Subtle neuropsychiatric and neurocognitive changes in hereditary gelsolin amyloidosis (AGel amyloidosis)

Abstract

Hereditary gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominant form of systemic amyloidosis caused by a c.640G>A or c.640G>T mutation in the gene coding for gelsolin. Principal clinical manifestations include corneal lattice dystrophy, cranial neuropathy and cutis laxa with vascular fragility. Signs of minor CNS involvement have also been observed, possibly related to cerebral amyloid angiopathy (CAA). To investigate further if AGel amyloidosis carries a risk for a specific neuropsychological or psychiatric symptomatology we studied 35 AGel patients and 29 control subjects. Neuropsychological tests showed abnormalities in visuocontructional and -spatial performance in AGel patients, also some indication of problems in processing efficacy was found. At psychiatric evaluation the patient group showed more psychiatric symptomatology, mainly depression. In brain MRI, available in 16 patients and 14 controls, we found microhemorrhages or microcalcifications only in the patient group, although the number of findings was small. Our study shows that AGel amyloidosis can be associated with visuoconstructional problems and depression, but severe neuropsychiatric involvement is not characteristic. The gelsolin mutation may even induce cerebrovascular fragility, but further epidemiological and histopathological as well as longitudinal follow-up studies are needed to clarify gelsolin-related vascular pathology and its clinical consequences.

Gene‐level associations in suicide attempter families show overrepresentation of synaptic genes and genes differentially expressed in brain development

“…GSN encodes a calcium‐dependent actin regulatory protein and is ubiquitously implicated in human health (Li, Arora, Chen, McCulloch, & Liu, ). Mutations in GSN can result in hereditary gelsolin amyloidosis, with potential for psychiatric symptoms (Kantanen, Kiuru‐Enari, Salonen, Kaipainen, & Hokkanen, ). GNAS encodes a G‐protein of importance for multiple signaling transduction pathways, including at the synapse, and has been shown to have increased expression in prefrontal cortex of suicides (Dwivedi et al, ).…”

Gelsolin amyloid angiopathy causes severe disruption of the arterial wall

“…Hereditary gelsolin amyloidosis (HGA), also known as familial amyloidosis Finnish type, gelsolinrelated amyloidosis (AGel amyloidosis), and Meretoja disease (OMIM #105120), is a systemic amyloidosis with an autosomal dominant pattern of inheritance (1)(2)(3). HGA is characterized mainly by ophthalmological (corneal lattice dystrophy) (1,3), neurological, most typically cranial and peripheral (somatic and autonomic) neuropathy (4)(5)(6)(7)(8) and lesser central nervous system (spinal and cerebral) (9)(10)(11), and dermatological (cutis laxa) (1, 3) manifestations. Occasionally renal and cardiac signs also occur (3,12).…”

GSNgene frameshift mutations in Alzheimer’s disease

“…Interestingly, reported patients with FAF with GSN missense mutations were usually cognitive normal. 7 27-30 Only one study reported that patients with FAF appeared slightly with abnormalities in visuocontructional and spatial performance, 31 which further confirmed the genotype-phenotype heterogeneity of the GSN gene. The phenomenon of genotype-phenotype heterogeneity has also been reported in other genes previously.…”