Fahr’s Disease: Understanding Familial Basal Ganglia Calcification

Fahr’s disease is a rare genetic condition which affects a region of the brain called the basal ganglia. It afflicts fewer than 1 in 1,000,000 individuals and shares several symptoms with other neurological conditions, which makes it challenging to diagnose and research. As such, scientific understanding of Fahr’s disease is limited, and there is currently no known cure. Despite these challenges, a moderate body of literature on Fahr’s disease exists, and the core features of the condition are generally agreed upon. This article will cover the etiology, pathophysiology, symptoms, diagnosis, and management of Fahr’s disease.
Faith Wershba

Faith Wershba

Postgraduate researcher at the University of Cambridge.

An image with a blue background with text saying "Fahr's disease".

What is Fahr’s disease?

Fahr’s disease is a neurological disorder that occurs due to a buildup of calcified deposits in both the right and left basal ganglia [2].

Accumulation of calcium carbonate (CaCO3) and phosphate (PO43-) in the blood vessels and gray matter of this brain region leads to disturbances in the structure and function of neural tissue. Such disturbances are visible in histopathological slides, appearing as small granules and nodules within the tissue [2]. The resulting neurodegeneration can be seen upon neuroimaging via CT or MRI scan. Damage and degeneration occurs progressively as calcified deposits amass in the basal ganglia over time. As such, Fahr’s disease tends to manifest symptomatically later in life, typically emerging in adults between their 30s and 50s [1, 2].

What causes Fahr’s disease?

Fahr’s disease is an idiopathic condition, meaning that the exact causes of the disease are not known. The defining pathological feature of Fahr’s disease is abnormal basal ganglia calcification; however, what triggers this process remains unclear. Two hypotheses have been proposed: dysfunctional calcium metabolism in the brain, and metastatic deposition of CaCO3 and PO43- from the circulation due to increased permeability of the blood-brain barrier (BBB) [2]. These two processes may act in tandem, and further research is needed to clarify the extent to which these processes contribute to the development of Fahr’s disease.

Role of genetics in Fahr’s disease

Genetics also play an important role in the development of Fahr’s disease. In the majority of cases, the disease is inherited in an autosomal dominant pattern, with variable and age-dependent penetrance [2]. As such, Fahr’s disease is sometimes called familial basal ganglia calcification [1]. Four specific mutations have been identified as key genetic players in the disease.

Genetic mutations involved in Fahr’s disease [1,2]:

  • IBGC1: mutations in this gene are commonly observed in Fahr’s disease. The gene is actually named “Idiopathic Basal Ganglia Calcification 1” due to its connection to cases of Fahr’s disease. The exact function of this gene remains ambiguous.
  • SLC20A2: encodes type 3 sodium-dependent phosphate transporter 2 (PiT2). Loss-of-function mutations are commonly seen in patients with Fahr’s disease.
  • XPR1: encodes a retroviral receptor that functions in the cellular export of phosphate ions.
  • PDGFRB and PDGFB: encode receptors that bind to members of the platelet-derived growth factor (PDGF) protein family.

While these genes have been associated with cases of Fahr’s disease, whether they play a significant causal role in the development of Fahr’s disease remains undetermined. Further research is needed to identify the functional contributions of these genes to the disease.

Related Posts

Fahr’s disease vs Fahr’s syndrome

What is the difference between Fahr’s disease and Fahr’s syndrome?

The terms “Fahr’s disease” and “Fahr’s syndrome” are often used synonymously in the literature, which can be a source of confusion. While the symptoms of Fahr’s disease are shared with Fahr’s syndrome, the two are distinguished by their etiological roots.

Fahr’s disease describes cases where there is symmetrical basal ganglia calcification and a family history of the disease (i.e., a genetic basis) [3]. The primary cause of brain calcification is rooted in genetics, so Fahr’s disease is a form of primary basal ganglia calcification [2]. The specific underlying causes remain unknown.

Fahr’s syndrome describes cases where there is symmetrical basal ganglia calcification caused by a separate pathology, such as a metabolic disorder, endocrinopathy, or infection [3]. Because brain calcification is a collateral result of a different pathology, Fahr’s syndrome is a form of secondary basal ganglia calcification [2]. The underlying causes can be traced to the primary disease, whether this be metabolic, endocrine, or infectious.

