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Primary Familial Brain Calcification

Includes: Primary Familial Brain Calcification 1, Primary Familial Brain Calcification 2, Primary Familial Brain Calcification 3, Primary Familial Brain Calcification 4

, MD, PhD, , MD, , MD, PhD, , MS, PhD, and , MD, PhD.

Author Information
, MD, PhD
Fundación Pública Galega de Medicina Xenómica-SERGAS
Santiago de Compostela, Spain
, MD
Departments of Psychiatry and Neurology
David Geffen School of Medicine
University of California Los Angeles
Los Angeles, California
, MD, PhD
Neuropsychiatry Department
Federal University of Pernambuco
Recife, Brazil
, MS, PhD
Senior Research Associate
University Health Services
Pennsylvania State University
University Park, Pennsylvania
, MD, PhD
Department of Neurology
Reed Neurological Research Center
University of California, Los Angeles
Los Angeles, California

Initial Posting: ; Last Update: June 27, 2013.

Summary

Disease characteristics. Primary familial brain calcification (PFBC) is a neurodegenerative disorder with characteristic calcium deposits in the basal ganglia and other brain areas visualized on neuroimaging. Most affected individuals are in good health during childhood and young adulthood and typically present in the fourth to fifth decade with gradually progressive neuropsychiatric and movement disorders. The main manifestations include clumsiness, fatigability, unsteady gait, slow or slurred speech, dysphagia, involuntary movements, or muscle cramping. Migraine is frequent and seizures of various types may also occur. Neuropsychiatric symptoms, often the first or most prominent manifestations, range from mild difficulty with concentration and memory to changes in personality and/or behavior, to psychosis and dementia.

Diagnosis/testing. The diagnosis of PFBC relies on visualization of bilateral calcification of the basal ganglia on neuroimaging; presence of progressive neurologic dysfunction; absence of metabolic, infectious, toxic, or traumatic cause; and a family history consistent with autosomal dominant inheritance. Thus, the diagnosis of PFBC should be left for those cases where other neurologic or systemic disorders potentially associated with ectopic calcium deposits have not been identified after appropriate examinations. Mutations in SLC20A2 (IBGC3) and PDGFRB have been reported to cause PFBC.

Management. Treatment of manifestations: Pharmacologic treatment to improve anxiety, depression, obsessive-compulsive behaviors, as well as for movement disorders (such as tremors) or dystonia; anticholinergics for urinary incontinence; appropriate antiepileptic drugs (AEDs) for seizures; migraine headaches may be alleviated with common symptomatic and preventive drugs used for migraine.

Surveillance: Annual neurologic and neuropsychiatric assessments.

Agents/circumstances to avoid: Cautious use of neuroleptic medication as it may exacerbate extrapyramidal symptoms.

Other: Generally poor response of parkinsonian features to levodopa therapy.

Genetic counseling. Primary familial brain calcification is inherited in an autosomal dominant manner. The proportion of cases caused by de novo gene mutations is unknown. Offspring of an affected individual have a 50% risk of being affected. If the disease-causing mutation has been identified in a family member, prenatal testing is possible either through a clinical laboratory or a laboratory offering custom prenatal testing.

Diagnosis

Clinical Diagnosis

The diagnosis of primary familial brain calcification (PFBC) is supported by the following criteria [modified from Moskowitz et al 1971, Ellie et al 1989, Manyam 2005]:

  • Bilateral calcification of the basal ganglia visualized on neuroimaging. Other brain regions may also be affected, including the cerebellar gyri, the brain stem, the centrum semiovale, and the subcortical white matter.
  • Progressive neurologic dysfunction, generally including a movement disorder and/or neuropsychiatric manifestations. Age of onset is typically in the fourth or fifth decade, although this dysfunction may present in childhood or later in life. Of note, the presence of brain calcifications in asymptomatic individuals is possible. Conversely, in rare cases symptomatic individuals with PFBC do not show brain calcifications.
  • Absence of biochemical abnormalities and somatic features suggestive of a mitochondrial or metabolic disease or other systemic disorder.
  • Absence of an infectious, toxic, or traumatic cause
  • Family history consistent with autosomal dominant inheritance

Imaging studies. The calcifications in PFBC are generally not distinguishable from those due to hypoparathyroidism or to other causes. However, some clues, such as the appearance and localization of the calcium deposits, may point to specific, mostly non idiopathic causes [Livingston et al 2013].

