Medicine:Primary familial brain calcification

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Short description: Genetic disorder involving calcification of the basal ganglia
Primary familial brain calcification
Other namesFamilial idiopathic basal ganglia calcification
CT scan of characteristic calcifications of the disease

Primary familial brain calcification[1] (PFBC), also known as familial idiopathic basal ganglia calcification (FIBGC) and Fahr's disease,[1] is a rare,[2] genetically dominant or recessive, inherited neurological disorder characterized by abnormal deposits of calcium in areas of the brain that control movement. Through the use of CT scans, calcifications are seen primarily in the basal ganglia and in other areas such as the cerebral cortex.[3]

Signs and symptoms

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.[4]

The disease usually manifests itself in the third to fifth decade of life but may appear in childhood or later in life.[5] 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.[6]

Causes

Mutation

A locus at 14q has been suggested, but no gene has been identified.[7] A second locus has been identified on chromosome 8[8] and a third has been reported on chromosome 2.[9] This suggests there may be some genetic heterogeneity in this disease.[10]

A mutation in the gene encoding the type III sodium dependent phosphate transporter 2 (SLC20A2) located on chromosome 8 has been reported.[11] Biochemical evidence suggests that phosphate transport may be involved in this disease.


Another gene junctional adhesion molecule 2 (JAM2) has been associated with an autosomal recessive form of this condition.[12]

The most recently found gene to be associated with PFBC is Nα-acetyltransferase 60 (NAA60).[13] 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.[14] 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-).[15][16][17]

Pathology

The most commonly affected region of the brain is the lenticular nucleus and in particular the internal globus pallidus.[18] Calcifications in the caudate, dentate nuclei, putamen and thalami are also common. Occasionally calcifications begin or predominate in regions outside the basal ganglia.


Diagnosis

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.[19] 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. Serology for toxoplasmosis is also indicated.


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.[20]

  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


Differential diagnosis

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.[21][22][23][24]

Management

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.[25] One case report described an improvement with the use of a bisphosphonate.[26]

Prognosis

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.[27]


History

The disease was first noted by German pathologist Karl Theodor Fahr in 1930.[28][29] 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.[30][31]

Fewer than 20 families had been reported in the literature up to 1997.[32]

