MAPT Q336H mutation: Intrafamilial phenotypic heterogeneity in a new Italian family

Abstract

Background and purpose: Q336H is a rare MAPT mutation, previously found in a single patient with behavioral variant frontotemporal dementia and tau pathology (Pick bodies).Here, we describe the clinical characteristics of two members of a new family carrying the Q336H MAPT mutation.Methods: Clinical, genetic, and neuroradiological assessment and follow-up of the proband were made.Results: At age 37 years, the proband developed naming and object recognition impairment, due to a lack of knowledge. After 3 years, he developed behavioral disorders.Magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography showed the involvement of the left temporal pole. A diagnosis of semantic variant primary progressive aphasia (svPPA) was made. At follow-up after 6 and 12 months, a rapid worsening of cognitive deficits occurred. His parent presented, at age 65 years, slowly progressive memory deficits without behavioral impairment, and, on MRI, evidence of mesial temporal atrophy, consistent with a clinical diagnosis of Alzheimer disease (AD).Conclusions: This is the second family carrying the MAPT Q336H mutation reported so far. We showed that svPPA and AD-like phenotype can be associated with this mutation. A wide clinical variability exists at the intrafamilial level for Q336H MAPT mutation, pointing to genetic and/or environmental influencing factors on disease expression. We also confirmed that svPPA can be associated with MAPT mutations, suggesting that this gene should be analyzed also in patients with svPPA, especially with early onset. In addition, an AD-like phenotype may be associated with this mutation, suggesting its different effects on protein misfolding and aggregation.

Semantic and right temporal variant of FTD: Next generation sequencing genetic analysis on a single-center cohort

“…We found three mutations in the microtubule-associated protein tau ( MAPT ) gene, which was the first causative gene to be linked to FTD: P301L, Q336H ( Villa et al, 2022 ) and N286N. In addition, we discovered single mutations in the following genes: SQSTM1 , VCP , presenilin 1 ( PSEN1 ), TBK1 , optineurin (OPTN), coiled-coil-helix-coiled-coil-helix domain containing protein 10 ( CHCHD10 ), parkin ( PRKN ) and dynactin 1 ( DCTN1 ).…”

“…Different FTD clinical phenotypes have been associated with the mutation, including svFTD ( Ishizuka et al, 2011 ). Q336H MAPT mutation, carried by patient P12, was recently published as associated with svFTD ( Villa et al, 2022 ). This mutation had been previously functionally and neuropathologically characterized as pathogenic ( Tacik et al, 2015 ).…”

“…Twenty-three patients with clinical diagnosis of svFTD and rtvFTD (15 and 8 respectively) were retrospectively selected from FTD patients followed-up at Fondazione IRCCS Istituto Neurologico Carlo Besta from 2015 to 2020. One of them, carrying a MAPT mutation has been recently published ( Villa et al, 2022 ). Clinical diagnosis of svFTD was made on the basis of current criteria ( Gorno-Tempini et al, 2011 ).…”

“…By single variant analysis, we found 12 variants described as pathogenic in the scientific literature (reported in Human Gene Mutation Database, HGMD) or classified as variant of unknown significance (VUS)/likely pathogenic in 9 patients (39% of patients) and none in control subjects (Table 2). We found three mutations in the microtubule-associated protein tau (MAPT) gene, which was the first causative gene to be linked to FTD: P301L, Q336H (Villa et al, 2022) and N286N. In addition, we discovered single mutations in the following genes: SQSTM1, VCP, presenilin 1 (PSEN1), TBK1, optineurin (OPTN), coiled-coil-helix-coiled-coil-helix domain containing protein 10 (CHCHD10), parkin (PRKN) and dynactin 1 (DCTN1).…”