Primary familial brain calcification

Last updated
Primary familial brain calcification
Other namesFamilial idiopathic basal ganglia calcification
Fahr syndrome.gif
CT scan of characteristic calcifications of the disease
Specialty Neurology   OOjs UI icon edit-ltr-progressive.svg

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]

Contents

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

This condition can be inherited in an autosomal dominant or recessive fashion. Several genes have been associated with this condition[ citation needed ]

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.[ citation needed ]

Two other genes have been associated with this condition: PDGFB on chromosome 22 and PDGFRB on chromosome 5. [12] 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 ]

A fourth gene associated with this condition is XPR1. This gene is the long arm of located on chromosome 1 (1q25.3).[ citation needed ]

Another gene that has been associated with this condition is MYORG. [13] [14] 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 ]

Another gene junctional adhesion molecule 2 (JAM2) has been associated with an autosomal recessive form of this condition. [15] Other genes that have been associated with this condition are Junctional adhesion molecule C (JAM3) and Occludin (OCLN).[ citation needed ]

Pathology

The most commonly affected region of the brain is the lenticular nucleus and in particular the internal globus pallidus. [16] 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 ]

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 ]

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 ]

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 ]

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

Brain CT scan is the preferred method of localizing and assessing the extent of cerebral calcifications.[ citation needed ]

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. [18]

The diagnosis requires the following criteria be met:[ citation needed ]

  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 ]

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. [19] [20] [21] [22]

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. [23] One case report described an improvement with the use of a bisphosphonate. [24]

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. [25]

Progressive neurological deterioration generally results in disability and death.[ citation needed ]

History

The disease was first noted by German pathologist Karl Theodor Fahr in 1930. [26] [27] 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. [28] [29]

Fewer than 20 families had been reported in the literature up to 1997. [30]

In literature

Fahr's syndrome features in Norwegian Jo Nesbø's crime fiction novel "The Snowman" (the seventh novel in the Harry Hole detective series).

See also

Related Research Articles

<span class="mw-page-title-main">Genetic disorder</span> Health problem caused by one or more abnormalities in the genome

A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.

<span class="mw-page-title-main">Parkinsonism</span> Medical condition

Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia, rigidity, and postural instability. Both hypokinetic as well as hyperkinetic features are displayed by Parkinsonism.These are the four motor symptoms found in Parkinson's disease (PD) – after which it is named – dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), and many other conditions. This set of symptoms occurs in a wide range of conditions and may have many causes, including neurodegenerative conditions, drugs, toxins, metabolic diseases, and neurological conditions other than PD.

<span class="mw-page-title-main">Macrocephaly</span> Abnormally large head size

Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to determine whether the syndrome is accompanied by particular disorders. Those with benign or familial macrocephaly are considered to have megalencephaly.

<span class="mw-page-title-main">Dystonia</span> Neurological movement disorder

Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions occur involuntarily, resulting in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often intensified or exacerbated by physical activity, and symptoms may progress into adjacent muscles.

<span class="mw-page-title-main">Primrose syndrome</span> Medical condition

Primrose syndrome is a rare, slowly progressive genetic disorder that can vary symptomatically between individual cases, but is generally characterised by ossification of the external ears, learning difficulties, and facial abnormalities. It was first described in 1982 in Scotland's Royal National Larbert Institution by Dr D.A.A. Primrose.

<span class="mw-page-title-main">CADASIL</span> Medical condition

CADASIL or CADASIL syndrome, involving cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, is the most common form of hereditary stroke disorder, and is thought to be caused by mutations of the Notch 3 gene on chromosome 19. The disease belongs to a family of disorders called the leukodystrophies. The most common clinical manifestations are migraine headaches and transient ischemic attacks or strokes, which usually occur between 40 and 50 years of age, although MRI is able to detect signs of the disease years prior to clinical manifestation of disease.

<span class="mw-page-title-main">Behr syndrome</span> Medical condition

Behr syndrome is characterized by the association of early-onset optic atrophy with spinocerebellar degeneration resulting in ataxia, pyramidal signs, peripheral neuropathy and developmental delay.

Pantothenate kinase-associated neurodegeneration (PKAN), formerly called Hallervorden–Spatz syndrome, is a genetic degenerative disease of the brain that can lead to parkinsonism, dystonia, dementia, and ultimately death. Neurodegeneration in PKAN is accompanied by an excess of iron that progressively builds up in the brain.

<span class="mw-page-title-main">McLeod syndrome</span> Medical condition

McLeod syndrome is an X-linked recessive genetic disorder that may affect the blood, brain, peripheral nerves, muscle, and heart. It is caused by a variety of recessively inherited mutations in the XK gene on the X chromosome. The gene is responsible for producing the Kx protein, a secondary supportive protein for the Kell antigen on the red blood cell surface.

<span class="mw-page-title-main">Sjögren–Larsson syndrome</span> Medical condition

Sjögren–Larsson syndrome is a rare autosomal recessive form of ichthyosis with neurological symptoms. It can be identified by a triad of medical disorders. The first is ichthyosis, which is a buildup of skin to form a scale-like covering that causes dry skin and other problems. The second identifier is paraplegia which is characterized by leg spasms. The final identifier is intellectual delay.

