Early-onset Alzheimer´s disease - APP, PSEN1 or PSEN2 genes.

Alzheimer's disease is a neurodegenerative disorder that affects the central especially cholinergic neurons in the hippocampus, the area of neurocortical association and other limbic structures. Neuropathological changes include cortical atrophy, extracellular neuritic plaques, neurofibrillary tangles and interneuronal amyloid deposits in the walls of cerebral arteries. It is characterized by a progressive loss of cognitive function comprising the recent memory, abstract reasoning, concentration, visual perception and spatio function. Eventually, patients can not work and need continuous supervision. In the final phase of the disease most patients develop rigidity, mutism and incontinence. Usually those affected survive 8 to 10 years after the onset of symptoms, but the course of the disease can vary from 1 to 25 years. Death is usually caused by pneumonia, malnutrition, or general body emaciation.

Alzheimer's disease can be classified as early - onset or late - onset. Signs and symptoms of early stage appear before age 65, while the late - onset form appears after age 65. The early onset form is much less common than late - onset form, and represents less than 5% of all cases of Alzheimer's disease.

Most cases of early onset Alzheimer's disease are caused by genetic mutations in one of three genes: APP, PSEN1, or PSEN2. When altering any of these genes, large amounts of a peptide fragment called ?-amyloid is toxic to the brain are produced. This peptide can accumulate in the brain amyloid plaques forming characteristic of Alzheimer's disease. The accumulation of ?-amyloid toxic plaques can lead to death of nerve cells and progressive signs and symptoms of this disease.

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 little is known about the function of the amyloid precursor protein, it is believed to bind to other proteins on the cell surface or to help the cells joined together. Probably in the brain, help direct the migration of neurons in early development. The amyloid precursor protein is cleaved by enzymes to create peptides, some of which are released outside the cell. Two of these fragments are called soluble amyloid precursor protein (sAPP) and ?-amyloid peptide. It is believed that SAPP has properties that promote growth and may play a role in the formation of neurons in the brain, both before and after birth. SAPP peptide can also control the function of certain other proteins inhibiting its activity. It is also likely that ?-amyloid part of the plasticity of neurons.

There are more than 50 different mutations in the APP gene that can cause Alzheimer's disease early onset. These mutations are responsible for less than 10% of all cases of early - onset Alzheimer's disease. The most common genetic mutation APP amino acid replaces the amino acid isoleucine valine at position 717 of the protein (V717I Val717Ile or). Mutations in the APP gene may result in an increased amount of ?-amyloid peptide or a longer peptide form. When these protein fragments are released from the cell, they can accumulate in brain groups and form amyloid plaques characteristic of Alzheimer's disease.

Some evidence suggests that people with Down syndrome have an increased risk of developing Alzheimer's disease. Down syndrome, a disease characterized by mental retardation and other health problems, occurs when a person is born with an extra copy of chromosome 21 in each cell. As a result, people with Down 's syndrome have three copies of many genes in each cell, including the APP gene, instead of the normal two copies. Although the connection between Down syndrome and Alzheimer's disease is unclear, encoding ?-amyloid peptide in excess cells may explain the increased risk.

The genes PSEN1, located on the long arm of chromosome 14 (14q24.3) and PSEN2, located on the long arm of chromosome 1 (1q42.13), coding for the proteins presenilin 1 and presenilin 2, respectively. These proteins carry out the primary function of the ?-secretase complex, it is peptide cleave other proteins (proteolysis). ?-secretase complex is located in the membrane around the cells, which cleaves many transmembrane proteins. This cleavage is an important chemical signaling multiple paths that transmit signals from outside the cell to the nucleus step. One of these pathways, known as Notch signaling is essential for the normal maturation and division of the hair follicle cells and other skin cells. Notch signaling is also involved in the normal function of the immune system. Furthermore, the ?-secretase complex plays a role in processing amyloid precursor protein (APP), described above.

There are more than 150 genetic mutations PSEN1 in patients with early - onset Alzheimer's disease. Mutations in the PSEN1 gene are the most common cause of Alzheimer's disease with early onset, which represents up to 70% of cases. Almost all mutations in the PSEN1 gene nucleotide change in a particular segment of the PSEN1 gene. These mutations result encoding a presenilin 1 protein that interferes with altered function ?-secretase complex, which alters APP processing and causes overproduction of a longer version of ?-amyloid peptide toxic. Copies of this protein fragment bind and accumulate in the brain, forming amyloid plaques.

11 described mutations in the gene PSEN2 associated with Alzheimer's disease with early onset. Mutations in this gene are responsible for 5% of all cases of early onset of the disease. Two of the most frequent mutations change PSEN2 amino acids used for encoding presenilin 2. A mutation replaces the amino acid asparagine at the amino acid isoleucine at position 141 (Asn141Ile or N141I). The other mutation changes the amino acid methionine for the amino acid valine at position 239 (Met239Val or M239V). These mutations seem to disrupt the processing of amyloid precursor protein, resulting in an overproduction of ?- amyloid peptide. This protein fragment can accumulate in the brain and form amyloid plaques.

Alzheimer's disease with early onset inherited in an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient to express the disease. In most cases, an affected person inherits the altered gene from one affected parent.

Tests in IVAMI: in IVAMI perform detection of mutations associated with familial Alzheimer's disease early onset, by complete PCR amplification of the exons of the APP, PSEN1 and PSEN2, respectively, genes and subsequent sequencing. Recommended for the study of genes associated with this disease order it is as follows: First the complete study of PSEN1 gene (10 exons), where most mutations accumulate is recommended. If this result is negative recommend proceeding to the study of exons 16 and 17 of the APP gene, which are most mutations in this gene. If negative result can proceed to examine the remainder of the exons of the APP gene (exons 1 to 15) and subsequently the PSEN2 gene (10 exons).

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).