An APP mutation family exhibiting white matter hyperintensities and cortical calcification in East China
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ORIGINAL ARTICLE
An APP mutation family exhibiting white matter hyperintensities and cortical calcification in East China Yang Yi 1 & Ye Xiaobin 1,2 & Chen Hui 3 & Zhong Yufa 3 & Zhang Qiaowei 4 & Hu Xingyue 1 & Cai Huaying 1 Received: 9 July 2019 / Accepted: 13 March 2020 # Fondazione Società Italiana di Neurologia 2020
Abstract Heterozygous amyloid precursor protein (APP) mutations cause hereditary cerebral amyloid angiopathy (CAA) and autosomal dominant Alzheimer’s disease (AD). This study aimed at reporting an APP mutation and its associated clinical and neuroimaging features. The proband and her family members presented with memory loss, psychiatric, and visual symptoms. Neuroimaging revealed bilateral white matter intensities (WMH) in cranial magnetic resonance imaging (MRI), cortical calcification, and brain atrophy. Next-generation sequencing-based comprehensive gene panel revealed heterozygous missense variant c.2059A>C (p.K687Q) mutation in the APP gene. Co-segregation analysis identified seven family members to be APP mutation carriers while normal neuroimaging features were seen in all family members lacking the APP mutation. WMH and cortical calcification were observed in patients with CAA, including those with the Iowa (D694N) and Italian (E693K) mutations. Further studies should investigate the functional changes associated with the heterozygous APP mutation (K687Q). Keywords Amyloid precursor protein . Cerebral amyloid angiopathy . Alzheimer’s disease . K687Q . White matter intensities . Cortical calcification
Introduction Specific APP mutations have been associated with cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD). The APP gene encodes the amyloid precursor protein (APP), and mutations in the APP gene lead to increased production of amyloid-β (Aβ) Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10072-020-04342-4) contains supplementary material, which is available to authorized users. * Hu Xingyue [email protected] * Cai Huaying [email protected]
peptide and/or an increase in aggregated forms Aβ40 and Aβ42. Aggregation of the Aβ oligomer in the brain parenchyma is associated with AD [1, 2], while CAA is characterized by the deposition of the Aβ oligomer in the wall of cortical and leptomeningeal blood vessels [3]. Different APP mutation types are responsible for AD, CAA, or both of them [4]. Individuals with APP mutation may have an increased risk of developing dementia [4, 5], stroke [6], and seizures [7]. Neuroimaging features include lobar hematoma, subarachnoid hemorrhages (SAH), cortical and subcortical microbleeds, white matter hyperintensities (WMH), and cortical atrophy [8, 9]. Cortical calcification in APP mutation is not common and has only been reported in familial CAA cases of Iowa and Italian APP mutations carriers [9–14]. The underlying mechanism of cortical calcification is not well established. However, it has been potentially associated with severe amyloidosis of cerebral vessels [14]. This study re
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