<span class="mw-page-title-main">Cerebrotendineous xanthomatosis</span> Medical condition

Cerebrotendinous xanthomatosis, also called cerebral cholesterosis, is an autosomal recessive form of xanthomatosis. It falls within a group of genetic disorders called the leukodystrophies.

<span class="mw-page-title-main">SLC20A2</span> Protein-coding gene in the species Homo sapiens

Sodium-dependent phosphate transporter 2 is a protein that in humans is encoded by the SLC20A2 gene.

<span class="mw-page-title-main">Keutel syndrome</span> Medical condition

Keutel syndrome (KS) is a rare autosomal recessive genetic disorder characterized by abnormal diffuse cartilage calcification, hypoplasia of the mid-face, peripheral pulmonary stenosis, hearing loss, short distal phalanges (tips) of the fingers and mild mental retardation. Individuals with KS often present with peripheral pulmonary stenosis, brachytelephalangism, sloping forehead, midface hypoplasia, and receding chin. It is associated with abnormalities in the gene coding for matrix gla protein, MGP. Being an autosomal recessive disorder, it may be inherited from two unaffected, abnormal MGP-carrying parents. Thus, people who inherit two affected MGP alleles will likely inherit KS.

<span class="mw-page-title-main">Paroxysmal exercise-induced dystonia</span> Medical condition

Paroxysmal exercise-induced dystonia or PED is a rare neurological disorder characterized by sudden, transient, involuntary movements, often including repetitive twisting motions and painful posturing triggered by exercise or other physical exertion. PED is in the class of paroxysmal dyskinesia which are a group of rare movement disorders characterized by attacks of hyperkinesia with intact consciousness. The term paroxysmal indicates that the episodes are sudden and short lived and usually unpredicted, and return to normal is rapid. The number of reported cases of people with PED is very small leading to difficulty in studying and classifying this disease and most studies are limited to a very small number of test subjects.

<span class="mw-page-title-main">Basal ganglia disease</span> Group of physical problems resulting from basal ganglia dysfunction

Basal ganglia disease is a group of physical problems that occur when the group of nuclei in the brain known as the basal ganglia fail to properly suppress unwanted movements or to properly prime upper motor neuron circuits to initiate motor function. Research indicates that increased output of the basal ganglia inhibits thalamocortical projection neurons. Proper activation or deactivation of these neurons is an integral component for proper movement. If something causes too much basal ganglia output, then the ventral anterior (VA) and ventral lateral (VL) thalamocortical projection neurons become too inhibited, and one cannot initiate voluntary movement. These disorders are known as hypokinetic disorders. However, a disorder leading to abnormally low output of the basal ganglia leads to reduced inhibition, and thus excitation, of the thalamocortical projection neurons which synapse onto the cortex. This situation leads to an inability to suppress unwanted movements. These disorders are known as hyperkinetic disorders.

<span class="mw-page-title-main">Gillespie syndrome</span> Medical condition

Gillespie syndrome, also called aniridia, cerebellar ataxia and mental deficiency, is a rare genetic disorder. The disorder is characterized by partial aniridia, ataxia, and, in most cases, intellectual disability. It is heterogeneous, inherited in either an autosomal dominant or autosomal recessive manner. Gillespie syndrome was first described by American ophthalmologist Fredrick Gillespie in 1965.

<span class="mw-page-title-main">Kohlschütter–Tönz syndrome</span> Medical condition

Kohlschütter–Tönz syndrome (KTS), also called amelo-cerebro-hypohidrotic syndrome, is a rare inherited syndrome characterized by epilepsy, psychomotor delay or regression, intellectual disability, and yellow teeth caused by amelogenesis imperfecta. It is a type A ectodermal dysplasia.

<span class="mw-page-title-main">Aicardi–Goutières syndrome</span> Medical condition

Aicardi–Goutières syndrome (AGS), which is completely distinct from the similarly named Aicardi syndrome, is a rare, usually early onset childhood, inflammatory disorder most typically affecting the brain and the skin. The majority of affected individuals experience significant intellectual and physical problems, although this is not always the case. The clinical features of AGS can mimic those of in utero acquired infection, and some characteristics of the condition also overlap with the autoimmune disease systemic lupus erythematosus (SLE). Following an original description of eight cases in 1984, the condition was first referred to as 'Aicardi–Goutières syndrome' (AGS) in 1992, and the first international meeting on AGS was held in Pavia, Italy, in 2001.

Nasu–Hakola disease also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy is a rare disease characterised by early-onset dementia and multifocal bone cysts. It is caused by autosomal recessive loss of function mutations in either the TREM2 or TYROBP gene that are found most frequently in the Finnish and Japanese populations.

PRICKLE1-related progressive myoclonus epilepsy with ataxia is a very rare genetic disorder which is characterized by myoclonic epilepsy and ataxia.

