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Primary familial brain calcification Initial Posting: April 18, 2004; Last Update: August 24, 2017. (PFBC), also known as familial idiopathic basal ganglia calcification (FIBGC) and Fahr's disease, is a rare, genetically dominant or recessive, inherited
neurological Neurology (from , "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the nervous system, which comprises the brain, the s ...
disorder characterized by abnormal deposits of
calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
in areas of the
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
that control movement. Through the use of
CT scans A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or ...
, calcifications are seen primarily in the
basal ganglia The basal ganglia (BG) or basal nuclei are a group of subcortical Nucleus (neuroanatomy), nuclei found in the brains of vertebrates. In humans and other primates, differences exist, primarily in the division of the globus pallidus into externa ...
and in other areas such as the
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...
.


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. 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)
Familial idiopathic basal ganglia calcification
" In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. SourceGeneReviews nternet Seattle (WA): University of Washington, Seattle; 1993–2004
It usually presents with clumsiness, fatigability, unsteady gait, slow or slurred speech,
difficulty swallowing Dysphagia is difficulty in swallowing. Although classified under " symptoms and signs" in ICD-10, in some contexts it is classified as a condition in its own right. It may be a sensation that suggests difficulty in the passage of solids or li ...
, involuntary movements or
muscle cramp A cramp is a sudden, involuntary, painful skeletal muscle contraction or overshortening associated with electrical activity. While generally temporary and non-damaging, they can cause significant pain and a paralysis-like immobility of the affe ...
ing.
Seizures A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
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.


Causes

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


Mutation

A locus at 14q has been suggested, but no gene has been identified. A second locus has been identified on chromosome 8 and a third has been reported on chromosome 2. This suggests there may be some
genetic heterogeneity Genetic heterogeneity refers to different genetic causes for the same disease and can be classified into three types: allelic heterogeneity, locus heterogeneity, and phenotypic heterogeneity. Allelic heterogeneity occurs when different mutations wi ...
in this disease. A mutation in the gene encoding the type III sodium dependent phosphate transporter 2 ( SLC20A2) located on
chromosome 8 Chromosome 8 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 8 spans about 146 million base pairs (the building material of DNA) and represents between 4.5 and 5.0% of the total DNA i ...
has been reported. Biochemical evidence suggests that phosphate transport may be involved in this disease. Two other genes have been associated with this condition:
PDGFB Platelet-derived growth factor subunit B is a protein that in humans is encoded by the ''PDGFB'' gene. Function The protein encoded by this gene is a member of the platelet-derived growth factor family. The four members of this family are mito ...
on
chromosome 22 Chromosome 22 is one of the 23 pairs of chromosomes in human cells. Humans normally have two copies of chromosome 22 in each cell. Chromosome 22 is the second smallest human chromosome, spanning about 51 million DNA base pairs and representing b ...
and
PDGFRB Platelet-derived growth factor receptor beta is a protein that in humans is encoded by the ''PDGFRB'' gene. Mutations in PDGFRB are mainly associated with the clonal eosinophilia class of malignancies. Gene The ''PDGFRB'' gene is located on h ...
on
chromosome 5 Chromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 182 million base pairs (the building blocks of DNA) and represents almost 6% of the total DNA in cells. Ch ...
.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. A fourth gene associated with this condition is XPR1. This gene is the long arm of located on
chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which a ...
(1q25.3). 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 Chromosome 9 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome, as they normally do with all chromosomes. Chromosome 9 spans about 138 million base pairs of nucleic acids (the building blocks of DN ...
(9p13.3). This gene is associated with an autosomal recessive inheritance pattern in this condition. Another gene junctional adhesion molecule 2 (
JAM2 Junctional adhesion molecule B is a protein that in humans is encoded by the ''JAM2'' gene. JAM2 has also been designated as CD322 (cluster of differentiation 322). Function Tight junctions represent one mode of cell-to-cell adhesion in endoth ...
) 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). 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. 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-).


