The historical background of hereditary cystatin C amyloid angiopathy: Genealogical, pathological, and clinical manifestations

Abstract

Hereditary cystatin C amyloid angiopathy (HCCAA) is an Icelandic disease that belongs to a disease class called cerebral amyloid angiopathy, a group of heterogenous diseases presenting with aggregation of amyloid complexes and deposition predominantly in the central nervous system. HCCAA is dominantly inherited, caused by L68Q mutation in the cystatin C gene, leading to aggregation of the cystatin C protein. HCCAA is a very progressive and severe disease, with widespread cerebral and parenchymal cystatin C and collagen IV deposition within the central nervous system (CNS) but also in other organs in the body, for example, in the skin. Most L68Q carriers have clinical symptoms characterized by recurrent hemorrhages and dementia, between the age of 20-30 years. If the carriers survive the first hemorrhage, the frequency and severity of the hemorrhages tend to increase, resulting in death at average of 30 years with mean number of major hemorrhages ranging from 3.2 to 3.9 over a 5-year average life span. The pathogenesis of the disease in carriers is very similar in the CNS and in the skin based on autopsy studies, thus skin biopsies can be used to monitor the progression of the disease by quantifying the cystatin C immunoreactivity. The cystatin C deposition always colocalizes with collagen IV and fibroblasts in the skin are found to be the main cell type responsible for the deposition of both proteins. No therapy is available for this devastating disease.

Keywords: N‐acetylcysteine; cerebral amyloid angiopathy; collagen IV; cystatin C; hemorrhage; hereditary cystatin C amyloid angiopathy.

FIGURE 1

Carriers/patients born each decade since 1800. A graph showing the rate of births and deaths for carriers, living carriers are not included. The number of deaths peaked three decades after births.

FIGURE 2

Map of Iceland showing where the HCCAA families lived in 1800. The stripes on the map show where the HCCAA family lived. The oldest known common carriers were a sib pair, a man (born 1684) who moved from the Snæfellsnes peninsula (marked by a star) to the South coast and started a big family, and his sister (born 1670) an ancestor of a big family in the west country.

FIGURE 3

Pedigree of a typical HCCAA family. The pedigree shows a typical HCCAA family, women are depicted as circles, men as squares. The year of birth and the age at death are shown under each symbol. Obligate carriers are labeled with a dot and those who got a diagnosis, either in parish records or a death certificate are shown as full symbols. The oldest male is linked to another family.

FIGURE 4

Life span of HCCAA carriers and spouses. (A) A graph showing the relationship between the life span and the year of birth of carriers since 1800. The life span fell during the 19th century from about 60 years on average to about age 30 at the end of the century. This was noticeable for both female and male patients. (B) A graph showing the relationship between the life span of the spouses of HCCAA carriers. As shown, the life span of spouses increased slightly after 1800 in contrast to the carriers who's life span dropped significantly after 1800. The dotted lines present the trendlines. Adapted from [23] with more individuals.

FIGURE 5

Number of childless carriers born. A graph showing that the number of childless carriers born increased relative to the total number of carriers born. The number of childless individuals increased as the penetrance of the cystatin C L68Q mutation increased during the 19th century. The first signs of disease or death often occurred too early for marriage or childbirth.

FIGURE 6

Maternal or paternal inheritance. A graph shows that carriers who got the L68Q gene from their mother had a shorter life span than those who inherited it from their father.

FIGURE 7

Brain pathology in HCCAA patients. (A)–(I) Post‐mortem brain samples showing leptomeningeal vessels and the surface of a sulcus in the cerebrum. (A) H&E staining shows thickened and acellular arterial vessel walls, smaller arteries/arterioles are more affected, and affected vessel with double barrel lumen (arrow). (B) Severe cystatin C deposition (cystatin C amyloid complexes) in all layers of the vessel wall in almost all vessels in leptomeningeal space and in the cerebral cortex, with deposition most prominently in medium and small‐sized arteries and arterioles. Some arterioles with completely occluded lumen. (C) Cystatin C immunostaining showing focal parenchymal cystatin C deposits/plaques (amyloid cystatin C complexes) at the surface of a sulcus of the cerebrum (arrow pointing to one plaque). Deposition is also evident in vein (arrow). (D) Arrow pointing to plaque in the surface of a sulcus in the cerebrum in H&E staining. (E) Collagen IV immunostaining in vessels, dense accumulation of collagen IV in both arteries/arterioles and veins/venules, in all layers of the vessel walls. (F) Cystatin C deposition in same vessels as seen in (E) shows very similar distribution as collagen IV accumulation. (G), (H) Same focal deposits/plaques in adjacent sections stained with cystatin C (G) and collagen IV (H), arrows point to collagen IV staining in same focal deposits as seen in cystatin C staining. (I) Affected arteries/arterioles with scarce SMA staining and arterioles with no SMA cells left (arrow), red arrow pointing to venule with mostly intact SMA layer. Scale bar: 250 μm on all figures.

FIGURE 8

Skin pathology in HCCAA patients. (A) H&E staining in skin biopsy from a carrier shows normal skin structure, apart from increased density of cells in the upper dermis, right beneath the epidermis (arrows). (B) Cystatin C immunostaining in asymptomatic carrier with relativity weak staining in the basement membrane between epidermis and dermis and in basement membranes in vessels in the dermis. (C) Extensive cystatin C deposition (reflective of cystatin C amyloid complexes) in a symptomatic carrier, most evident in the basement membrane between epidermis and dermis and in basement membrane vessels in the dermis. (D) Higher magnification of H&E staining showing eosinophilic material right beneath epidermis and increased density of cells (arrows). (E) Increased density of vimentin‐positive cells in the same area as seen in (D), that is, in the upper dermis. (F) A higher magnification of vimentin‐positive cells, these cells have the activated appearance of fibroblasts (arrows point to two examples). (G) SMAD 2/3 positivity in activated fibroblasts in the upper dermis and in vessels (arrows). (H) Collagen IV immunostaining with intense positivity in basement membranes, especially between epidermis and dermis. (I) Collagen IV immunostaining in higher magnification shows cells (which are also vimentin‐positive) with collagen IV staining (arrows). Scale bar: 250 μm on all figures.

FIGURE 9

Confocal immunofluorescence staining in cerebral vessel and in skin biopsy from patient/carrier. (A)–(C) Immunofluorescence staining in the vessel wall of cerebral artery, showing especially the media of the wall, where initial cystatin C deposition (amyloid cystatin C complexes) occurs. The immunoreactivity for collagen IV and cystatin C reveals a close association between both proteins. The arrows point to a basement membrane around one smooth muscle cell with collagen IV and cystatin C positivity. A spatial overlap (purple color) of both fluorescent labels is noticeable in (C). (D)–(F) Immunofluorescence staining in skin biopsy, revealing close association between collagen IV and cystatin C with spatial overlap of both fluorescent labels (yellow color) in (F). Scale bar: 50 μm on all figures.

FIGURE 10

Age at first symptoms. The graph shows age at first symptoms in L68Q carries born after the year 1900. Age at first symptoms range from 16 to 79‐years‐old with only three carriers over 50 years. Most carriers have the first symptoms between 20 and 30‐years‐old with mean age at death 30‐years‐old.