  • Brain CT scan, which easily detects calcium, is the preferred method of localizing and assessing the extent of cerebral calcifications. Most frequently affected is the lenticular nucleus, especially the internal globus pallidus. Calcifications in the putamen, thalami, caudate, and dentate nuclei are common. Occasionally, calcium deposits begin or predominate in regions outside the basal ganglia. Calcification seems to be progressive, since these deposits are generally more extensive in older individuals and an increase in calcification can sometimes be documented on follow-up of affected individuals.

    Cerebellar gyri, the brain stem, centrum semiovale, and subcortical white matter may also be affected [Manyam et al 1992].

    Diffuse atrophic changes with dilatation of the subarachnoid space and/or ventricular system may coexist with calcifications.
  • Magnetic resonance imaging (MRI). Calcified areas in the basal ganglia give a low-intensity signal on T2-weighted images and a low- or high-intensity signal on T1-weighted planes. In the cerebellum and cerebral white matter, the lesions may be more heterogeneous, sometimes seen as high signal on both T1 and T2, perhaps as a result of reactive gliosis or degenerating tissue within the calcified areas [Avrahami et al 1994].

    MRI provides better anatomical detail than CT, but is less sensitive in detecting calcification. Calcified lesions on MRI produce various levels of signal intensities that may be misinterpreted as not representing brain calcification. Kozic et al [2009] reported three individuals with brain calcification easily identified on CT scan for which MRI was interpreted as either completely normal, inconclusive or wrongly compatible with toxic/metabolic demyelination.
  • Plain skull radiograph. The calcifications appear as clusters of punctate densities symmetrically distributed above the sella turcica and lateral to the midline. Subcortical and cerebellar calcifications may appear wavy. Although the sensitivity of CT scan largely surpasses that of plain skull radiographs, the latter are still useful to evaluate abnormalities of bone structures suggestive of other diagnoses.

Testing

In order to evaluate for other genetic and acquired causes of strio-pallido-dentate calcifications, a diagnostic approach has been revised for adults [Bonazza et al 2011]. In individuals with PFBC the following evaluations are typically normal:

  • Serum concentration of calcium, phosphorus, magnesium, alkaline phosphatase, calcitonin, and parathyroid hormone (PTH)
  • Routine hematologic and biochemical investigations
  • Workup for metabolic, inflammatory, and infectious conditions
  • Blood and urine heavy metal concentrations
  • Ellsworth Howard test (i.e., a 10- to 20-fold increase of urinary cAMP excretion following stimulation with 200µ of PTH)
  • Cerebrospinal fluid evaluation for bacteria, viruses, and parasites; however, a slight increase in protein has been described [Boller et al 1977]

Neuropathology

  • Gross pathologic examination shows accumulation of a granular material and solid nodules in the striatum, internal capsule, white matter, and cerebellum. Circumscribed calcium deposits may also be seen in the thalamus and cerebral cortex. Mild lobar atrophy is common [Wider et al 2009].
  • Histologic examination of affected areas shows concentric calcium deposits within the walls of small and medium-sized arteries and, less frequently, veins [Norman & Urich 1960, Cervos-Navarro & Urich 1995]. Droplet calcifications can be observed along capillaries. These deposits may eventually obliterate the lumina of vessels. Multifocal parenchymal mineral deposits may also be present. The pallidal deposits stain positive for iron [Cervos-Navarro & Urich 1995]. Diffuse gliosis may surround the large deposits, but significant loss of nerve cells is rare. Ischemic changes may be present in the basal ganglia, as well as in cortical and subcortical regions [Wider et al 2009].
  • 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.

Molecular Genetic Testing

Gene. Mutations in SLC20A2 (IBGC3) have been reported in families worldwide [Wang et al 2012, Hsu et al 2013]. Also, mutations in PDGFRB have been reported in one family and in one simplex case of basal ganglia calcification [Nicolas et al 2013].

Evidence for locus heterogeneity

Research testing

  • Sequence analysis may be available on a research basis.
  • Linkage analysis may be available on a research basis in informative families with at least two affected family members of different generations.

Table 1. Summary of Molecular Genetic Testing Used in PFBC

Gene 1Proportion of PFBC Attributed to Mutations in This GeneTest MethodMutations Detected 2
SLC20A2~40%Sequence analysisSequence variants 3
Deletion/duplication analysis 4Unknown, none reported 5
PDGFRBUnknownSequence analysisSequence variants 3

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. No deletions or duplications involving SLC20A2 have been reported to cause primary familial brain calcification 3.

