Clinical Description

All individuals with primary familial brain calcification (PFBC) have calcifications in the basal ganglia on neuroimaging, and many individuals also have calcifications in other areas of the brain. Clinical manifestations – when present – can be motor or non-motor involvement or a combination of both (see Section 2).

Neuroimaging. Cranial computed tomography (CCT) is the gold standard for detecting brain calcifications due to its high sensitivity. Magnetic resonance imaging (MRI), particularly susceptibility-weighted imaging (SWI), also reliably detects brain calcifications [Sahin et al 2015].

While the basal ganglia invariably are affected in individuals with PFBC, other areas of the brain that can also be affected include the cerebellum, thalamus, and subcortical white matter. The extent and distribution of calcifications vary among individuals with PFBC and correlate, at least in part, with the genetic etiology and clinical manifestations [Balck et al 2021] (see Section 2).

Clinical manifestations mainly result from neurodegeneration of the central nervous system caused by the calcifications.

Motor manifestations, ranging from most common to less common, are parkinsonism (including bradykinesia, rigidity, tremor, postural instability), speech disturbance, dystonia, ataxia, seizures, and chorea.

Non-motor manifestations, ranging from most common to less common, are cognitive deficits, headache, and neurobehavioral/psychiatric manifestations (including depression, anxiety, and psychosis).

An affected individual may have only motor manifestations, only non-motor manifestations, or a combination of both.

Clinical manifestations vary by genetic cause (see Section 2). In addition, clinical manifestations show great intra- and interfamilial variability.

Recent studies have also suggested an association between PFBC and cerebral vascular involvement secondary to vascular calcifications such as stroke and transient ischemic attacks [Maheshwari et al 2023, Yektay Farahmand et al 2024].

Calcifications may not be restricted to the brain; histologic analyses have demonstrated increased calcification in the skin, potentially serving as a future diagnostic marker [Emmi et al 2025].

Diagnosis

The diagnosis of PFBC is established in a proband with bilateral calcification mainly in the basal ganglia; presence of progressive neurologic dysfunction; and absence of metabolic, infectious, toxic, or traumatic causes. Identification of a heterozygous pathogenic variant in PDGFB, PDGFRB, SLC20A2, or XPR1 or biallelic pathogenic variants in JAM2, MYORG, or NAA60 (see Table 1) by molecular genetic testing confirms the clinical diagnosis of PFBC. Pathogenic variant(s) in one of the known PFBC genes may be identified in an estimated 30%-60% of those individuals with a clinical diagnosis of PFBC (estimation based on the proportion of individuals with PFBC-SLC20A2 in clinically diagnosed PFBC cohorts [Hsu et al 2013, Ramos et al 2018, Chen et al 2019, Guo et al 2019b] and the proportion of individuals with PFBC-SLC20A2 among all individuals with genetically diagnosed PFBC (Table 1).

Nomenclature

PFBC has been referred to in the literature by about 35 different names [Manyam 2005], including Fahr disease (a misnomer that should not be used) and familial idiopathic basal ganglia calcification (FIBGC) (the preferred term until recently).

With the identification of the first causative genetic variants, the term "idiopathic" (i.e., calcifications of unknown cause) ceased to be appropriate and was replaced by "primary" (as opposed to calcifications secondary to infectious, inflammatory, toxic, or other causes). Therefore, and because calcium deposits are not limited to the basal ganglia but can also be seen in other brain areas, the designation "primary familial brain calcification" (PFBC) was proposed.

Although the term Fahr disease is still used frequently to designate either familial basal ganglia calcification or basal ganglia calcification of unknown cause, it is unknown whether these conditions represent the same disease.

PFBC-JAM2

Mean age at onset is 21 years.

Clinical penetrance is 94%.

• Motor manifestations. Parkinsonism (80%)
• Non-motor manifestations. Cognitive deficit (50%)

Brain calcifications. Additional regions of the brain in which calcifications occur include the cerebellum and white matter (90%).

Pathogenic variants. Single-nucleotide variants (SNVs), including nonsense and missense variants, are the most frequent variants; however, small frameshift insertions/deletions and structural or splice site/region variants have also been reported.

