Challenging the concept of diffuse neurofibrillary tangles with calcification (Kosaka-Shibayama disease).

Abstract

Since 1994, the term ‘diffuse neurofibrillary tangles with calcification’ (DNTC) has defined a novel and independent neurological condition, also known as Kosaka–Shibayama disease. This condition is characterized by dementia, psychosis, localized brain atrophy, and bilateral brain calcification with neurofibrillary tangles (NFT).1 According to Ukai and Kosaka,1 those characteristics set DNTC distinctly apart from primary familial brain calcification (PFBC), a neuropsychiatric condition, also known as ‘Fahr's disease’ (now considered a misnomer), which is also characterized by bilateral and symmetrical brain calcifications. Another characteristic of DNTC identified by those authors is the absence of familial cases. Intriguingly, the majority of DNTC cases are from necropsies carried out in Japan. First of all, the clinical symptoms of DNTC might also be found in PFBC cases, as well as brain atrophy.2 Ukai and Kosaka performed a historic review of DNTC cases and suggested clinical criteria to classify suspect cases as possible or probable DNTC. However, we postulate that DNTC could be a different phenotype of PFBC.1 Considering the obvious clinical and neuroimaging resemblances between DNTC and PFBC, we suggest that NFT findings could be due to cohort bias, considering that, according to the same authors, 57.6% of cases were over 60 years old. Moreover, genetic studies provide the most powerful evidence of our hypothesis. Since 2012, four genes have been linked to PFBC, SLC20A2, PDGFRB, PDGFB, and XPR1, explaining approximately 60% of the familial cases and a few sporadic subjects with de novo mutations, in many different countries and from various ethnic backgrounds, including Japan.3 Recently, Yamada et al. 4 reported a family linked to a SLC20A2 mutation, with a proband previously diagnosed as having DNTC. Additionally, Kimura et al. 5 reported another PFBC case linked to a different SLC20A2 mutation, also presenting NFT. This confirms that Tau deposition might be an incidental finding linked to an older population of patients.4, 5 Nunomura6 wrote a recent editorial in this journal regarding some of the issues we highlighted here. Hence, we strongly suggest that all patients diagnosed with or suspected of having DNTC need to be screened for mutations linked to PFBC. Only with genetic studies we can ensure that DNTC is really a new entity and not a phenotype of PFBC.6 This study received no direct financial support. The authors declare no conflicts of interest.