Hereditary cerebral amyloid angiopathy - APP, CST3 and ITM2B genes

Amyloidosis are a group of esporadic degenerative processes, familial and/or hereditary, linked to the deposit in affected tissues of an abnormal folded protein (amyloid). When deposited on tissues, amyloid disrupts normal tissue structure, and thus tissue function. Signs and symptoms of each process depend on the location and size of deposits. Deposits can be located (localized amyloidosis) or distributed throughout the body (systemic amyloidosis). They can also be differentiated according to their cause if known, secondary (caused by another disease), or primary (without known cause). Primary amyloidosis generally affects nerves, skin, tongue, joint, heart and liver. Secondary amyloidosis usually affects spleen, kidney, liver and adrenal glands.

Hereditary cerebral amyloidosis angiopathic, also known as cerebral amyloid angiopathy, leads to progressive loss of intellectual function (dementia), as well as stroke or other neurological disorders, starting at middle age. Because of the type of neurological disorder, the process is usually fatal in a significant proportion of those affected, although this depends on the severity of signs and symptoms. Most individuals die a decade after the first manifested signs and symptoms, although some survive longer.

There are many different types of this variety of amyloidosis, which differ according to their genetic cause and the signs and symptoms presented by the case. The different types are often referred as the region where they were initially diagnosed.

The Dutch type (Dutch type) is the most common form, being often the initial sign stroke. About half of individuals with Dutch type have recurrent seizures. The Flemish and Italian types (Flemish type / Italian Type), often have recurrent stroke and dementia. The Piedmontese type (Piedmont type) has one or more strokes and in movement disorders, paresthesias, confusion and dementia. The Icelandic type (type Iceland) presents stroke followed by dementia. Type in the Arctic (Arctic type), the first sign is usually memory loss and progresses to severe dementia. In Iowa type strokes are rare, and patients have memory loss, vocabulary and word problems, personality changes, and involuntary movements (myoclonus). In the British type exists dementia and movement problems but it is rare stroke. In the Danish type, it occurs as in the British type, but can coexist lens opacity (cataract) and deafness.

The most common cause of cerebral amyloidosis hereditary angiopathic are mutations in the APP gene (Danish types, Italian, Arctic, Iowa, Flamenco, Piedmont). Mutations in the gene cause CST3 Icelandic type. Mutations in British and Danish types are due to mutations in the gene ITM2B. A mutation APOA1 gene has been found in the Iowa amyloidosis polineuropática nephropathic type (type III).

The APP gene, located on the long arm of chromosome 21 (21q21.3), encodes a protein called amyloid precursor protein. This protein is found in many tissues and organs, including the central nervous system. Although the exact function of this protein is unknown, it is believed that binding to other proteins on the surface of cells or contribute to the adhesion of cells to each other. The amyloid precursor protein is cleaved by enzymes to create peptides, some of which are released outside the cell. Two of these fragments are the soluble amyloid precursor protein (sAPP) and beta - amyloid peptide. It is believed that sAPP has growth stimulating properties and can play a role in the formation of neurons, both before and after birth. Meanwhile, the sAPP peptide can also control the function of certain other proteins inhibiting its activity. Moreover, amyloid β peptide is likely to be involved in the plasticity of neurons.

There have been described at least 6 mutations in the APP gene in individuals with hereditary cerebral amyloidosis angiopathy. These mutations change the individual amino acids in amyloid precursor protein. Each of these mutations causes a different type of disease. The most common of all types, Dutch type is caused by the substitution of glutamic acid amino acid with the amino acid glutamine in position 22 in the protein sequence (E22Q or Glu22Gln). Italian and arctic type are also caused by changes of glutamic acid at position 22. In the Italian type, the glutamic acid is replaced by the amino acid lysine (Glu22Lys or E22K) and in the Arctic type, the glutamic acid is replaced by the amino acid glycine (Glu22Gly or E22G). Flamenco type is due to the substitution of alanine for glycine at position 21 (Ala21Gly or A21G). In the type of Iowa, the amino acid aspartic acid is replaced by the amino acid asparagine at position 23 (Asp23Asn or D23N). The Piedmont type is due to substitution of amino acid leucine at position 34 by the amino acid valine (Leu34Val or L34V). All these mutations lead to a β-amyloid peptide that is more prone to aggregate than the normal peptide. Consequently, amyloid plaques that accumulate in the brain blood vessels are formed. Amyloid plaques replace muscle and elastic fibers, causing the blood vessels become weak and prone to breakage. In the brain, such rupture causes hemorrhagic cerebrovascular accident, which can cause brain damage and dementia. Amyloid plaques in specific parts of the brain can interfere with brain function, resulting in convulsions, movement problems and other neurological functions.

The CST3 gene, located on the short arm of chromosome 20 (20p11.21), cystatin encoding protein C. This protein inhibits the activity of cathepsins that cleave other proteins. Cystatin C is in biological fluids such as blood. Their concentrations are particularly high in the cerebrospinal fluid. It has identified at least one mutation in the gene CST3, causing the Icelandic type of hereditary cerebral amyloidosis angiopathy. This mutation replaces the amino acid leucine by the amino acid glutamine at position 68 in the protein cystatin C (Leu68Gln or L68Q), resulting in a less stable protein that is more prone to aggregate forming amyloid plaques that accumulate not only in walls of cerebral blood vessels, but also in blood vessels in other areas of the body such as skin, spleen and lymph nodes.

The ITM2B gene, located on the long arm of chromosome 13 (13q14.3), encodes a protein found in all tissues. Although the exact function of the protein ITM2B is unclear, it appears to play a role in apoptosis and in maintaining cell growth that is not too fast or divide uncontrollably. Furthermore, ITM2B protein may be involved in processing amyloid precursor protein. They have identified at least two mutations in the gene ITM2B associated with hereditary cerebral amyloidosis angiopathy British and Danish types. The responsible genetic mutation of the British type results encoding a protein that is longer than normal. This mutation (Ter267Arg or X267R) changes the stop signal so that the protein is elongated. The mutation that causes the Danish type is similar, but instead of changing the stop signal, additional DNA nucleotides are added to the gene, meaning that the protein is longer (795-796insTTTAATTTGT). These altered proteins tend to clump together to form amyloid deposits, which accumulate in specific areas of the brain and blood vessels.

The hereditary cerebral amyloidosis angiopathy due to mutations in the APP, CST3, or ITM2B gene is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the disease. There is also a non-hereditary form amyloid angiopathy brain that occurs in people with no history of disease in your family, and whose cause is unknown. These cases are known as sporadic and not inherited.

Tests in IVAMI: in IVAMI perform the detection of mutations associated with amyloidosis angiopathic hereditary cerebral, by complete PCR amplification of the exons of the APP (Danish types, Italian, Arctic, Iowa, Flamenco, Piedmontese) genes, CST3 (type Icelandic) and ITM2B (British and Danish type), respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).