While this distinction may seem minor, it is not a trivial one. A diagnosis of Fahr’s disease vs Fahr’s syndrome can influence approaches to treatment. In the case of Fahr’s disease, treatment focuses mainly on symptom management and patient care, since the ultimate cause of brain calcification is unknown. In cases of Fahr’s syndrome, on the other hand, treatment should focus on remedying the underlying pathology in order to halt progressive brain calcification [3].

Symptoms of Fahr’s disease

The basal ganglia plays an important role in coordinating movement and motor skills . As such, the symptoms of Fahr’s disease commonly include disturbances to motor function [2, 4]. However, neuropsychiatric symptoms have also been observed [1].

Symptoms of Fahr’s disease include:

  • Features of parkinsonism (muscle rigidity; tremors; and bradykinesia, or slowness of movement)
  • Speech difficulties or slurred speech
  • Shuffling gait
  • Clumsiness
  • Involuntary muscle movements, muscle jerking
  • Headache
  • Seizures
  • Inability to concentrate
  • Behavioural changes
  • Depression
  • Memory impairment

Due to the wide-ranging functions of the basal ganglia, the symptoms of Fahr’s disease are quite variable. In addition, many of the symptoms overlap with those of other neurological conditions, such as Parkinson’s disease. This can make differential diagnosis difficult [1]. However, there are several diagnostic criteria used to diagnose Fahr’s disease.

Diagnosing Fahr’s disease

Diagnostic criteria for Fahr’s disease include [1]:

  • Bilateral calcification of the basal ganglia (i.e., affecting both left and right sides). This is ascertained via neuroimaging.
  • Progressive appearance of neurological dysfunction. Such dysfunctions usually include some sort of movement disorder and/or psychiatric symptoms.
  • Age of onset around age 40-50. Due to the progressive nature of Fahr’s disease, symptoms typically manifest later in adult life. However, the disease can occur in younger individuals, so this criterion is not definitive.
  • Family history suggests a pattern of autosomal dominant inheritance.

Fahr’s disease is not the only instance in which basal ganglia calcification leads to neurological abnormalities. Biochemical and metabolic disorders can also result in symmetrical calcification of the basal ganglia, as can infectious agents and traumatic insults [1]. As such, competing diagnoses should be considered and ruled out before concluding that an individual has Fahr’s disease.

Fahr’s disease treatment

Presently, there is no cure for Fahr’s disease. Therefore, intervention is focused on treatment and management of symptoms.

Appropriate treatment will depend upon an individual’s particular symptoms. For example, antiepileptics may be recommended for patients who suffer seizures; pain killers may be prescribed to alleviate headache; selective-serotonin reuptake inhibitors (SSRIs) may aid those with disease-associated depression and anxiety; and antipsychotic medications can help address movement disorders [2]. In addition to pharmacological treatment, physical rehabilitation can help patients maintain their range of motion and strengthen their muscle tone, leading to benefits such as improved balance and stabilization, reduced muscle spasticity, and lower risk of fall [2].

Challenges and future research for Fahr’s disease

Because Fahr’s disease is so rare, it is difficult to study in a clinical setting. As such, scientific knowledge about the disease’s underlying mechanisms is hazy, and treatment remains palliative rather than curative. Moreover, an individual may not know that they have the disease until later in life, at which point they may already have children who inherited the disease. Genetic counselling and prenatal testing may be useful for individuals who have a family history of the disease or are known to be at higher risk. Unfortunately, many individuals with a family history of Fahr’s disease may not be aware of it due to confounding diagnoses, early death of a parent, or low penetrance, which results in milder symptoms. Ultimately, what is needed is the participation of patients with Fahr’s disease and their relatives in the research process [4]. This can both lead to better scientific understanding and help clinicians assess how they can best care for individuals and their families facing the disease.

Faith Wershba

Faith Wershba

Faith obtained her Honour’s Bachelor Degree in Human Biology, Immunology and History & Philosophy of Science at the University of Toronto. Currently, she is a postgraduate researcher at the University of Cambridge, focusing on the philosophy of medicine, science, biomedical research methods, and bioethics.