Fahr syndrome

Fahr syndrome, also known as bilateral striopallidodentate calcinosis, is characterised by abnormal calcium deposition with subsequent atrophy involving particularly the basal ganglia, cerebellar dentate nuclei and white matter.

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

There is confusion in the literature as to whether or not 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 (an underlying metabolic, infective or other defined cause is present).

It has, however, been argued 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 6. 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. moyamoya disease and moyamoya 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 the article. 

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 40 and 60 years of age 5. Incidence is unknown. 

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 6.

Fahr disease is characterised 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, aluminium, and iron have also been found deposited in the vessels.

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

Genetics

Fahr disease (aka primary familial brain calcification) is due to a variety of mutations, accounting for the majority (~60%) of diagnosed cases 5,7. These are inherited in an autosomal dominant pattern, although other mutations with a recessive mode of inheritance are likely present in the remaining, so far 'idiopathic' group. 

Known mutations include 5,7:

  • phosphate metabolism
    • SLC20A2 gene mutations: encodes sodium-dependent phosphate transporter 2 (PiT2)
    • XPR1gene mutations: encodes for a retroviral receptor with phosphate export function
  • blood brain barrier integrity/pericytes maintenance
    • PDGFB gene mutations: encodes for platelet-derived growth factor beta (PDGFb)
    • 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 6:

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

Fahr syndrome is diagnosed, typically 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 some care must be taken not to over call Fahr syndrome. Causes include 5,6

CT

Calcification is extensive and has a fairly typical distribution 3:

  • 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 of calcium crystals 4.
  • 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 4
FDG-PET

May show decreased FDG uptake, particularly in basal ganglia.

Primary familial brain calcification (Fahr disease) progresses steadily, and there is no known cure or specific treatment currently. 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 4.

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

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

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

Toxic and metabolic encephalopathies
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Article Information

rID: 7289
Synonyms or Alternate Spellings:
  • Familial cerebral ferrocalcinosis
  • Fahr's disease
  • Bilateral striopallidodentate calcification
  • Fahr's disease
  • Fahr syndrome
  • Fahr's syndrome
  • Primary familial brain calcification
  • Idiopathic basal ganglia calcifications

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Cases and Figures

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