Central nervous system amyloidoses
Beta protein amyloid
The amyloid beta precursor protein (AbPP), which is a transmembrane glycoprotein, is the precursor protein in beta protein amyloid (Ab). Three distinct clinical settings are as follows:
- Alzheimer disease has a normal-sequence protein, except in some cases of familial Alzheimer disease, in which mutant beta protein is inherited in an autosomal dominant manner.
- Down syndrome has a normal-sequence protein that forms amyloids in most patients by the fifth decade of life.
- Hereditary cerebral hemorrhage with amyloidosis (HCHWA), Dutch type, is inherited in an autosomal dominant manner. The beta protein contains a point mutation. These patients typically present with cerebral hemorrhage followed by dementia.
Prion protein amyloidosis
The precursor protein in prion protein amyloidosis (APrP) is a prion protein, which is a plasma membrane glycoprotein. The etiology is either infectious (ie, kuru) or genetic (ie, Creutzfeldt-Jakob disease [CJD], Gerstmann-Sträussler-Scheinker [GSS] syndrome, fatal familial insomnia [FFI]). The infectious unit is the prion protein, which induces a conformational change in a homologous protein encoded by a host chromosomal gene. Patients with CJD, GSS, and FFI carry autosomal dominant amyloidogenic mutations in the prion protein gene; therefore, the amyloidosis forms even in the absence of an infectious trigger.
Similar infectious animal disorders include scrapie in sheep and goats and bovine spongiform encephalitis (ie, mad cow disease).
Cystatin C amyloidosis
The precursor protein in cystatin C amyloidosis (ACys) is cystatin C, which is a cysteine protease inhibitor that contains a point mutation. This condition is clinically termed HCHWA, Icelandic type.
ACys is autosomal dominant. Clinical presentation includes multiple strokes and mental status changes beginning in the second or third decade of life. Many of the patients die by age 40 years. This disease is documented in a 7-generation pedigree in northwest Iceland. The pathogenesis is one of mutant cystatin that is widely distributed in tissues, but fibrils form only in the cerebral vessels; therefore, local conditions must play a role in fibril formation.
Non-amyloid beta cerebral amyloidosis (chromosome 13 dementias)
Two syndromes (British and Danish familial dementia) that share many aspects of clinical Alzheimer disease have been identified. Findings include the presence of neurofibrillary tangles, parenchymal preamyloid and amyloid deposits, cerebral amyloid angiopathy, and amyloid-associated proteins. Both conditions have been linked to specific mutations on chromosome 13; they cause abnormally long protein products (ABri and ADan) that ultimately result in different amyloid fibrils.
Other localized amyloidoses
The precursor protein in gelsolin amyloidosis (AGel) is the actin-modulating protein gelsolin. Amyloid fibrils include a gelsolin fragment that contains a point mutation. Two amyloidogenic gelsolin mutations are described. One example is Asp187Asn, which is endemic in southeast Finland.
Clinical characteristics include slowly progressive cranial neuropathies, distal peripheral neuropathy, and lattice corneal dystrophy.
Atrial natriuretic factor amyloidosis
The precursor protein is atrial natriuretic factor (ANF), a hormone controlling salt and water homeostasis, and it is synthesized by the cardiac atria. Amyloid deposits are localized to the cardiac atria. This condition is highly prevalent in elderly people and generally is of little clinical significance. Atrial natriuretic factor amyloidosis (AANF) is most common in patients with long-standing congestive heart failure, presumably because of persistent ANF production. No relation exists to the amyloidoses that involve the cardiac ventricles (ie, AL, ATTR).
Keratoepithelin amyloidosis and lactoferrin amyloidosis
Point mutations occur in a gene termed BIGH3, which encodes keratoepithelin and leads to autosomal dominant corneal dystrophies characterized by the accumulation of corneal amyloid. Some BIGH3 mutations cause amyloid deposits, and others cause nonfibrillar corneal deposits. Another protein, lactoferrin, is also reported as the major fibril protein in familial subepithelial corneal amyloidosis. The relationship between keratoepithelin and lactoferrin in familial corneal amyloidosis is not yet clear.
In calcitonin amyloid (ACal), the precursor protein is calcitonin, a calcium regulatory hormone synthesized by the thyroid. Patients with medullary carcinoma of the thyroid may develop localized amyloid deposition in the tumors, consisting of normal-sequence procalcitonin (ACal). The presumed pathogenesis is increased local calcitonin production, leading to a sufficiently high local concentration of the peptide and causing polymerization and fibril formation.
Islet amyloid polypeptide amyloidosis
In islet amyloid polypeptide amyloidosis (AIAPP), the precursor protein is an islet amyloid polypeptide (IAPP), also known as amylin. IAPP is a protein secreted by the islet beta cells that are stored with insulin in the secretory granules and released in concert with insulin. Normally, IAPP modulates insulin activity in skeletal muscle. IAPP amyloid is found in insulinomas and in the pancreas of many patients with diabetes mellitus type 2.
In prolactin amyloid (Apro), prolactin or prolactin fragments are found in the pituitary amyloid. This condition is often observed in elderly people and has also been reported in an amyloidoma in a patient with a prolactin-producing pituitary tumor.
Some forms of cutaneous amyloid react with antikeratin antibodies. The identity of the fibrils is not chemically confirmed in keratin amyloid (Aker).
Aortic medial amyloid occurs in most people older than 60 years. Medin amyloid (AMed) is derived from a proteolytic fragment of lactadherin, a glycoprotein expressed by mammary epithelium.