Primary familial brain calcification

Symptoms of this disease include deterioration of motor functions and speech, seizures, and other involuntary movement. Other symptoms are headaches, dementia, and vision impairment. Characteristics of Parkinson's Disease are also similar to PFBC.{{cite web|title=NINDS Fahr's Syndrome Information Page|url=http://www.ninds.nih.gov/disorders/fahrs/fahrs.htm|publisher=National Institute of Neurological Disorders and Stroke|access-date=13 January 2007|archive-url=https://web.archive.org/web/20070205071541/http://www.ninds.nih.gov/disorders/fahrs/fahrs.htm|archive-date=5 February 2007|url-status=dead}}

The disease usually manifests itself in the third to fifth decade of life but may appear in childhood or later in life.Sobrido MJ, Hopfer S, Geschwind DH (2007) "[https://www.ncbi.nlm.nih.gov/books/NBK1421/ Familial idiopathic basal ganglia calcification]." In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. SourceGeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2004 It usually presents with clumsiness, fatigability, unsteady gait, slow or slurred speech, difficulty swallowing, involuntary movements or muscle cramping. Seizures of various types are common. Neuropsychiatric symptoms, which may be the first or the most prominent manifestations, range from mild difficulty with concentration and memory to changes in personality and/or behavior, to psychosis and dementia.{{cite journal |author1=Chiu HF| author2=Lam LC| author3=Shum PP | author4=Li KW |title=Idiopathic calcification of the basal ganglia |journal=Postgrad Med J |volume=69 |issue=807 |pages=68–70 |date=January 1993 |pmid=8446558 |pmc=2399589 |doi=10.1136/pgmj.69.807.68}}

This condition can be inherited in an autosomal dominant or recessive fashion. Several genes have been associated with this condition.{{citation needed|date=December 2020}}

A locus at 14q has been suggested, but no gene has been identified.{{cite journal |vauthors=Geschwind DH, Loginov M, Stern JM |title=Identification of a locus on chromosome 14q for idiopathic basal ganglia calcification (Fahr disease) |journal=Am. J. Hum. Genet. |volume=65 |issue=3 |pages=764–72 |date=September 1999 |pmid=10441584 |pmc=1377984 |doi=10.1086/302558 }} A second locus has been identified on chromosome 8{{cite journal |vauthors=Dai X, Gao Y, Xu Z, etal |title=Identification of a novel genetic locus on chromosome 8p21.1-q11.23 for idiopathic basal ganglia calcification |journal=Am. J. Med. Genet. B Neuropsychiatr. Genet. |volume=153B |issue=7 |pages=1305–10 |date=October 2010 |pmid=20552677 |doi=10.1002/ajmg.b.31102 |s2cid=21165897 }} and a third has been reported on chromosome 2.{{cite journal |vauthors=Volpato CB, De Grandi A, Buffone E, etal |title=2q37 as a susceptibility locus for idiopathic basal ganglia calcification (IBGC) in a large South Tyrolean family |journal=J. Mol. Neurosci. |volume=39 |issue=3 |pages=346–53 |date=November 2009 |pmid=19757205 |doi=10.1007/s12031-009-9287-3 |s2cid=23235853 }} This suggests there may be some genetic heterogeneity in this disease.{{cite journal |vauthors=Oliveira JR, Spiteri E, Sobrido MJ, etal |title=Genetic heterogeneity in familial idiopathic basal ganglia calcification (Fahr disease) |journal=Neurology |volume=63 |issue=11 |pages=2165–7 |date=December 2004 |pmid=15596772 |doi=10.1212/01.wnl.0000145601.88274.88|s2cid=22046680 |url=https://escholarship.org/uc/item/79v1w0dv }}

A mutation in the gene encoding the type III sodium dependent phosphate transporter 2 (SLC20A2) located on chromosome 8 has been reported.{{cite journal |vauthors=Wang C, Li Y, Shi L, etal |title=Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis |journal=Nat. Genet. |volume=44 |issue=3 |pages=254–6 |date=March 2012 |pmid=22327515 |doi=10.1038/ng.1077 |s2cid=2515200 }} Biochemical evidence suggests that phosphate transport may be involved in this disease.{{citation needed|date=November 2020}}

