Fahr disease

Fahr syndrome, also known as bilateral striatopallidodentate calcinosis, is characterized by abnormal vascular calcium deposition, particularly in the basal ganglia, cerebellar dentate nuclei, and white matter, with subsequent atrophy.

It can be either primary (usually autosomal dominant) or secondary to a large number of underlying illnesses or metabolic disturbances.

Terminology

There is confusion in the literature as to whether Fahr disease and Fahr syndrome are synonymous or not. Generally, the terms are used interchangeably, further divided into:

  • primary: equivalent to familial cerebral ferrocalcinosis or primary familial brain calcification (now the preferred term), with no underlying other cause, and
  • secondary: due to an underlying metabolic, infective or other cause

It has been argued, however, that the term Fahr disease should be reserved for – and, in fact, perhaps replaced by – primary familial brain calcification, whereas Fahr syndrome should be used only for secondary causes . This distinction has merit as it serves to clarify an otherwise confusing topic, and is also in line with similar usage in other conditions (e.g. Cushing disease vs. syndrome, moyamoya disease vs. syndrome).

The term idiopathic basal ganglia calcification is best avoided.

As the imaging features are similar, both Fahr disease (primary) and syndrome (secondary) are discussed in the remainder of this article.

Epidemiology

Calcification of basal ganglia is very common, and age dependent, with small amounts of calcification confined to the globus pallidus, considered a 'normal' finding in the elderly.

Symptomatic onset for primary familial brain calcification (Fahr disease) tends to be between age 40 and 60 . Incidence is unknown.

Clinical presentation

The clinical presentation is variable, with many individuals remaining asymptomatic. Severe forms can later present with progressive psychosis, cognitive impairment, dementia, gait disturbance, basal ganglia movement disorders, and sensory changes .

Pathology

Fahr disease is characterized by deposition of calcium in the walls of the capillaries and larger arteries and veins. Other compounds, such as mucopolysaccharides, and elements, including magnesium, zinc, aluminum, and iron, have also been found deposited in the vessels.

Calcification can be found in the globus pallidus, putamen, caudate, thalamus, cerebellum (especially in the dentate nucleus), corona radiata, and subcortical white matter.

Genetics

Fahr disease (primary familial brain calcification) is due to a variety of mutations, accounting for the majority (~60%) of diagnosed cases . These are inherited in an autosomal dominant pattern, although other mutations with a recessive mode of inheritance are likely to be present in the remaining, 'idiopathic' group.

Known mutations include :

  • phosphate metabolism
    • SLC20A2 gene mutations: encodes sodium-dependent phosphate transporter 2 (PiT2)
    • XPR1 gene mutations: encodes for a retroviral receptor with phosphate export function
  • blood brain barrier integrity/pericyte maintenance
    • PDGFB gene mutations: encodes for platelet-derived growth factor beta (PDGF-b)
    • PDGFRB gene mutations: encodes for platelet-derived growth factor receptor beta (PDGFR-b)
Primary familial brain calcification (Fahr disease)

In patients with supporting imaging findings (see radiographic features below) and in most cases some of the aforementioned clinical features, suggested diagnostic criteria for Fahr disease are :

  • genetic abnormality detected (see above): autosomal dominant or autosomal recessive inheritance with a positive family history
  • typically presents 40 to 60 years of age
  • typical distribution calcification with progression
  • causes of Fahr syndrome (secondary) are excluded (see below)
  • Fahr syndrome (secondary)

    Fahr syndrome is typically diagnosed in younger individuals when a secondary cause is identified with appropriate intracranial imaging features. It should be noted that not all of the following causes result in typical patterns of calcification, so care must be taken not to overcall Fahr syndrome. Causes include :

    Radiographic features

    CT

    Calcification is extensive and has a relatively typical distribution :

    • basal ganglia and thalami
      • symmetric involvement of caudate, lentiform nucleus, thalamus, and dentate nuclei
      • globus pallidus affected first
    • subcortical white matter

    Bilateral calcification of the basal ganglia on neuroimaging or other brain regions, although in isolated cases patients from families with FIBGC may not present such findings.

    MRI

    The MRI appearance varies depending on the degree of calcification and the stage of the disease.

    • T1: contrary to expectation, the calcified areas are of high signal, attributed to the surface area effect of the calcium crystals
    • T2
      • calcified areas demonstrate low to isointense signal
      • high signal regions may be identified in the basal ganglia, white matter and internal capsule which are not in the areas of calcification
    FDG-PET

    May show decreased F-FDG uptake, particularly in the basal ganglia.

    Treatment and prognosis

    Primary familial brain calcification (Fahr disease) progresses steadily, and there currently is no known cure or specific treatment. Interestingly, there is no direct correlation between the amount of calcification and the degree of neurological impairment, which perhaps correlates to the amount of T2 high signal affected brain .

    Treatment for secondary causes should be aimed at the underlying illness/condition.

    History and etymology

    It was first noted in 1930 by Karl Theodor Fahr, a German neurologist.

    Differential diagnosis

    The differential for primary familial brain calcification (Fahr disease) is that of Fahr syndrome (see above). Also, refer to the article basal ganglia calcification.