Pathology

The most commonly affected region of the brain is the
lenticular nucleus The lentiform nucleus (or lentiform complex, lenticular nucleus, or lenticular complex) are the putamen (laterally) and the globus pallidus (medially), collectively. Due to their proximity, these two structures were formerly considered one, howev ...
and in particular the internal
globus pallidus The globus pallidus (GP), also known as paleostriatum or dorsal pallidum, is a major component of the Cerebral cortex, subcortical basal ganglia in the brain. It consists of two adjacent segments, one external (or lateral), known in rodents simpl ...
. Calcifications in the caudate, dentate nuclei,
putamen The putamen (; from Latin, meaning "nutshell") is a subcortical nucleus (neuroanatomy), nucleus with a rounded structure, in the basal ganglia nuclear group. It is located at the base of the forebrain and above the midbrain. The putamen and c ...
and thalami are also common. Occasionally calcifications begin or predominate in regions outside the
basal ganglia The basal ganglia (BG) or basal nuclei are a group of subcortical Nucleus (neuroanatomy), nuclei found in the brains of vertebrates. In humans and other primates, differences exist, primarily in the division of the globus pallidus into externa ...
. 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. As well as the usual sites the cerebellar gyri,
brain stem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is co ...
,
centrum semiovale In neuroanatomy, the centrum semiovale, semioval center or centrum ovale is the central area of white matter found underneath the cerebral cortex. The white matter, located in each hemisphere between the cerebral cortex The cerebral cortex, ...
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. 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 An electron microscope is a microscope that uses a beam of electrons as a source of illumination. It uses electron optics that are analogous to the glass lenses of an optical light microscope to control the electron beam, for instance focusing i ...
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 Hypoparathyroidism is decreased function of the parathyroid glands with underproduction of parathyroid hormone (PTH). This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany (involuntary m ...
or other causes.


Diagnosis

In addition to the usual routine haematologic and biochemical investigations, the serum
calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
,
phosphorus Phosphorus is a chemical element; it has Chemical symbol, symbol P and atomic number 15. All elemental forms of phosphorus are highly Reactivity (chemistry), reactive and are therefore never found in nature. They can nevertheless be prepared ar ...
,
magnesium Magnesium is a chemical element; it has Symbol (chemistry), symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 ...
,
alkaline phosphatase The enzyme alkaline phosphatase (ALP, alkaline phenyl phosphatase, also abbreviated PhoA) is a phosphatase with the physiological role of dephosphorylating compounds. The enzyme is found across a multitude of organisms, prokaryotes and eukaryo ...
,
calcitonin Calcitonin is a 32 amino acid peptide hormone secreted by parafollicular cells (also known as C cells) of the thyroid (or endostyle) in humans and other chordates in the ultimopharyngeal body. It acts to reduce blood calcium (Ca2+), opposing the ...
and
parathyroid hormone Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates serum calcium and phosphate through its actions on the bone, kidneys, and small intestine. PTH incre ...
should also be measured. The
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
(CSF) should be examined to exclude
bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
,
virus A virus is a submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Viruses are ...
es and
parasite Parasitism is a Symbiosis, close relationship between species, where one organism, the parasite, lives (at least some of the time) on or inside another organism, the Host (biology), host, causing it some harm, and is Adaptation, adapted str ...
s. 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 Toxoplasmosis is a parasitic disease caused by ''Toxoplasma gondii'', an apicomplexan. Infections with toxoplasmosis are associated with a variety of neuropsychiatric and behavioral conditions. Occasionally, people may have a few weeks or month ...
is also indicated. Brain CT scan is the preferred method of localizing and assessing the extent of cerebral calcifications. Elevated levels of
copper Copper is a chemical element; it has symbol Cu (from Latin ) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkish-orang ...
,
iron Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...
, magnesium and
zinc Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...
but not calcium have been reported in the CSF but the significance of this finding—if any—is not known. The diagnosis requires the following criteria be met: # the presence of bilateral calcification of the basal ganglia # the presence of progressive neurologic dysfunction # the absence of an alternative metabolic, infectious, toxic or traumatic cause # 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.


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.


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 Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease (PD) and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. ...
therapy. Case reports have suggested that
haloperidol Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychos ...
or
lithium carbonate Lithium carbonate is an inorganic compound, the lithium salt of carbonic acid with the chemical formula, formula . This white Salt (chemistry), salt is widely used in processing metal oxides. It is on the WHO Model List of Essential Medicines, Wor ...
may help with
psychotic In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or incoher ...
symptoms. One case report described an improvement with the use of a
bisphosphonate Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed to treat osteoporosis. Evidence shows that they reduce the risk of fracture in ...
.


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 A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or ...
could be negative in a gene carrier who is younger than the age of 55. Progressive neurological deterioration generally results in disability and death.


History

The disease was first noted by
German German(s) may refer to: * Germany, the country of the Germans and German things **Germania (Roman era) * Germans, citizens of Germany, people of German ancestry, or native speakers of the German language ** For citizenship in Germany, see also Ge ...
pathologist Karl Theodor Fahr in 1930. 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. Fewer than 20 families had been reported in the literature up to 1997.


See also

*
Primrose syndrome 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 f ...


References


External links


Fahr Syndrome Images (MedPix)

National Organization for Rare Disorders (NORD)

National Institute on Aging (NIA)

National Institute of Mental Health (NIMH)
{{DEFAULTSORT:Fahr's Syndrome Neurological disorders Genetic disorders with OMIM but no gene Rare syndromes Syndromes affecting the nervous system