Huntington's chorea (Huntington Disease type types 1 to 4) (Huntington disease-like syndrome) - Genes PRNP, JPH3, and TBP.

Chorea Huntington disease type (HDL), is a progressive brain disorder characterized by uncontrolled movements, emotional problems and loss of the ability to think. This disease resembles Huntington's disease. Described four syndromes HDL, ranging from the type 1 (HDL1) to type 4 (HDL4).

HDL1 types, HDL2 and HDL4 usually appear in early to mid-adulthood, but can start earlier. Early signs and symptoms often include irritability, emotional problems, small involuntary movements, poor coordination and difficulty learning new information or make decisions. Many affected people develop sudden or jerky movements known as chorea involuntary. As the disease progresses, these abnormal movements become more pronounced. Affected individuals may develop trouble walking, speaking and swallowing, in addition to expressing personality changes and reduce thinking and reasoning skills. Individuals with this disease can live for a few years more than a decade after starting the signs and symptoms.

Meanwhile, HDL3 begins long before most of the other types, usually around 3 or 4 years old. Affected children experience a decline in thinking ability, movement difficulties and speech and seizures.

This process is due to mutations in the PRNP, JPH3 and TBP genes. HDL1 is caused by mutations in the gene PRNP, while HDL2 results from mutations in the gene JPH3. Mutations in the TBP gene are responsible for HDL4 (also known as spinocerebellar ataxia type 17). HDL3 genetic cause is unknown.

The PRNP gene, located on the short arm of chromosome 20 (20p13), encoding the prion protein (PrP), which is active in the brain and other tissues. Although the precise function of this protein is unknown, it is believed to play a role in copper transport in cells and in protecting neurons from injury. Studies have also suggested a role for PrP in synapse formation where communication from cell to cell occurs. Mutations in this gene are the cause of Huntington's disease type 1. Mutations in the gene PRNP involve repetition of a DNA segment (octapeptide). This segment encodes eight amino acids that are linked to form a protein fragment called peptide. The octapeptide repeat typically repeated five times in the PRNP gene. In people with HDL1, this segment is repeated eleven or thirteen times. An increase in the size of repetition in the octapeptide leads to the production of an abnormally long version of PrP. It is unclear how abnormal proteins damage and ultimately destroy neurons, causing the characteristic features of HDL1.

The JPH3 gene, located on the long arm of chromosome 16 (16q24.3), encoding junctophilin-3 protein, which is found primarily in the brain. Although the exact function of this protein is not clear, it is believed to play a role in the complex formation of the membrane binding. This complex connects certain channels within cells with other channels on the cell surface. The complex membrane binding seems to be involved in the release of calcium ions, which are critical to signal transmission within the cells. As part of the membrane complex binding, the protein is probably involved in signaling within and between neurons in the brain. A region JPH3 gene contains a particular DNA segment known as a CAG / CTG trinucleotide repeat. This segment consists of a series of three nucleotides that are repeated several times in a sequence. Typically the CTG / CAG repeats segment 6 and 28 times within the gene. Mutations in this gene are the cause of Huntington's disease type 2 mutation associated increases the size of the CAG trinucleotide repeat / CTG in the gene. People with this condition have from 44 to 59 CAG repeats / CTG. People with between 29 and 43 CAG repeats / CTG may or may not develop signs and symptoms of HDL2.

The TBP gene, located on the long arm of chromosome 6 (6q27), encoding the TATA binding protein homebox. This protein is active in cells and tissues throughout the body, where it plays an essential role in regulating the activity of most genes. Aggregates homeobox protein binding TATA bind to a particular DNA sequence known as the TATA homebox. This sequence occurs in a regulatory region of DNA near the beginning of many genes. Once the protein binds to the TATA homebox near a gene, it acts as a reference point to indicate where other enzymes should start reading the gene. A region of the TBP gene contains the DNA segment trinucleotide CAG repeat / CAA. This segment consists of a series of three nucleotides that appear several times in a sequence. Typically, the CAG / CAA repeats segment 25 to 42 times within the gene. Mutations in this gene are the cause of Huntington's disease associated with type 4. HDL4 / SCA17 mutation increases the size of the trinucleotide CAG repeat / CAA in the TBP gene. People with this disorder have from 43 to 66 CAG repeats / CAA. People with 43 to 48 repetitions CAG / CAA may or may not have signs and symptoms, while those with 49 or more reps almost always develop the disease. An increased number of CAG repeats / CAA in the gene encoding leads to an abnormally long version of the binding protein TATA homebox. The abnormal protein accumulates in the neurons and disrupt normal functions of these cells. Dysfunction and eventual death of neurons in certain areas of the brain are the basis of the signs and symptoms of HDL4 / SCA17. Because the TBP gene is active throughout the body, it is unclear why the effects of a mutation in this gene are limited to the brain.

The HDL1, HDL2 and HDL4 types are inherited in an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to cause disease. In most cases, an affected person inherits the mutation from an affected parent. HDL3 is probably inherited with an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.  

Tests in IVAMI: in IVAMI perform detection of mutations associated with Huntington chorea disease type, by complete PCR amplification of the exons of the PRNP, JPH3 and TBP genes, 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).