Alternative titles; symbols
SNOMEDCT: 45639009, 724357007; ORPHA: 100008, 85458; DO: 0070027;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20p11.21 | Cerebral amyloid angiopathy | 105150 | Autosomal dominant | 3 | CST3 | 604312 |
A number sign (#) is used with this entry because of evidence that this form of cerebral amyloid angiopathy (CAA) is caused by heterozygous mutation in the gene encoding cystatin C (CST3; 604312) on chromosome 20p11.
For a discussion of genetic heterogeneity of CAA, see 605714.
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).
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.
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).
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).
The transmission pattern of CST3-related cerebral amyloid angiopathy in the families reported by Palsdottir et al. (1988) was consistent with autosomal dominant inheritance.
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.
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.
Abrahamson, M., Grubb, A., Olafsson, I., Lundwall, A. Molecular cloning and sequence analysis of cDNA coding for the precursor of the human cysteine proteinase inhibitor cystatin C. FEBS Lett. 216: 229-233, 1987. [PubMed: 3495457] [Full Text: https://doi.org/10.1016/0014-5793(87)80695-6]
Abrahamson, M., Jonsdottir, S., Olafsson, I., Jensson, O., Grubb, A. Hereditary cystatin C amyloid angiopathy: identification of the disease-causing mutation and specific diagnosis by polymerase chain reaction based analysis. Hum. Genet. 89: 377-380, 1992. [PubMed: 1352269] [Full Text: https://doi.org/10.1007/BF00194306]
Arnason, A. Apoplexie und ihre Vererbung. Acta Psychiat. Neurol. 7 (suppl.): 1-180, 1935.
Cohen, D. H., Feiner, H., Jensson, O., Frangione, B. Amyloid fibril in hereditary cerebral hemorrhage with amyloidosis (HCHWA) is related to the gastroentero-pancreatic neuroendocrine protein, gamma trace. J. Exp. Med. 158: 623-628, 1983. [PubMed: 6886625] [Full Text: https://doi.org/10.1084/jem.158.2.623]
Ghiso, J., Jensson, O., Frangione, B. Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C). Proc. Nat. Acad. Sci. 83: 2974-2978, 1986. [PubMed: 3517880] [Full Text: https://doi.org/10.1073/pnas.83.9.2974]
Ghiso, J., Pons-Estel, B., Frangione, B. Hereditary cerebral amyloid angiopathy: the amyloid fibrils contain a protein which is a variant of cystatin C, an inhibitor of lysosomal cysteine proteases. Biochem. Biophys. Res. Commun. 136: 548-554, 1986. [PubMed: 3707586] [Full Text: https://doi.org/10.1016/0006-291x(86)90475-4]
Graffagnino, C., Herbstreith, M. H., Roses, A. D., Alberts, M. J. A molecular genetic study of intracerebral hemorrhage. Arch. Neurol. 51: 981-984, 1994. [PubMed: 7945009] [Full Text: https://doi.org/10.1001/archneur.1994.00540220027011]
Greenberg, S. M. Cerebral amyloid angiopathy: prospects for clinical diagnosis and treatment. Neurology 51: 690-694, 1998. [PubMed: 9748011] [Full Text: https://doi.org/10.1212/wnl.51.3.690]
Grubb, A., Jensson, O., Gudmundsson, G., Arnason, A., Lofberg, H., Malm, J. Abnormal metabolism of gamma-trace alkaline microprotein: the basic defect in hereditary cerebral hemorrhage with amyloidosis. New Eng. J. Med. 311: 1547-1549, 1984. [PubMed: 6390199] [Full Text: https://doi.org/10.1056/NEJM198412133112406]
Gudmundsson, G., Hallgrimsson, J., Jonasson, T. A., Bjarnason, O. Hereditary cerebral haemorrhage with amyloidosis. Brain 95: 387-404, 1972. [PubMed: 4655034] [Full Text: https://doi.org/10.1093/brain/95.2.387]
Hochwald, G. M., Thorbecke, G. J. Abnormal metabolism or reduced transport of CSF gamma-trace microprotein in hereditary cerebral hemorrhage with amyloidosis. (Letter) New Eng. J. Med. 312: 1127-1128, 1985. [PubMed: 3982473] [Full Text: https://doi.org/10.1056/nejm198504253121715]
Jensson, O., Arnason, A., Thorsteinsson, L., Petursdottir, I., Gudmundsson, G., Blondal, H., Grubb, A., Lofberg, H., Luyendijk, W., Bots, G. T. A. M., Frangione, B. Cystatin C (gamma-trace) amyloidosis.In: Turk, V. : Cysteine Proteinases and their Inhibitors. New York: Walter de Gruyter and Co. (pub.) 1986.
