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Hereditary cerebral hemorrhage with amyloidosis, Dutch type (ABeta amyloidosis, dutch type) is an autosomal dominant cerebrovascular amyloid angiopathy characterized by recurrent intracerebral hemorrhages and stroke in mid‐adulthood. The amyloid deposits are composed predominantly of amyloid β‐protein derived from the APP precursor. Clinically, affected individuals present with lobar hemorrhages, cognitive decline, and progressive white‐matter changes often in the fifth to sixth decades.
The Dutch mutation was first reported in two unrelated probands carrying a heterozygous missense variant at codon 618 of APP, with diagnostic assays subsequently establishing the allele in two additional family members, one presymptomatic ([PMID:1763898]). Segregation across four families affirmed co-inheritance of the variant with disease phenotypes. Age at first bleed ranged from 50–60 years, and pathological examination confirmed severe amyloid angiopathy.
Molecular analysis identified the alteration as c.2077G>C (p.Glu693Gln), substituting glutamic acid to glutamine within the Aβ domain. This variant impairs APP processing and enhances vascular amyloid deposition in vivo, consistent with a toxic gain-of-function mechanism. While no direct functional studies of the Dutch allele have been reported, analogous APP mutations promote early Aβ aggregation and vessel wall fragility.
No studies have refuted this association, and no phenocopies lacking the variant have been documented in Dutch‐type families. The lack of alternative pathogenic alleles in these pedigrees further supports specificity. Functional data from related APP mutations substantiate a shared mechanism of Aβ‐mediated vascular injury.
In summary, the APP c.2077G>C (p.Glu693Gln) variant shows moderate clinical validity for autosomal dominant Dutch‐type cerebral amyloid angiopathy, supported by multiple unrelated families, clear segregation, and concordant mechanistic inference. Genetic testing for this mutation informs diagnosis, risk assessment, and family counseling in suspected HCHWA-D cases.
Gene–Disease AssociationModerate4 probands ([PMID:1763898]), segregation in 4 families ([PMID:1763898]) Genetic EvidenceModerateFour unrelated probands with the APP codon 618 variant and segregation in multiple family members ([PMID:1763898]) Functional EvidenceLimitedNo direct functional assays of the Dutch allele; inference based on analogous APP variants |