References

  1. 1 2 Eliana Marisa Ramos; Joao Oliveira; Maria J Sobrido; Giovanni Coppola (1993). "Primary Familial Brain Calcification". GeneReviews, at National Center for Biotechnology Information . University of Washington, Seattle. PMID   20301594. 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". Archived from the original on 2009-05-11. Retrieved 2009-06-13.
  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. PMC   1739167 . PMID   15258221.
  4. ↑ "NINDS Fahr's Syndrome Information Page". National Institute of Neurological Disorders and Stroke. Archived from the original on 5 February 2007. Retrieved 13 January 2007.
  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. PMC   2399589 . PMID   8446558.
  7. ↑ Geschwind DH, Loginov M, Stern JM (September 1999). "Identification of a locus on chromosome 14q for idiopathic basal ganglia calcification (Fahr disease)". Am. J. Hum. Genet. 65 (3): 764–72. doi:10.1086/302558. PMC   1377984 . PMID   10441584.
  8. ↑ Dai X, Gao Y, Xu Z, et al. (October 2010). "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. doi:10.1002/ajmg.b.31102. PMID   20552677. S2CID   21165897.
  9. ↑ Volpato CB, De Grandi A, Buffone E, et al. (November 2009). "2q37 as a susceptibility locus for idiopathic basal ganglia calcification (IBGC) in a large South Tyrolean family". J. Mol. Neurosci. 39 (3): 346–53. doi:10.1007/s12031-009-9287-3. PMID   19757205. S2CID   23235853.
  10. ↑ Oliveira JR, Spiteri E, Sobrido MJ, et al. (December 2004). "Genetic heterogeneity in familial idiopathic basal ganglia calcification (Fahr disease)". Neurology. 63 (11): 2165–7. doi:10.1212/01.wnl.0000145601.88274.88. PMID   15596772. S2CID   22046680.
  11. ↑ Wang C, Li Y, Shi L, et al. (March 2012). "Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis". Nat. Genet. 44 (3): 254–6. doi:10.1038/ng.1077. PMID   22327515. S2CID   2515200.
  12. ↑ 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
  13. ↑ 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):106-113
  14. ↑ Yao 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
  15. ↑ 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
  16. ↑ Bonazza S, La Morgia C, Martinelli P, Capellari S (August 2011). "Strio-pallido-dentate calcinosis: a diagnostic approach in adult patients". Neurol. Sci. 32 (4): 537–45. doi:10.1007/s10072-011-0514-7. PMID   21479613. S2CID   11316462.
  17. ↑ Morita M, Tsuge I, Matsuoka H, et al. (May 1998). "Calcification in the basal ganglia with chronic active Epstein-Barr virus infection". Neurology. 50 (5): 1485–8. doi:10.1212/wnl.50.5.1485. PMID   9596016. S2CID   7376355.
  18. ↑ Hozumi I, Kohmura A, Kimura A, et al. (2010). "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. doi:10.1159/000313920. PMC   2905580 . PMID   20671856.
  19. ↑ Niwa A, Naito Y, Kuzuhara S (2008). "Severe cerebral calcification in a case of LEOPARD syndrome". Intern. Med. 47 (21): 1925–9. doi: 10.2169/internalmedicine.47.1365 . PMID   18981639.
  20. ↑ Preusser M, Kitzwoegerer M, Budka H, Brugger S (October 2007). "Bilateral striopallidodentate calcification (Fahr's syndrome) and multiple system atrophy in a patient with longstanding hypoparathyroidism". Neuropathology. 27 (5): 453–6. doi:10.1111/j.1440-1789.2007.00790.x. PMID   18018479. S2CID   34345069.
  21. ↑ Saito Y, Shibuya M, Hayashi M, et al. (July 2005). "Cerebellopontine calcification: a new entity of idiopathic intracranial calcification?". Acta Neuropathol. 110 (1): 77–83. doi:10.1007/s00401-005-1011-y. PMID   15959794. S2CID   2726661. Archived from the original on 2013-02-12.
  22. ↑ Tojyo K, Hattori T, Sekijima Y, Yoshida K, Ikeda S (June 2001). "[A case of idiopathic brain calcification associated with dyschromatosis symmetrica hereditaria, aplasia of dental root, and aortic valve sclerosis]". Rinsho Shinkeigaku (in Japanese). 41 (6): 299–305. PMID   11771159.
  23. ↑ 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.
  24. ↑ 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. S2CID   29240690.
  25. ↑ "NINDS Fahr's Syndrome Information Page". National Institute of Neurological Disorders and Stroke. Archived from the original on 5 February 2007. Retrieved 13 February 2007.
  26. ↑ Fahr, T. (1930–1931). "Idiopathische Verkalkung der Hirngefässe". Zentralblatt für Allgemeine Pathologie und Pathologische Anatomie. 50: 129–133.
  27. ↑ Fahr's disease at Who Named It?
  28. ↑ Chavany-Brunhes syndrome at Who Named It?
  29. ↑ "Chavany-Brunhes syndrome". Archived from the original on 2012-05-31. Retrieved 2009-06-13.
  30. ↑ 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. S2CID   1061208.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.