Primary Familial Brain Calcification

Primary Familial Brain Calcification

Overview

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by the presence of abnormal calcium/hydroxyapatite deposits (calcifications) in the brain. The clinical presentations generally attributed to these brain calcifications are highly heterogeneous, ranging from asymptomatic patients to severe cases with progressive neuropsychiatric features. To date, disease-causing changes (pathogenic variants or mutations) in six genes have been associated with PFBC: SLC20A2, PDGFB, PDGFRB, XPR1, MYORG and JAM-2. PFBC has recently become the preferred name for this condition because variants in specific genes are now known to be the cause of the condition. Previously, familial idiopathic basal ganglia calcification was the preferred name, and Fahr’s disease is often used for either familial or sporadic brain calcification, and it is unknown if these are the same or different diseases.

Symptoms

PFBC is characterized by symmetric and bilateral brain calcifications mainly in the basal ganglia, but also seen in the cerebellum, thalami, cerebral white matter and/or pons. These calcium phosphate deposits are commonly found in the fourth to fifth decade of life, while symptoms usually begin in the third to fifth decade of life, even though some individuals with PFBC may be clinically asymptomatic for several decades. PFBC is rare among children but, when present, most of these children present with seizures. Neuropsychiatric and movement disorders are the main PFBC clinical presentations in adults.

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 characterized by irregular, rapid, jerky moves (chorea) and seizures can also occur. Occasional symptoms include sensory changes, headaches and urinary incontinence. Other associated symptoms include loss of contact with reality (psychosis), mood swings, depression and loss of acquired motor skills. As the condition progresses, paralysis may develop associated with increased muscle stiffness (rigidity) and restricted movements (spastic paralysis). Recently, stroke in young people with no risk factors has been related to MYORG gene variants (Yang et al, 2022).

A recent study indicated that Parkinsonism was the most frequent symptom in a group of 44 PFBC patients, followed by cognitive impairment, psychiatric symptoms and cerebellar signs (Ramos et al., 2018). Other analyses have also suggested that males are more severely affected than females, especially those who have SLC20A2 gene variants, followed by those with PDGFB and PDGFRB gene variants (Nicolas et al., 2015).

Causes

PFBC is caused by variants in several different genes, and it can either be inherited or develop spontaneously. In inherited cases, the vast majority follow autosomal dominant inheritance, but autosomal recessive inheritance have also been reported.

As previously mentioned, autosomal dominant genetic disorders occur when a single copy of an abnormal gene is necessary to cause a disease. The abnormal gene can be inherited from either parent, and the risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy, being the same for males and females. Variants in four different genes have been described to cause PFBC in an autosomal dominant fashion: SLC20A2, PDGFB, PDGFRB and XPR1.

Wang and colleagues (2012) reported 7 families with PFBC from China, Spain and Brazil, with different variants in the SLC20A2 gene on chromosome 8, encoding for a phosphate inorganic transporter (PiT-2). In the following years, more than 50 variants in this gene have been identified, and variants in this gene are the most common cause of PFBC (Lemos et al., 2015).

Since then, three other genes have been linked to autosomal dominant forms of PFBC: the beta subunit of platelet-derived growth factor (PDGFB) and its receptor (PDGFRB), which are involved in the blood brain barrier integrity (Nicolas et al., 2013; Keller et al., 2013); and more recently, the xenotropic and polytropic retrovirus receptor 1 (XPR1) gene, which is involved in intracellular phosphate homeostasis (Legati et al., 2015).

Autosomal recessive genetic disorders occur when two copies of an abnormal gene are necessary to cause a disease. The abnormal gene then must be inherited from both parents in order to cause the disease in children. So far, two genes have been linked to a recessive pattern: MYORG and JAM-2 (Yao et al., 2018; Schottlaender et al, 2020). Patients with variants in these genes are generally more severely affected. Patients with MYORG gene variants often have calcification present in the pons as a very predictable finding.

Lastly, in some individuals the disorder is due to spontaneous (de novo) genetic variants that may occur in the egg or sperm cell. It is not known how many people have PFBC as a result of a new gene variant, but there is a case linked to SLC20A2 and twins linked to PDGFB pathogenic variants. In such situations, the disorder is not inherited from the parents, but can still be passed on to children (with a 50% chance for each child) (Keller et al, 2013; Ferreira et al, 2014).