PFBC-MYORG

Mean age at onset is 45 years.

Clinical penetrance is 91%.

• Motor manifestations. Almost all clinically affected individuals have motor signs, most frequently bradykinesia (45%) and ataxia (37%), as well as speech disturbances (78%).
• Non-motor manifestations. Cognitive deficits (43%), depression (11%)

Brain calcifications. More than 90% of individuals have calcifications in other brain regions, and more than 60% of individuals have calcifications in at least four brain regions. Brain stem calcifications are a typical finding.

Pathogenic variants. Of all variants reported to date, two thirds are SNVs and one third are small insertions or deletions including in-frame deletions.

Heterozygotes. About 50% of MYORG heterozygotes have brain calcifications of varying severity and patterns. Among these individuals, one third may have clinical manifestations [Balck et al 2021]. Thus, monoallelic MYORG pathogenic variants may represent a risk factor for developing PFBC [Chen et al 2020].

PFBC-NAA60

Mean age at onset is 21 years.

Clinical penetrance is 100%. Clinical manifestations appear to be more complex and severe than those seen in PFBC caused by pathogenic variants in other genes.

• Motor manifestations. Almost all individuals have motor involvement (mostly parkinsonism).
• Non-motor manifestations. Developmental delay is present in some affected individuals, and cognitive deficits in 60%. Dysmorphic features may include any of the following: macrocephaly with long face, low-set ears, almond-shaped palpebral fissures, microcephaly, and proptosis [Chelban et al 2024].
  Note: Because consanguinity is reported in most affected families, it is possible that at least some manifestations (e.g., dysmorphic features) could be attributable to undiagnosed coexisting conditions.

Brain calcifications. More than 90% of individuals have another brain region affected, and more than 60% of individuals have at least four affected brain regions.

Pathogenic variants. All individuals reported to date have homozygous variants, of which most are missense SNVs, and a smaller fraction are frameshift deletions, insertions, or splice site region variants.

PFBC-PDGFB

Mean age at onset is 30 years.

Clinical penetrance is 84%.

• Motor manifestations. Parkinsonism (18%), ataxia (15%), chorea (13%)
• Non-motor manifestations. Cognitive deficits (35%), headaches or migraines (42%)

Brain calcifications. Clinically symptomatic heterozygotes have more extensive calcifications in the thalamus, cerebellum, and white matter compared to clinically asymptomatic heterozygotes [Balck et al 2021].

Pathogenic variants. The most common variants are SNVs; however, other reported variants include structural variants and small frameshift insertions or deletions [A Balck, unpublished data].

PFBC-PDGFRB

Mean age at onset is 40 years.

Clinical penetrance is 50%.

• Motor manifestations are present in 42% of individuals; primarily parkinsonism and bradykinesia (17% each)
• Non-motor manifestations. Cognitive deficits (25%), headaches or migraines (33%)

Brain calcifications. In addition to the basal ganglia, brain calcifications are also often found in the thalamus, cerebellum, and white matter. In clinically symptomatic heterozygotes, brain calcifications affect more regions of the brain compared to clinically asymptomatic heterozygotes [Balck et al 2021].

Pathogenic variants. All variants reported to date are SNVs including predominantly missense variants.

PFBC-SLC20A2

Mean age at onset is 46 years.

Clinical penetrance is 64%.

• Motor manifestations. Seventy-eight percent of clinically affected individuals develop motos symptoms including parkinsonism (28%), bradykinesia (22%), rigidity (17%), tremor (15%), and speech disturbance (14%).
• Non-motor manifestations. Cognitive deficits (30%), headache (29%)

Brain calcifications. In addition to the basal ganglia, brain calcifications are also often found in the thalamus, cerebellum, and white matter. In clinically symptomatic heterozygotes, brain calcifications affect more regions of the brain compared to clinically asymptomatic heterozygotes.

Pathogenic variants. SNVs, structural variants, and in-frame insertions/deletions

PFBC-XPR1

Mean age at onset is 44 years.

Clinical penetrance is 74%.