See also

References

  1. ↑ 1.0 1.1 Eliana Marisa Ramos; Joao Oliveira; Maria J Sobrido; Giovanni Coppola (1993). Primary Familial Brain Calcification. University of Washington, Seattle. PMID 20301594. https://www.ncbi.nlm.nih.gov/books/NBK1421/.  Initial Posting: April 18, 2004; Last Update: August 24, 2017.
  2. ↑ "Genetic and Rare Diseases Information Center (GARD) – an NCATS Program | Providing information about rare or genetic diseases". https://rarediseases.info.nih.gov/diseases/. 
  3. ↑ Benke T; Karner E; Seppi K; Delazer M; Marksteiner J; Donnemiller E (August 2004). "Subacute dementia and imaging correlates in a case of Fahr's disease". J. Neurol. Neurosurg. Psychiatry 75 (8): 1163–5. doi:10.1136/jnnp.2003.019547. PMID 15258221. 
  4. ↑ "NINDS Fahr's Syndrome Information Page". National Institute of Neurological Disorders and Stroke. http://www.ninds.nih.gov/disorders/fahrs/fahrs.htm. 
  5. ↑ Sobrido MJ, Hopfer S, Geschwind DH (2007) "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
  6. ↑ Chiu HF; Lam LC; Shum PP; Li KW (January 1993). "Idiopathic calcification of the basal ganglia". Postgrad Med J 69 (807): 68–70. doi:10.1136/pgmj.69.807.68. PMID 8446558. 
  7. ↑ "Identification of a locus on chromosome 14q for idiopathic basal ganglia calcification (Fahr disease)". Am. J. Hum. Genet. 65 (3): 764–72. September 1999. doi:10.1086/302558. PMID 10441584. 
  8. ↑ "Identification of a novel genetic locus on chromosome 8p21.1-q11.23 for idiopathic basal ganglia calcification". Am. J. Med. Genet. B Neuropsychiatr. Genet. 153B (7): 1305–10. October 2010. doi:10.1002/ajmg.b.31102. PMID 20552677. 
  9. ↑ "2q37 as a susceptibility locus for idiopathic basal ganglia calcification (IBGC) in a large South Tyrolean family". J. Mol. Neurosci. 39 (3): 346–53. November 2009. doi:10.1007/s12031-009-9287-3. PMID 19757205. 
  10. ↑ "Genetic heterogeneity in familial idiopathic basal ganglia calcification (Fahr disease)". Neurology 63 (11): 2165–7. December 2004. doi:10.1212/01.wnl.0000145601.88274.88. PMID 15596772. https://escholarship.org/uc/item/79v1w0dv. 
  11. ↑ "Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis". Nat. Genet. 44 (3): 254–6. March 2012. doi:10.1038/ng.1077. PMID 22327515. 
  12. ↑ 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
  13. ↑ Chelban, Viorica; Aksnes, Henriette; Maroofian, Reza; LaMonica, Lauren C.; Seabra, Luis; Siggervåg, Anette; Devic, Perrine; Shamseldin, Hanan E. et al. (2024-03-13). "Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications" (in en). Nature Communications 15 (1): 2269. doi:10.1038/s41467-024-46354-0. ISSN 2041-1723. PMID 38480682. Bibcode: 2024NatCo..15.2269C. 
  14. ↑ Aksnes, Henriette; Ree, Rasmus; Arnesen, Thomas (2019). "Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases" (in en). Molecular Cell 73 (6): 1097–1114. doi:10.1016/j.molcel.2019.02.007. PMID 30878283. 
  15. ↑ Aksnes, Henriette; Van Damme, Petra; Goris, Marianne; Starheim, Kristian K.; Marie, Michaël; Støve, Svein Isungset; Hoel, Camilla; Kalvik, Thomas Vikestad et al. (2015). "An Organellar Nα-Acetyltransferase, Naa60, Acetylates Cytosolic N Termini of Transmembrane Proteins and Maintain Golgi Integrity" (in en). Cell Reports 10 (8): 1362–1374. doi:10.1016/j.celrep.2015.01.053. PMID 25732826. https://linkinghub.elsevier.com/retrieve/pii/S2211124715000789. 
  16. ↑ Støve, Svein Isungset; Magin, Robert S.; Foyn, Håvard; Haug, Bengt Erik; Marmorstein, Ronen; Arnesen, Thomas (2016). "Crystal Structure of the Golgi-Associated Human Nα-Acetyltransferase 60 Reveals the Molecular Determinants for Substrate-Specific Acetylation" (in en). Structure 24 (7): 1044–1056. doi:10.1016/j.str.2016.04.020. PMID 27320834. 
  17. ↑ Van Damme, Petra; Evjenth, Rune; Foyn, Håvard; Demeyer, Kimberly; De Bock, Pieter-Jan; Lillehaug, Johan R.; Vandekerckhove, Joël; Arnesen, Thomas et al. (2011). "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" (in en). Molecular & Cellular Proteomics 10 (5). doi:10.1074/mcp.M110.004580. PMID 21383206. 
  18. ↑ "Strio-pallido-dentate calcinosis: a diagnostic approach in adult patients". Neurol. Sci. 32 (4): 537–45. August 2011. doi:10.1007/s10072-011-0514-7. PMID 21479613. 
  19. ↑ "Calcification in the basal ganglia with chronic active Epstein-Barr virus infection". Neurology 50 (5): 1485–8. May 1998. doi:10.1212/wnl.50.5.1485. PMID 9596016. 
  20. ↑ "High Levels of Copper, Zinc, Iron and Magnesium, but not Calcium, in the Cerebrospinal Fluid of Patients with Fahr's Disease". Case Rep Neurol 2 (2): 46–51. 2010. doi:10.1159/000313920. PMID 20671856. 
  21. ↑ "Severe cerebral calcification in a case of LEOPARD syndrome". Intern. Med. 47 (21): 1925–9. 2008. doi:10.2169/internalmedicine.47.1365. PMID 18981639. 
  22. ↑ "Bilateral striopallidodentate calcification (Fahr's syndrome) and multiple system atrophy in a patient with longstanding hypoparathyroidism". Neuropathology 27 (5): 453–6. October 2007. doi:10.1111/j.1440-1789.2007.00790.x. PMID 18018479. 
  23. ↑ "Cerebellopontine calcification: a new entity of idiopathic intracranial calcification?". Acta Neuropathol. 110 (1): 77–83. July 2005. doi:10.1007/s00401-005-1011-y. PMID 15959794. http://link.springer.de/link/service/journals/00401/bibs/5110001/51100077.htm. 
  24. ↑ "[A case of idiopathic brain calcification associated with dyschromatosis symmetrica hereditaria, aplasia of dental root, and aortic valve sclerosis]" (in ja). Rinsho Shinkeigaku 41 (6): 299–305. June 2001. PMID 11771159. 
  25. ↑ Munir KM (February 1986). "The treatment of psychotic symptoms in Fahr's disease with lithium carbonate". J Clin Psychopharmacol 6 (1): 36–8. doi:10.1097/00004714-198602000-00008. PMID 3081601. 
  26. ↑ Loeb JA (March 1998). "Functional improvement in a patient with cerebral calcinosis using a bisphosphonate". Mov. Disord. 13 (2): 345–9. doi:10.1002/mds.870130225. PMID 9539353. 
  27. ↑ "NINDS Fahr's Syndrome Information Page". National Institute of Neurological Disorders and Stroke. http://www.ninds.nih.gov/disorders/fahrs/fahrs.htm. 
  28. ↑ Fahr, T. (1930–1931). "Idiopathische Verkalkung der Hirngefässe". Zentralblatt für Allgemeine Pathologie und Pathologische Anatomie 50: 129–133. 
  29. ↑ Fahr's disease at Who Named It?
  30. ↑ Chavany-Brunhes syndrome at Who Named It?
  31. ↑ "Chavany-Brunhes syndrome". https://rarediseases.info.nih.gov/diseases/. 
  32. ↑ Kobari M; Nogawa S; Sugimoto Y; Fukuuchi Y (March 1997). "Familial idiopathic brain calcification with autosomal dominant inheritance". Neurology 48 (3): 645–9. doi:10.1212/wnl.48.3.645. PMID 9065541. 
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