Fahr syndrome

Fahr syndrome

Fahr syndrome also called primary familial brain calcification, is a inherited neurodegenerative disorder characterized by calcium deposits in the basal ganglia, a part of the brain that helps start and control movement 1). Other brain regions may also be affected. The first symptoms often include clumsiness, fatigue, unsteady walking (gait), slow or slurred speech, difficulty swallowing (dysphagia) and dementia. Migraines and seizures frequently occur. Symptoms typically start in an individual’s 30’s to 40’s but may begin at any age. The neuropsychiatric symptoms and movement disorders worsen over time. Mutations in the SLC20A2, PDGFRB, and PDGFB genes have been found to cause Fahr syndrome. Fahr’s disease is inherited in an autosomal dominant manner 2).

Fahr syndrome main signs and symptoms 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 Fahr syndrome or 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 Fahr syndrome or 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.

Fahr syndrome or 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 3).

There is no cure for Fahr’s syndrome, nor is there a standard course of treatment. Treatment typically addresses symptoms on an individual basis. Medications may be used to improve anxiety, depression, obsessive-compulsive behaviors, and dystonia. Antiepileptic drugs can be prescribed for seizures. Oxybutynin may be prescribed for urinary incontinence (loss of bladder control). Surveillance typically includes yearly neurologic and neuropsychiatric assessments 4).

Fahr syndrome causes

Fahr syndrome 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 Fahr syndrome 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 Fahr syndrome. 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 Fahr syndrome also have roles in cell signaling and phosphate homeostasis.

Researchers suggest that calcium deposits lead to the features of Fahr syndrome 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 Fahr syndrome than people with little or no calcification. However, this association does not apply to all people with Fahr syndrome.

Fahr syndrome inheritance pattern

In most cases, Fahr syndrome 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, Fahr syndrome 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.

Figure 1. Fahr syndrome autosomal dominant inheritance pattern

Fahr syndrome autosomal dominant inheritance pattern

Figure 2. Fahr syndrome autosomal recessive inheritance pattern

Fahr syndrome autosomal recessive inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

Fahr syndrome symptoms

Fahr syndrome is characterized by symmetric and bilateral brain calcifications mainly in the basal nuclei, but also seen in the cerebellum (dentate nucleus), thalami and/or cerebral white matter. These calcium deposits are commonly found in the fourth to fifth decade of life, while neuropsychiatric symptoms (when present) usually begin in the third to fifth decade of life. Additionally, some individuals with Fahr syndrome may be clinically asymptomatic for several decades.

Early symptoms may include clumsiness, fatigue, slow or slurred speech and difficulty swallowing (dysphagia). Progressive deterioration of mental/cognitive abilities (dementia) and loss of previous motor development are accompanied by spastic paralysis and in some patients, twisting movements of the hands and feet (athetosis). Features of Parkinson disease found in this disorder may include tremors and rigidity (Parkinsonism), a masklike facial expression, shuffling walk, and a pill rolling motion of the fingers. Muscle cramping (dystonia), uncontrollable spasmodic irregular movements (chorea), and seizures can also occur. Occasional symptoms include sensory changes, headaches and urinary incontinence.

Associated symptoms include loss of contact with reality (psychosis), mood swings and loss of acquired motor skills. As the condition progresses, paralysis may develop that is associated with increased muscle stiffness (rigidity) and restricted movements (spastic paralysis). Additional abnormalities may include relatively slow, involuntary, continual writhing movements (athetosis) or chorea, a related condition characterized by irregular, rapid, jerky movements.

A recent study 5) indicated that Parkinsonism was the most frequent symptom in a group of 44 Fahr syndrome patients, followed by cognitive impairment, psychiatric symptoms and cerebellar signs. Other analyses have also suggested that males are more severely affected than females, especially those who have SLC20A2 gene mutations, followed by those with PDGFB and PDGFRB gene mutations 6).

Fahr syndrome diagnosis

The diagnosis of Fahr syndrome relies upon 7):

  1. Visualization of bilateral (on both sides) calcification of the basal ganglia on neuroimaging,
  2. Presence of progressive neurological dysfunction,
  3. Absence of a metabolic, infectious, toxic, or traumatic cause, and
  4. A family history consistent with autosomal dominant inheritance (a person must inherit one copy of the altered gene from one parent to have the condition).

Molecular genetic testing can help confirm the diagnosis 8).

Neuroimaging techniques such as computed tomography (CT) of the brain (the most sensitive technique) and magnetic resonance imaging (MRI) are used to diagnose the calcium deposits in the brain. Although not necessary, the combination of these findings with a progressive movement disorder, neuropsychiatric problems beginning in the 40’s or 50’s, and a lack of biochemical abnormalities or other known causes (infection, toxic exposure, trauma) makes the diagnosis very likely.

Additionally, genetic screening for mutations on Fahr syndrome-causative genes SLC20A2, PDGFB, PDGFRB, XPR1 and MYORG should be performed, as it is currently the best way to determine with certainty if an individual has Fahr syndrome or not. This screening requires molecular diagnostic tests on DNA and can usually be performed by either private diagnostic laboratories or Fahr syndrome research groups. The molecular assays may be a simple DNA sequencing or any high-throughput DNA sequencing technologies, such as whole exome sequencing or whole genome sequencing.

Genetic counseling is recommended for affected individuals and their relatives, especially for those with mutations in Fahr syndrome-associated genes.

Fahr syndrome treatment

To date, no specific treatment for Fahr syndrome is known. Medications can be used to treat symptoms associated with this condition, such as movement disorders, seizures, anxiety, depression, psychosis and urinary incontinence. Off label prescription of biphosphanates have been reported in few patients 9).

Investigational therapies

Speech and gait were improved in one patient treated with disodium etidronate, but other neurologic symptoms and calcification were unchanged.

Levodopa therapy was found to be effective in treating parkinsonian features in one individual who had Fahr syndrome and Parkinson disease.

The anticonvulsant oxcarbazepine was effective in treating a Turkish patient with basal ganglia calcification and dyskinesia.

Fahr’s syndrome life expectancy

The prognosis for any individual with Fahr’s Syndrome is variable and hard to predict. There is no reliable correlation between age, extent of calcium deposits in the brain, and neurological deficit. Since the appearance of calcification is age-dependent, a CT scan could be negative in a gene carrier who is younger than the age of 55.

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