Jensson, O., Gudmundsson, G., Arnason, A., Blondal, H., Petursdottir, I., Thorsteinsson, L., Grubb, A., Lofberg, H., Cohen, D., Frangione, B. Hereditary cystatin C (gamma-trace) amyloid angiopathy of the CNS causing cerebral hemorrhage. Acta Neurol. Scand. 76: 102-114, 1987. [PubMed: 3673496] [Full Text: https://doi.org/10.1111/j.1600-0404.1987.tb03553.x]
Jensson, O., Palsdottir, A., Thorsteinsson, L., Arnason, A. The saga of cystatin C gene mutation causing amyloid angiopathy and brain hemorrhage--clinical genetics in Iceland. Clin. Genet. 36: 368-377, 1989. [PubMed: 2689007] [Full Text: https://doi.org/10.1111/j.1399-0004.1989.tb03215.x]
Kidd, H. A., Cumings, J. N. Cerebral angiomata in an Icelandic family. Lancet 249: 747-748, 1947. Note: Originally Volume I. [PubMed: 20241165] [Full Text: https://doi.org/10.1016/s0140-6736(47)91494-3]
Lofberg, H., Grubb, A. O., Nilsson, E. K., Jensson, O., Gudmundsson, G., Blondal, H., Arnason, A., Thorsteinsson, L. Immunohistochemical characterization of the amyloid deposits and quantitation of pertinent cerebrospinal fluid proteins in hereditary cerebral hemorrhage with amyloidosis. Stroke 18: 431-440, 1987. [PubMed: 2436360] [Full Text: https://doi.org/10.1161/01.str.18.2.431]
Mandybur, T. I., Bates, S. R. D. Fatal massive intracerebral hemorrhage complicating cerebral amyloid angiopathy. Arch. Neurol. 35: 246-248, 1978. [PubMed: 637762] [Full Text: https://doi.org/10.1001/archneur.1978.00500280064014]
Palsdottir, A., Abrahamson, M., Thorsteinsson, L., Arnason, A., Olafsson, I., Grubb, A., Jensson, O. Mutation in cystatin C gene causes hereditary brain haemorrhage. Lancet 332: 603-604, 1988. Note: Originally Volume II. [PubMed: 2900981] [Full Text: https://doi.org/10.1016/s0140-6736(88)90641-1]
Roosen, N., Martin, J.-J., De La Porte, C., Van Vyve, M. Intracerebral hemorrhage due to cerebral amyloid angiopathy: case report. J. Neurosurg. 63: 965-969, 1985. [PubMed: 4056911] [Full Text: https://doi.org/10.3171/jns.1985.63.6.0965]
Smith, D. B., Hitchcock, M., Philpott, P. J. Cerebral amyloid angiopathy presenting as transient ischemic attacks: case report. J. Neurosurg. 63: 963-964, 1985. [PubMed: 4056910] [Full Text: https://doi.org/10.3171/jns.1985.63.6.0963]
Stefansson, K., Antel, J. P., Oger, J., Burns, J., Noronha, A. B. C., Roos, R. P., Arnason, B. G. W., Gudmundsson, G. Autosomal dominant cerebrovascular amyloidosis: properties of peripheral blood lymphocytes. Ann. Neurol. 7: 436-440, 1980. [PubMed: 7396423] [Full Text: https://doi.org/10.1002/ana.410070508]
van Duinen, S. G., Castano, E. M., Prelli, F., Bots, G. T. A. M., Luyendijk, W., Frangione, B. Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is related to Alzheimer disease. Proc. Nat. Acad. Sci. 84: 5991-5994, 1987. [PubMed: 3475718] [Full Text: https://doi.org/10.1073/pnas.84.16.5991]
Vinters, H. V. Cerebral amyloid angiopathy: a critical review. Stroke 18: 311-324, 1987. [PubMed: 3551211] [Full Text: https://doi.org/10.1161/01.str.18.2.311]