with sporadic SROS and mutations of the tau gene are present in atypical cases of SROS. The role of tau has been excluded in other families with pathology proven SROS, suggesting that this syndrome may have multiple causes. An 82-year-old patient, father of 3 children with autosomal recessive juvenile parkinsonism due to combined heterozygous mutations of the parkin gene, developed clinical features of SROS 2 years before death. The diagnosis was confirmed by pathology. He carried the C212Y mutation of the parkin gene and was homozygous for the A0 polymorphism and for the H1 haplotype. The role of parkin in the processing of tau is discussed.