• Motor manifestations. Speech disturbance and parkinsonism (29% each)
• Non-motor manifestations. Cognitive deficits (38%)

Brain calcifications. In more than 60% of the reported individuals with XPR1 variants, three or four brain regions are affected [Balck et al 2021.

Pathogenic variants. All individuals with autosomal dominant XPR1 have SNVs that are predominantly missense variants. Note: The only individual reported to date with biallelic XPR1 variants had a missense variant and a frameshift variant and developed his first clinical manifestations in infancy [Tang et al 2021].

Genomic/Genetic Testing

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not.

• A basal ganglia calcification multigene panel that includes some or all the genes listed in Table 1 is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing. Exome sequencing is most commonly used; genome sequencing is also possible.
  Note: (1) To date, most pathogenic variants reported in these genes are within the coding region (e.g., missense, nonsense) and are likely to be identified on exome sequencing; however, intronic variants that are detectable through genome sequencing have been reported [Balck et at 2021]. Intronic variants that create alternatively spliced transcripts have been reported in individuals with PFBC-SLC20A2 [Chen et al 2019, Zhao et al 2024]. (2) Structural variants (including whole-exon or whole-gene deletions and duplications) have been reported in 5%-10% of probands with PFBC-PDGFB, PFBC-SLC20A2, and PFBC-JAM2 [David et al 2016, Giorgio et al 2019, Guo et al 2019a, Cen et al 2020, Duan et al 2021]. Therefore, if the presence of such variants was not investigated through exome or genome sequencing, quantitative PCR analysis of at least these three genes is recommended.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Mode of Inheritance

Primary familial brain calcification (PFBC) caused by a heterozygous pathogenic variant in PDGFB, PDGFRB, SLC20A2, or XPR1 is inherited in an autosomal dominant manner. Note: Autosomal recessive inheritance of PFBC-XPR1 has been reported in one individual to date [Tang et al 2021].

PFBC caused by biallelic pathogenic variants in JAM2, MYORG, or NAA60 is inherited in an autosomal recessive manner.

Note: Genetic counseling for individuals with suspected PFBC in whom a genetic cause has not been identified is not discussed in this section.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with autosomal dominant PFBC have an affected parent identified either clinically or by cranial computed tomography (CCT). However, the transmitting parent may be clinically asymptomatic throughout life or may develop disease manifestations that are later in onset or less severe than those in the proband.
• Some individuals diagnosed with PFBC have the disorder as the result of a de novo pathogenic variant [Keller et al 2013, Ferreira et al 2014, Nicolas et al 2014, Guo et al 2019a]. The proportion of individuals with genetically confirmed PFBC caused by a de novo heterozygous pathogenic variant is unknown.
• If the proband appears to be the only affected family member (i.e., a simplex case) molecular genetic testing for the PFBC-related pathogenic variant identified in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Physical and neurologic examination and CCT can also be considered. Note: An individual diagnosed with genetically confirmed PFBC may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced clinical penetrance, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, de novo occurrence of the pathogenic variant in the proband cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the PFBC-related pathogenic variant identified in the proband.
• If the PFBC-related pathogenic variant identified in the proband cannot be identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.

Sibs of a proband. The risk to the sibs of a proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to be heterozygous for an autosomal dominant PFBC-related pathogenic variant, sibs of a proband are at a 50% risk of inheriting the pathogenic variant; however, the risk to sibs of being clinically affected may be lower because of reduced clinical penetrance (see Table 1).
• Age at onset, clinical presentation, and severity of PFBC are variable among heterozygous family members.
• If the PFBC-related pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the genetic status of the parents is unknown but neither parent has evidence of brain calcification on CCT, the risk to sibs is presumed to be low but still increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with an autosomal dominant PFBC-related pathogenic variant has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has a PFBC-related pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for an autosomal recessive PFBC-related pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an autosomal recessive PFBC-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) for a pathogenic variant in JAM2 or NAA60 are asymptomatic and are not at risk of developing PFBC. Heterozygous MYORG pathogenic variants may represent a risk factor for developing PFBC [Chen et al 2020]. About 50% of MYORG heterozygotes have brain calcifications of varying severity and patterns. Among these individuals, one third may have clinical manifestations [Balck et al 2021].

