Primary familial brain calcification is a condition characterized by abnormal deposits of calcium (calcification) in blood vessels within the brain. These calcium deposits are visible only on medical imaging and typically occur in the basal ganglia, which are structures deep within the brain that help start and control movement of the body. Other brain regions may also be affected.

The main signs and symptoms of primary familial brain calcification are movement disorders and psychiatric or behavioral problems. These difficulties usually begin in mid-adulthood, and worsen over time. Most affected individuals have a group of movement abnormalities called parkinsonism, which include unusually slow movement (bradykinesia), muscle rigidity, and tremors. Other movement problems common in people with primary familial brain calcification include involuntary tensing of various muscles (dystonia), uncontrollable movements of the limbs (choreoathetosis), and an unsteady walking style (gait).

Psychiatric and behavioral problems occur in 20 to 30 percent of people with primary familial brain calcification. These problems can include difficulty concentrating, memory loss, changes in personality, a distorted view of reality (psychosis), and decline in intellectual function (dementia). Affected individuals may also have difficulty swallowing (dysphagia), impaired speech, headache, episodes of extreme dizziness (vertigo), seizures, or urinary problems.

The severity of primary familial brain calcification varies among affected individuals; some people have no symptoms related to the condition, whereas others have significant movement and psychiatric problems.

Interconnected brain areas called the basal ganglia (or basal nuclei), shown in Figureb, play important roles in movement control and posture. Damage to the basal ganglia, as in Parkinson's disease, leads to motor impairments like a shuffling gait when walking. The basal ganglia also regulate motivation. For example, when a wasp sting led to bilateral basal ganglia damage in a 25-year-old businessman, he began to spend all his days in bed and showed no interest in anything or anybody. But when he was externally stimulated-as when someone asked to play a card game with him-he was able to function normally. Interestingly, he and other similar patients do not report feeling bored or frustrated by their state.

These illustrations show the (a) coronal and (b) sagittal sections of the human brain.

Primary familial brain calcification is caused by mutations in one of several genes. The most commonly mutated gene is called SLC20A2, and accounts for an estimated 40 percent of cases, followed by the PDGFRB gene, which is mutated in about 10 percent of cases. Changes in other genes each account for a small percentage of cases. In about half of individuals with primary familial brain calcification the genetic cause is unknown. These individuals are thought to have mutations in genes that have not yet been linked to the condition.

The SLC20A2 gene provides instructions for making a protein called sodium-dependent phosphate transporter 2 (PiT-2). This protein is highly active in nerve cells (neurons) in the brain where it plays a major role in regulating phosphate levels (phosphate homeostasis) by transporting phosphate across cell membranes. SLC20A2 gene mutations lead to the production of a PiT-2 protein that cannot effectively transport phosphate into cells. As a result, phosphate levels in the bloodstream rise. In the brain, the excess phosphate combines with calcium and forms deposits within blood vessels in the brain.

The PDGFRB gene provides instructions for making a protein that transmits signals from the cell surface into the cell. These signals control a variety of cell processes. PDGFRB gene mutations result in a protein with impaired signaling ability. However, it is unclear how the mutations cause primary familial brain calcification. The altered signaling may result in an abnormally large amount of calcium entering the cells that line blood vessels in the brain, leading to calcification of these blood vessels. Alternatively, changes in PDGFRB signaling could disrupt processes that regulate levels of phosphate and calcium in brain cells, leading to the formation of calcium deposits. Other genes known to be associated with primary familial brain calcification also have roles in cell signaling and phosphate homeostasis.

Researchers suggest that calcium deposits lead to the features of primary familial brain calcification by disrupting the connections between the basal ganglia and other areas of the brain, particularly the frontal lobes. These areas at the front of the brain are involved in reasoning, planning, judgment, and problem-solving. The regions of the brain that regulate social behavior, mood, and motivation may also be affected.

Research has shown that people with significant calcification tend to have more signs and symptoms of primary familial brain calcification than people with little or no calcification. However, this association does not apply to all people with primary familial brain calcification.

Normal Function

The SLC20A2 gene provides instructions for making a protein called sodium-dependent phosphate transporter 2 (PiT-2). This protein is highly active in nerve cells (neurons) in the brain. It plays a major role in regulating the levels of a molecule called phosphate in cells (phosphate homeostasis). Specifically, the PiT-2 protein uses positively charged sodium atoms (ions) to transport phosphate in out and of cell membranes. Phosphate is needed for many cellular functions including the breakdown of substances (metabolic processes), signaling between cells, and the production of DNA building blocks (nucleic acids) and fats.

Health Conditions Related to Genetic Changes

Primary familial brain calcification

More than 60 SLC20A2 gene mutations have been found to cause primary familial brain calcification. This condition is characterized by abnormal deposits of calcium (calcification) in the brain and movement and psychiatric problems. Most of the mutations that cause primary familial brain calcification change single protein building blocks (amino acids) in the PiT-2 protein and severely impair its ability to transport phosphate into cells. As a result, phosphate levels in the bloodstream rise. The excess phosphate combines with calcium and forms deposits within blood vessels in the brain.

Although the SLC20A2 gene is active throughout the body, its activity is highest in structures deep within the brain that help start and control movement (basal ganglia) and in other brain regions that are involved in primary familial brain calcification, which may explain why the effects of these mutations are limited to these regions.

