Cerebral Amyloid Angiopathy, Cst3-Related

A number sign (#) is used with this entry because of evidence that this form of cerebral amyloid angiopathy (CAA) is caused by mutation in the gene encoding cystatin C (CST3; 604312) on chromosome 20p11.2.

For a discussion of genetic heterogeneity of CAA, see 605714.

Description

Cerebral amyloid angiopathy (CAA), defined by the deposition of congophilic material in the vessels of the cortex and leptomeninges, is a major cause of intracerebral hemorrhage in the elderly (Vinters, 1987, Greenberg, 1998). Palsdottir et al. (1988) referred to the disorder in Icelandic patients as hereditary cystatin C amyloid angiopathy (HCCAA).

Clinical Features

Arnason (1935) described 10 Icelandic families with a high incidence of cerebral hemorrhage and concluded that a hereditary form of the disease was present in these families. Also in Iceland, Gudmundsson et al. (1972) studied a kindred in which 18 persons in 3 generations had cerebral hemorrhage, some of them at a young age. Cerebral arteries showed thickening of the walls with deposition of material with the characteristics of amyloid. Amyloid was not found in other arteries except in a case of long-standing tuberculosis. Male-to-male transmission was observed, consistent with autosomal dominant inheritance.

Mandybur and Bates (1978) reported a 58-year-old normotensive woman who died 24 hours after a stroke. Two months earlier, she had a transient neurologic episode consistent with cerebrovascular insufficiency. Postmortem examination showed a massive recent hemorrhage in the right occipital lobe associated with severe cerebral amyloid angiopathy. The cerebral cortex showed interstitial and perivascular neuritic plaques but no tangles. There was no family history. A literature review indicated that massive intracerebral hemorrhage seemed to be more common in patients with familial Icelandic forms of cerebral amyloid angiopathy. The authors thus recognized cerebral amyloid angiopathy as a cause of sporadic intracerebral hemorrhage.

Cohen et al. (1983) stated that 75 cases of hereditary cerebral hemorrhage with amyloidosis (HCHWA) had been identified in the Icelandic population. Characteristically, nonhypertensive, previously healthy persons suffer sudden catastrophic, often multifocal cerebral hemorrhages from intraparenchymal and/or meningeal vessels extensively infiltrated with amyloid.

By 1986, the Icelandic experience included 128 affected members in 8 families originating from the same geographic area of Iceland (Jensson et al., 1986). Over 80% of those who died from this disease were less than 40 years of age. Abnormally low cystatin C in the cerebrospinal fluid was a characteristic that could be used in identifying asymptomatic affected persons.

Biochemical Features

Cohen et al. (1983) analyzed the amyloid proteins deposited in the cerebral arteries of 3 young Icelandic patients who died of cerebral hemorrhage. Amino-terminal sequencing showed the proteins to be similar to a human protein called gamma-trace, or cystatin C. The amyloid deposits in all 3 patients stained with rabbit anti-gamma-trace antiserum.

Grubb et al. (1984) found low levels of gamma-trace in 9 patients with the cerebrovascular form of amyloidosis. The CSF concentration of beta-2-microglobulin, a microprotein of about the same size as gamma-trace, did not differ from the normal. No structural abnormality of gamma-trace in the CSF of patients could be demonstrated. Grubb et al. (1984) concluded that the basic defect in this disease is an abnormality in the catabolic processing of gamma-trace. The findings provided a diagnostic index of high sensitivity and specificity.

Lofberg et al. (1987) found that amyloid angiopathy characterized by an immunoreactivity of cystatin C was present in a submandibular lymph node in addition to small arteries in the cerebrum, cerebellum, and leptomeninges. All 9 persons investigated showed low CSF cystatin C. The cystatin C in the CSF of these patients had an isoelectric point identical to that of normal persons. Fibroblasts and glial cells secrete cystatin C into tissue culture fluids (Palsdottir et al., 1988).

Diagnosis

Differential Diagnosis

The forms of HCHWA in Iceland and in the Netherlands (605714) represent fundamentally separate diseases (van Duinen et al., 1987). Differences that have been noted between the 2 forms include the following: Icelandic patients suffer the first stroke at a mean age of 27 years, whereas the Dutch patients are approximately 25 years older; the level of cystatin C in the cerebrospinal fluid of Icelandic patients is lower than that in Dutch patients or in healthy persons; and, immunohistochemically, intense staining for cystatin C is found in diseased Icelandic brain vessels, whereas in the Dutch material only weak or dubious staining is found. There is no evidence of genealogic connection between the Dutch and Icelandic families. A critical piece of evidence indicating a difference between the 2 diseases is the finding by van Duinen et al. (1987) that in the Dutch form of the disease the vascular amyloid deposits have immunohistochemical characteristics of Alzheimer disease-related beta-protein (APP; 104760).

Molecular Genetics

In Icelandic patients with hereditary cerebral hemorrhage with amyloidosis, Abrahamson et al. (1987) identified a heterozygous mutation in the CST3 gene (L68Q; 604312.0001). Palsdottir et al. (1988) identified this mutation in affected members of 8 families, establishing incontrovertibly that the mutation is the cause of this disorder.

Abrahamson et al. (1992) described a rapid and simple method of diagnosis of the Icelandic form of amyloidosis based on oligonucleotide-directed enzymatic amplification of a 275-bp genomic DNA segment containing exon 2 of the cystatin C gene from a blood sample, followed by digestion of the amplification product with AluI. This process could identify the common L68Q mutation.

Graffagnino et al. (1994) failed to find the Icelandic cystatin C mutation in any of 48 consecutive patients with intracerebral hemorrhage admitted to Duke University Hospital. No pathology was reported on these cases.

Population Genetics

Jensson et al. (1989) reviewed the history of the Icelandic variety in an article appropriately called 'The saga of the cystatin C mutation causing amyloid angiopathy and brain hemorrhage.' They pointed out that the patients show cystatin C amyloid as a regular histopathologic finding in lymphoid tissue, spleen, salivary glands, and seminal vesicles. A biopsy of these tissues can be used in confirmation of the diagnosis. Geographic distribution of the cases demonstrated 2 clusters in Iceland. Jensson et al. (1989) also gave a listing of autosomal dominant, autosomal recessive, and X-linked disorders that have been identified and studied in Iceland.