Sibs of a proband

• If both parents are known to be heterozygous for an autosomal recessive PFBC-related pathogenic variant, each sib of an affected individual has at conception:
  • A 25% chance of inheriting biallelic pathogenic variants and having PFBC (the risk to sibs of being clinically affected may be lower because of reduced clinical penetrance; see Table 1);
  • A 50% chance of being heterozygous;
  • A 25% chance of inheriting neither of the familial PFBC-related pathogenic variants.
• Heterozygotes (carriers) for a pathogenic variant in JAM2 or NAA60 are asymptomatic and are not at risk of developing PFBC. Heterozygous MYORG pathogenic variants may represent a risk factor for developing PFBC [Chen et al 2020]. About 50% of MYORG heterozygotes have brain calcifications of varying severity and patterns. Among these individuals, one third may have clinical manifestations [Balck et al 2021].

Offspring of a proband. Unless the reproductive partner of an individual with autosomal recessive PFBC also has PFBC or has PFBC-related pathogenic variant(s), their offspring will be obligate heterozygotes (carriers) for an autosomal recessive PFBC-related pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for an autosomal recessive PFBC-related pathogenic variant.

Heterozygote detection. Heterozygote testing for at-risk relatives requires prior identification of the autosomal recessive PFBC-related pathogenic variants in the family.

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive molecular genetic testing for at-risk relatives is possible once the PFBC-related pathogenic variant(s) have been identified in an affected family member.
• Since calcium deposits may precede the onset of clinical manifestations by several years, CCT also serves as a presymptomatic test in at-risk individuals. Thus, psychological and ethical considerations in offering such testing to asymptomatic adults should be similar to those applied for other neurodegenerative disorders in which a curative treatment is not currently available.
• Molecular genetic testing and testing for calcium deposits using CCT in the absence of definite clinical manifestations of the disease is predictive testing.
• Molecular genetic testing and CCT are not useful in predicting age of onset, severity or type of manifestations, or rate of progression in asymptomatic individuals.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes [Balck et al 2020] and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years) for typically adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality should be discussed in the context of formal genetic counseling. The autonomy of the minor is a primary concern, and consideration should be given to delaying predictive genetic testing until the at-risk individual is capable of informed decision making.

In a family with an established diagnosis of PFBC, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the PFBC-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for PFBC are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Author Notes

Alexander Balck (ed.kcebeul-inu@kclab.rednaxela), Christine Klein (ed.kcebeul-inu@nielk.enitsirhc), and Ana Westenberger (ed.kcebeul-inu@regrebnetsew.ana) are actively involved in clinical research regarding individuals with PFBC. They would be happy to communicate with persons who have any questions regarding the diagnosis of PFBC or other considerations. They are also interested in hearing from clinicians treating families affected by brain calcification in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr Westenberger to inquire about the review of PDGFB, PDGFRB, SLC20A2, or XPR1 variants of uncertain significance.

Author History

Alexander Balck, MD (2025-present)
Giovanni Coppola, MD; University of California Los Angeles (2013-2025)
Daniel H Geschwind, MD, PhD; University of California Los Angeles (2002-2017)
Suellen Hopfer, MD, PhD; Pennsylvania State University (2002-2017)
Christine Klein, MD (2025-present)
Joao Oliveira, MD, PhD; University of Pernambuco Recife (2013-2025)
Eliana Marisa Ramos, PhD; University of California Los Angeles (2017-2025)
Maria J Sobrido, MD, PhD; Fundación Pública Galega de Medicina Xenómica-SERGAS (2002-2025)
Ana Westenberger, PhD (2025-present)

Revision History

• 18 September 2025 (bp) Comprehensive update posted live; scope changed to overview
• 24 August 2017 (ha) Comprehensive update posted live
• 27 June 2013 (me) Comprehensive update posted live
• 20 September 2007 (me) Comprehensive update posted live
• 9 June 2004 (me) Comprehensive update posted live
• 18 April 2002 (me) Review posted live
• 28 September 2001 (ms) Original submission

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