Two other genes have been associated with this condition: PDGFB on chromosome 22 and PDGFRB on chromosome 5.Westenberger A1, Klein C (2014) The genetics of primary familial brain calcifications. Curr Neurol Neurosci Rep 14(10):490 doi: 10.1007/s11910-014-0490-4 These genes are biochemically linked: PDGFRB encodes the platelet-derived growth factor receptor β and PDGFB encodes the ligand of PDGF-Rβ. These genes are active during angiogenesis to recruit pericytes which suggests that alterations in the blood brain barrier may be involved in the pathogenesis of this condition.{{citation needed|date=November 2020}}

A fourth gene associated with this condition is XPR1. This gene is the long arm of located on chromosome 1 (1q25.3).{{citation needed|date=December 2020}}

Another gene that has been associated with this condition is MYORG.Arkadir D, Lossos A, Rahat D, Abu Snineh M, Schueler-Furman O, Nitschke S, Minassian BA, Sadaka Y, Lerer I, Tabach Y, Meiner V (2018) MYORG is associated with recessive primary familial brain calcification. Ann Clin Transl Neurol 6(1):106-113Yao XP, Cheng X, Wang C, Zhao M, Guo XX, Su HZ, Lai LL, Zou XH, Chen XJ, Zhao Y, Dong EL, Lu YQ, Wu S, Li X, Fan G, Yu H, Xu J, Wang N, Xiong ZQ, Chen WJ (2018) Biallelic Mutations in MYORG cause autosomal recessive primary familial brain calcification. Neuron 98(6):1116-1123 This gene is located on the long arm of chromosome 9 (9p13.3). This gene is associated with an autosomal recessive inheritance pattern in this condition.{{citation needed|date=November 2020}}

Another gene junctional adhesion molecule 2 (JAM2) has been associated with an autosomal recessive form of this condition.Cen Z, Chen Y, Chen S, Wang H, Yang D, Zhang H, Wu H, Wang L, Tang S, Ye J, Shen J, Wang H, Fu F, Chen X, Xie F, Liu P, Xu X, Cao J, Cai P, Pan Q1,12, Li J, Yang W, Shan PF, Li Y, Liu JY, Zhang B, Luo W (2019) Biallelic loss-of-function mutations in JAM2 cause primary familial brain calcification. Brain