Affected populations

The prevalence of PFBC is unknown, but more people are being diagnosed, probably due to the growing availability of neuroimaging screening and genetic testing.

A recent study by Nicolas and collaborators indicates that the prevalence of PFBC may be higher than what was initially thought. Through a population-based genomic analysis, the authors estimated that the prevalence of the condition ranges from 4.5/10,000 to 2.1/1,000, which means the disease is much more common than previously considered (Nicolas et al., 2018).

Disorders with Similar Symptoms

Calcification of the basal nuclei in the brain is found in many medical conditions and can be caused by infections as well as metabolic and other genetic syndromes. It is also not uncommon to observe calcium deposits of the basal ganglia in individuals over 60 years of age and this finding is not usually associated with diseases. Symptoms of the following disorders may be similar to those of PFBC. Comparisons may be useful for a differential diagnosis:

Parkinson disease is a slowly progressive neurologic condition characterized by involuntary trembling (tremor), muscular stiffness or inflexibility (rigidity), slowness of movement and difficulty carrying out voluntary movements. Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), causing a decrease in dopamine levels in the brain. Dopamine is a neurotransmitter, which is a chemical that sends a signal in the brain.

Hypoparathyroidism is a condition characterized by insufficient production of parathyroid hormones by the parathyroid glands, the small, oval glands located near the thyroid gland in the neck. Parathyroid hormones (along with vitamin D and the hormone calcitonin, which is produced by the thyroid gland) play a role in regulating levels of calcium in the blood. Due to deficiency of parathyroid hormones, affected individuals exhibit abnormally low levels of calcium in the blood (hypocalcemia). Symptoms and findings associated with hypoparathyroidism may include weakness, muscle cramps, excessive nervousness, headaches and/or increased excitability (hyperexcitability) of nerves resulting in uncontrollable twitching and cramping spasms of certain muscles such as those of the hands, feet, arms and/or face (tetany). Hypoparathyroidism may result from absence of the parathyroid glands, removal or damage to the parathyroid glands or from several different underlying disorders. In rare cases, hypoparathyroidism may be inherited in an autosomal recessive pattern. (For more information on this disorder, choose “hypoparathyroidism” as your search term in the Rare Disease Database.)

Pseudohypoparathyroidism is a hereditary disorder characterized by an inadequate response to the parathyroid hormone, although the hormone is present in normal amounts. This inadequate response affects bone growth and affected individuals may also experience headaches, unusual sensations, weakness, easy fatigue, reduced energy, blurred vision and/or hypersensitivity to light. Additional symptoms and findings may include stiffness or cramps in the arms and/or legs, palpitations and/or abdominal pain. In addition, individuals with pseudohypoparathyroidism may have an abnormally round face, thick short stature, unusually short fourth fingers and intellectual disability. Hormonal and calcium replacement therapy is often helpful, but the lack of growth may persist. (For more information on this disorder, choose “pseudohypoparathyroidism” as your search term in the Rare Disease Database.)

Diagnosis

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.

Genetic testing for variants in genes that cause PFBC (SLC20A2, PDGFB, PDGFRB, XPR1, MYORG and JAM-2), should be performed, as this is currently the best way to determine with certainty if an individual has PFBC. The molecular genetic testing may be DNA sequencing, whole exome sequencing (WES) or whole genome sequencing (WGS).

Standard Therapies

To date, no specific treatment for PFBC is known. Medications can be used to treat symptoms associated with this condition, such as movement disorders, seizures, anxiety, headaches, depression, psychosis and urinary incontinence (Oliveira JRM, 2011). Medications established in psychiatric clinical practice are generally prescribed to control other disorders, such as mood stabilizers (mainly anticonvulsants) that may be useful in managing depressive symptoms, irritability, euphoria or agitation. Antipsychotics are also used to treat symptoms such as delusions and hallucinations, but they are also useful for managing psychomotor agitation.

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

Type of Doctor Department : A Neurologist