Other Names for This Gene

• gibbon ape leukemia virus receptor 2
• GLVR-2
• GLVR2
• MLVAR
• murine leukemia virus, amphotropic, receptor for
• PIT-2
• PIT2
• S20A2_HUMAN
• sodium-dependent phosphate transporter 2
• solute carrier family 20 (phosphate transporter), member 2

Genomic Location

Normal Function

The PDGFRB gene provides instructions for making a protein called platelet-derived growth factor receptor beta (PDGFRβ), which is part of a family of proteins called receptor tyrosine kinases. Receptor tyrosine kinases transmit signals from the cell surface into the cell through a process called signal transduction. The PDGFRβ protein is found in the cell membrane of certain cell types, where a protein called platelet-derived growth factor attaches (binds) to it. This binding turns on (activates) the PDGFRβ protein, which then activates other proteins inside the cell by adding a cluster of oxygen and phosphorus atoms (a phosphate group) at specific positions. This process, called phosphorylation, leads to the activation of a series of proteins in multiple signaling pathways.

The signaling pathways stimulated by the PDGFRβ protein control many important processes in the cell such as growth and division (proliferation), movement, and survival. PDGFRβ protein signaling is important for the development of many types of cells throughout the body.

Health Conditions Related to Genetic Changes

PDGFRB-associated chronic eosinophilic leukemia

Genetic rearrangements (translocations) involving the PDGFRB gene cause a type of cancer of blood-forming cells called PDGFRB-associated chronic eosinophilic leukemia. This condition is characterized by an increased number of eosinophils, a type of white blood cell. The most common of these translocations brings together part of the PDGFRB gene with another gene called ETV6, whose function is to turn off gene activity. Together, these pieces create the ETV6-PDGFRB fusion gene. Occasionally, genes other than ETV6 are fused with the PDGFRB gene. The translocations that lead to these fusion genes are somatic mutations, which are acquired during a person's lifetime and occur initially in a single cell. This cell continues to grow and divide, producing a group of cells with the same mutation (a clonal population).

The protein produced from the ETV6-PDGFRB fusion gene (as well as other PDGFRB fusion genes) functions differently than the proteins normally produced from the individual genes. The ETV6/PDGFRβ fusion protein does not require ligand binding to be activated and cannot bind to DNA to turn off gene activity. As a result, signaling pathways are constantly turned on (constitutively activated) and gene activity is increased, which increases the proliferation and survival of cells.

When the ETV6-PDGFRB fusion gene mutation occurs in cells that develop into blood cells, the growth of eosinophils (and occasionally other white blood cells, such as neutrophils and mast cells) is poorly controlled, leading to PDGFRB-associated chronic eosinophilic leukemia. It is unclear why eosinophils are preferentially affected by this genetic change.

Primary familial brain calcification

At least six mutations in the PDGFRB gene have been found to cause primary familial brain calcification. This condition is characterized by abnormal deposits of calcium (calcification) in the brain, which can lead to movement and psychiatric problems. These mutations change single protein building blocks (amino acids) in the PDGFRβ protein. These changes impair the protein's signaling ability.

It is unclear how PDGFRB gene mutations cause primary familial brain calcification. The altered signaling may result in an abnormally large amount of calcium entering the cells that line blood vessels in the brain, leading to calcification of these blood vessels. Alternatively, changes in PDGFRB signaling could disrupt processes that regulate levels of phosphate and calcium in brain cells, leading to the formation of calcium deposits. In the brain, the excess phosphate combines with calcium and forms deposits.

The PDGFRB gene is active (expressed) throughout the body; it is unclear why the effects of these mutations are limited to structures deep within the brain that help start and control movement (basal ganglia) and to other brain regions that are involved in primary familial brain calcification.

Other disorders

Additional mutations in the PDGFRB gene cause a variety of disorders including infantile myofibromatosis; Kosaki overgrowth syndrome; and premature aging syndrome, Penttinen type.

Infantile myofibromatosis is a muscle disorder that causes the formation of multiple noncancerous (benign) tumors in the skin, muscles, or bones. These tumors are generally present at birth or in early infancy.

Kosaki overgrowth syndrome is characterized by above-average height and large hands and feet. Affected individuals have highly stretchy (elastic) and fragile skin. People with this condition also have distinctive facial features and brain abnormalities that result in intellectual disability and psychological problems.

Premature aging syndrome, Penttinen type is characterized by a lack of fatty tissue under the skin (lipoatrophy). This lack of fat, together with thin, wrinkled skin and veins visible beneath the skin, makes affected individuals look older than their biological age.

In all of these conditions, PDGFRB gene mutations result in increased cell signaling. While it is unclear how mutations in one gene can lead to so many different conditions, it is thought that particular mutations may affect different signaling pathways, leading to changes in specific body systems.

Other Names for This Gene

• beta-type platelet-derived growth factor receptor
• CD140 antigen-like family member B
• CD140B
• PDGF-R-beta
• PDGFR-1
• PDGFR-beta
• PDGFR1
• PGFRB_HUMAN
• platelet-derived growth factor receptor 1
• platelet-derived growth factor receptor beta
• platelet-derived growth factor receptor, beta polypeptide

Genomic Location

In most cases, primary familial brain calcification is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition.

Less commonly, primary familial brain calcification is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Primary familial brain calcification was thought to be a rare disorder; however, because brain imaging tests are needed to see the calcium deposits, this condition is believed to be underdiagnosed. Recent research has indicated that primary familial brain calcification may occur in 2 to 6 per 1,000 people, with many affected individuals not showing signs and symptoms of the condition.