The most recently found gene to be associated with PFBC is Nα-acetyltransferase 60 (NAA60).{{Cite journal |last1=Chelban |first1=Viorica |last2=Aksnes |first2=Henriette |last3=Maroofian |first3=Reza |last4=LaMonica |first4=Lauren C. |last5=Seabra |first5=Luis |last6=Siggervåg |first6=Anette |last7=Devic |first7=Perrine |last8=Shamseldin |first8=Hanan E. |last9=Vandrovcova |first9=Jana |last10=Murphy |first10=David |last11=Richard |first11=Anne-Claire |last12=Quenez |first12=Olivier |last13=Bonnevalle |first13=Antoine |last14=Zanetti |first14=M. Natalia |last15=Kaiyrzhanov |first15=Rauan |date=2024-03-13 |title=Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications |journal=Nature Communications |language=en |volume=15 |issue=1 |page=2269 |doi=10.1038/s41467-024-46354-0 |issn=2041-1723 |pmc=10937998 |pmid=38480682|bibcode=2024NatCo..15.2269C }} NAA60 is a protein belonging to the family of N-terminal acetyltransferases (NATs), which catalyze the transfer of an acetyl group from acetyl-coenzyme A (Ac-CoA) to the N-terminus of proteins.{{Cite journal |last1=Aksnes |first1=Henriette |last2=Ree |first2=Rasmus |last3=Arnesen |first3=Thomas |date=2019 |title=Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases |journal=Molecular Cell |language=en |volume=73 |issue=6 |pages=1097–1114 |doi=10.1016/j.molcel.2019.02.007 |pmc=6962057 |pmid=30878283}} NAA60 is specifically localized to the Golgi apparatus and can acetylate membrane proteins post-translationally that have cytosolic N-termini starting with methionine followed by hydrophobic- or amphipathic-type amino acids (ML-, MI-, MF-, MY-, and MK-).{{Cite journal |last1=Aksnes |first1=Henriette |last2=Van Damme |first2=Petra |last3=Goris |first3=Marianne |last4=Starheim |first4=Kristian K. |last5=Marie |first5=Michaël |last6=Støve |first6=Svein Isungset |last7=Hoel |first7=Camilla |last8=Kalvik |first8=Thomas Vikestad |last9=Hole |first9=Kristine |last10=Glomnes |first10=Nina |last11=Furnes |first11=Clemens |last12=Ljostveit |first12=Sonja |last13=Ziegler |first13=Mathias |last14=Niere |first14=Marc |last15=Gevaert |first15=Kris |date=2015 |title=An Organellar Nα-Acetyltransferase, Naa60, Acetylates Cytosolic N Termini of Transmembrane Proteins and Maintain Golgi Integrity |url=https://linkinghub.elsevier.com/retrieve/pii/S2211124715000789 |journal=Cell Reports |language=en |volume=10 |issue=8 |pages=1362–1374 |doi=10.1016/j.celrep.2015.01.053|pmid=25732826 |hdl=1956/10959 |hdl-access=free }}{{Cite journal |last1=Støve |first1=Svein Isungset |last2=Magin |first2=Robert S. |last3=Foyn |first3=Håvard |last4=Haug |first4=Bengt Erik |last5=Marmorstein |first5=Ronen |last6=Arnesen |first6=Thomas |date=2016 |title=Crystal Structure of the Golgi-Associated Human Nα-Acetyltransferase 60 Reveals the Molecular Determinants for Substrate-Specific Acetylation |journal=Structure |language=en |volume=24 |issue=7 |pages=1044–1056 |doi=10.1016/j.str.2016.04.020 |pmc=4938767 |pmid=27320834}}{{Cite journal |last1=Van Damme |first1=Petra |last2=Evjenth |first2=Rune |last3=Foyn |first3=Håvard |last4=Demeyer |first4=Kimberly |last5=De Bock |first5=Pieter-Jan |last6=Lillehaug |first6=Johan R. |last7=Vandekerckhove |first7=Joël |last8=Arnesen |first8=Thomas |last9=Gevaert |first9=Kris |date=2011 |title=Proteome-derived Peptide Libraries Allow Detailed Analysis of the Substrate Specificities of Nα-acetyltransferases and Point to hNaa10p as the Post-translational Actin Nα-acetyltransferase |journal=Molecular & Cellular Proteomics |language=en |volume=10 |issue=5 |pages=M110.004580 |doi=10.1074/mcp.M110.004580 |doi-access=free |pmc=3098586 |pmid=21383206}}

The most commonly affected region of the brain is the lenticular nucleus and in particular the internal globus pallidus.{{cite journal |vauthors=Bonazza S, La Morgia C, Martinelli P, Capellari S |title=Strio-pallido-dentate calcinosis: a diagnostic approach in adult patients |journal=Neurol. Sci. |volume=32 |issue=4 |pages=537–45 |date=August 2011 |pmid=21479613 |doi=10.1007/s10072-011-0514-7 |s2cid=11316462 }} Calcifications in the caudate, dentate nuclei, putamen and thalami are also common. Occasionally calcifications begin or predominate in regions outside the basal ganglia.{{citation needed|date=November 2020}}

Calcification seems to be progressive, since calcifications are generally more extensive in older individuals and an increase in calcification can sometimes be documented on follow up of affected subjects.{{citation needed|date=November 2020}}

As well as the usual sites the cerebellar gyri, brain stem, centrum semiovale and subcortical white matter may also be affected. Diffuse atrophic changes with dilatation of the subarachnoid space and/or ventricular system may coexist with the calcifications. Histologically concentric calcium deposits within the walls of small and medium-sized arteries are present. Less frequently the veins may also be affected. Droplet calcifications can be observed along capillaries. These deposits may eventually lead to closure of the lumina of vessels.{{citation needed|date=November 2020}}

The pallidal deposits stain positively for iron. Diffuse gliosis may surround the large deposits but significant loss of nerve cells is rare. On electron microscopy the mineral deposits appear as amorphous or crystalline material surrounded by a basal membrane. Calcium granules are seen within the cytoplasm of neuronal and glial cells. The calcifications seen in this condition are indistinguishable from those secondary to hypoparathyroidism or other causes.{{citation needed|date=November 2020}}

In addition to the usual routine haematologic and biochemical investigations, the serum calcium, phosphorus, magnesium, alkaline phosphatase, calcitonin and parathyroid hormone should also be measured. The cerebrospinal fluid (CSF) should be examined to exclude bacteria, viruses and parasites.{{cite journal |vauthors=Morita M, Tsuge I, Matsuoka H, etal |title=Calcification in the basal ganglia with chronic active Epstein-Barr virus infection |journal=Neurology |volume=50 |issue=5 |pages=1485–8 |date=May 1998 |pmid=9596016 |doi=10.1212/wnl.50.5.1485|s2cid=7376355 }} The Ellsworth Howard test (a 10–20 fold increase of urinary cyclic AMP excretion following stimulation with 200 micromoles of parathyroid hormone) may be worth doing also.{{citation needed|date=March 2014}} Serology for toxoplasmosis is also indicated.

Brain CT scan is the preferred method of localizing and assessing the extent of cerebral calcifications.{{citation needed|date=December 2020}}

Elevated levels of copper, iron, magnesium and zinc but not calcium have been reported in the CSF but the significance of this finding—if any—is not known.{{cite journal |vauthors=Hozumi I, Kohmura A, Kimura A, etal |title=High Levels of Copper, Zinc, Iron and Magnesium, but not Calcium, in the Cerebrospinal Fluid of Patients with Fahr's Disease |journal=Case Rep Neurol |volume=2 |issue=2 |pages=46–51 |year=2010 |pmid=20671856 |pmc=2905580 |doi=10.1159/000313920 }}

The diagnosis requires the following criteria be met:{{citation needed|date=December 2020}}

1. the presence of bilateral calcification of the basal ganglia
2. the presence of progressive neurologic dysfunction
3. the absence of an alternative metabolic, infectious, toxic or traumatic cause
4. a family history consistent with autosomal dominant inheritance

The calcification is usually identified on CT scan but may be visible on plain films of the skull.{{citation needed|date=December 2020}}

Basal ganglia calcification may occur as a consequence of several other known genetic conditions and these have to be excluded before a diagnosis can be made.{{cite journal |vauthors=Niwa A, Naito Y, Kuzuhara S |title=Severe cerebral calcification in a case of LEOPARD syndrome |journal=Intern. Med. |volume=47 |issue=21 |pages=1925–9 |year=2008 |pmid=18981639 |doi=10.2169/internalmedicine.47.1365|doi-access=free }}{{cite journal |vauthors=Preusser M, Kitzwoegerer M, Budka H, Brugger S |title=Bilateral striopallidodentate calcification (Fahr's syndrome) and multiple system atrophy in a patient with longstanding hypoparathyroidism |journal=Neuropathology |volume=27 |issue=5 |pages=453–6 |date=October 2007 |pmid=18018479 |doi=10.1111/j.1440-1789.2007.00790.x|s2cid=34345069 }}{{cite journal |vauthors=Saito Y, Shibuya M, Hayashi M, etal |title=Cerebellopontine calcification: a new entity of idiopathic intracranial calcification? |journal=Acta Neuropathol. |volume=110 |issue=1 |pages=77–83 |date=July 2005 |pmid=15959794 |doi=10.1007/s00401-005-1011-y |s2cid=2726661 |url=http://link.springer.de/link/service/journals/00401/bibs/5110001/51100077.htm |archive-url=https://archive.today/20130212042907/http://link.springer.de/link/service/journals/00401/bibs/5110001/51100077.htm |url-status=dead |archive-date=2013-02-12 }}{{cite journal |vauthors=Tojyo K, Hattori T, Sekijima Y, Yoshida K, Ikeda S |title=[A case of idiopathic brain calcification associated with dyschromatosis symmetrica hereditaria, aplasia of dental root, and aortic valve sclerosis] |language=ja |journal=Rinsho Shinkeigaku |volume=41 |issue=6 |pages=299–305 |date=June 2001 |pmid=11771159 }}

There is currently no cure for PFBC nor a standard course of treatment. The available treatment is directed symptomatic control. If parkinsonian features develop, there is generally poor response to levodopa therapy. Case reports have suggested that haloperidol or lithium carbonate may help with psychotic symptoms.{{cite journal |author=Munir KM |title=The treatment of psychotic symptoms in Fahr's disease with lithium carbonate |journal=J Clin Psychopharmacol |volume=6 |issue=1 |pages=36–8 |date=February 1986 |pmid=3081601 |doi=10.1097/00004714-198602000-00008 }} One case report described an improvement with the use of a bisphosphonate.{{cite journal |author=Loeb JA |title=Functional improvement in a patient with cerebral calcinosis using a bisphosphonate |journal=Mov. Disord. |volume=13 |issue=2 |pages=345–9 |date=March 1998 |pmid=9539353 |doi=10.1002/mds.870130225 |s2cid=29240690 }}

The prognosis for any individual with PFBC is variable and hard to predict. There is no reliable correlation between age, extent of calcium deposits in the brain, and neurological deficit. Since the appearance of calcification is age-dependent, a CT scan could be negative in a gene carrier who is younger than the age of 55.{{cite web|title=NINDS Fahr's Syndrome Information Page|url=http://www.ninds.nih.gov/disorders/fahrs/fahrs.htm|publisher=National Institute of Neurological Disorders and Stroke|access-date=13 February 2007|archive-url=https://web.archive.org/web/20070205071541/http://www.ninds.nih.gov/disorders/fahrs/fahrs.htm|archive-date=5 February 2007|url-status=dead}}

Progressive neurological deterioration generally results in disability and death.{{citation needed|date=November 2020}}

The disease was first noted by German pathologist Karl Theodor Fahr in 1930.{{cite journal |author=Fahr, T. |title=Idiopathische Verkalkung der Hirngefässe |journal=Zentralblatt für Allgemeine Pathologie und Pathologische Anatomie |volume=50 |pages=129–133 |year=1930–1931 }}

{{WhoNamedIt|synd|451|Fahr's disease}} A less common name for the condition is Chavany-Brunhes syndrome and Fritsche's syndrome, the former named after Jacques Brunhes, Jean Alfred Émile Chavany, while the later named after R. Fritsche.{{WhoNamedIt|synd|1518|Chavany-Brunhes syndrome}}{{Cite web |url=http://rarediseases.info.nih.gov/GARD/QnA.aspx?PageID=4&CaseID=22373&DiseaseID=8272 |title=Chavany-Brunhes syndrome |access-date=2009-06-13 |archive-date=2012-05-31 |archive-url=https://web.archive.org/web/20120531191623/http://rarediseases.info.nih.gov/GARD/QnA.aspx?PageID=4&CaseID=22373&DiseaseID=8272 |url-status=dead }}

Fewer than 20 families had been reported in the literature up to 1997.{{cite journal |author1=Kobari M|author2=Nogawa S|author3=Sugimoto Y|author4=Fukuuchi Y |title=Familial idiopathic brain calcification with autosomal dominant inheritance |journal=Neurology |volume=48 |issue=3 |pages=645–9 |date=March 1997 |pmid=9065541 |doi=10.1212/wnl.48.3.645|s2cid=1061208 }}

• Primrose syndrome

{{Reflist}}

{{Medical resources

| DiseasesDB = 32200

| ICD10 = {{ICD10|G|23|8|g|23}}

| ICD9 =

| ICDO =

| OMIM = 213600

| MedlinePlus =

| eMedicineSubj =

| eMedicineTopic =

| MeshID =

| GeneReviewsNBK = NBK1421

| GeneReviewsName = Familial Idiopathic Basal Ganglia Calcification

}}

• [https://web.archive.org/web/20070927220226/http://rad.usuhs.edu/medpix/master.php3?mode=topic_images&pk=4582&quiz=#top Fahr Syndrome Images (MedPix)]
• [http://www.rarediseases.org National Organization for Rare Disorders (NORD)]
• [http://www.nia.nih.gov National Institute on Aging (NIA)]
• [http://www.nimh.nih.gov National Institute of Mental Health (NIMH)]

{{DEFAULTSORT:Fahr's Syndrome}}

Category:Neurological disorders

Category:Genetic disorders with OMIM but no gene

Category:Rare syndromes

Category:Syndromes affecting the nervous system