Testing Strategy

To confirm/establish the diagnosis in a proband. For individuals in whom a diagnosis of PFBC is being considered, other causes of brain calcification should be eliminated prior to pursuing genetic testing, particularly in simplex cases. Such evaluations may include the following:

  • Biochemical analysis of blood and urine to evaluate for disorders of calcium metabolism and heavy metal intoxication
  • Cerebrospinal fluid (CSF) analysis to evaluate for an infectious etiology, and autoimmune diseases such as systemic lupus erythematosus

If no other primary cause for brain calcification is detected or if the family history is suggestive of autosomal dominant inheritance, molecular genetic testing should be considered.

Predictive testing for at-risk asymptomatic adult family members may include brain CT to evaluate for calcium deposits. The presence of calcium deposits in this situation may be predictive of disease even in the absence of an identifiable familial mutation. In at-risk asymptomatic adult family members without brain calcifications, predictive testing requires prior identification of the disease-causing mutation in the family. (See Related Genetic Counseling Issues, Testing of at-risk asymptomatic adults.)

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

The clinical manifestations of primary familial brain calcification (PFBC) are limited to the nervous system. Most individuals with PFBC are in good health during childhood and young adulthood. Typically, the age of onset is between 30 and 60 years with gradual progression of the movement disorder and neuropsychiatric symptoms.

Since the first description of the disease [Foley 1951], over 50 affected kindreds (which further highlight the heterogeneous clinical presentation) have been reported [Manyam et al 2001a, Volpato et al 2009, Ashtari & Fatehi 2010].

The age at onset, clinical presentation, and severity of PFBC are variable both between and within families. No correlation has been identified between age of onset, extent of calcium deposits, and neurologic deficits. In some instances, calcifications precede the clinical manifestations by several years [Manyam et al 1992]; in other instances, young symptomatic individuals with no changes observed on CT scan later develop radiologically visible calcification [Geschwind et al 1999].

The movement disorder often first manifests as clumsiness, fatigability, unsteady gait, slow or slurred speech, dysphagia, involuntary movements, or muscle cramping [Manyam et al 1992, Manyam et al 2001b]. Neurologic evaluation generally reveals an extrapyramidal syndrome with variable combination of bradykinesia, rigidity, festinating gait, hypophonia, mask-like facies, diminished blinking, dystonia, tremor, choreoathetosis, or dyskinesia. Palmomental and other frontal release signs may be elicited.

Pyramidal or cerebellar signs may also be present and, in some cases, the cerebellar picture predominates.

Dystonia is prominent in a few families [Larsen et al 1985].

Neuropsychiatric symptoms, often the first or most prominent manifestations, range from mild difficulty with concentration and memory to changes in personality or behavior to psychosis and dementia [Geschwind et al 1999, Benke et al 2004, Shakibai et al 2005]. It has been suggested that those who become symptomatic early in adulthood are more likely to have psychosis.

The pattern of dementia includes frequent frontal-executive dysfunction and resembles that occurring in other disorders affecting subcortical structures, including Wilson disease and Huntington disease [Geschwind et al 1999, Benke et al 2004, Modrego et al 2005, Weisman et al 2007].

Although premorbid psychomotor development is generally normal, low IQ and mild delay in motor or intellectual milestones during school age are described.

Other

  • Seizures of various types occur frequently.
  • Some individuals experience chronic headache and vertigo [Geschwind et al 1999].
  • Urinary urgency or incontinence and impotence may be present [Manyam et al 1992].
  • Severe hypertension has been reported in two sisters with basal ganglia calcification with no other neurologic or systemic abnormalities; whether this represents a random association, a rare manifestation of PFBC, or a distinct genetic disorder with basal ganglia calcification is unknown.
  • General medical examination, growth, and facial appearance are normal. Strength and sensation are generally intact. Specifically, no abnormalities are detected in the skull, hands, teeth, nails, or skin, and there is no evidence of a parathyroid disorder.
  • Neurophysiologic studies are generally normal.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been observed in individuals with an SLC20A2 mutation [Wang et al 2012]. In addition, affected individuals with PDGFRB mutations show clinical and radiologic manifestations that are indistinguishable from families with mutations in SCL20A2 and from affected individuals with no detected mutations [Nicolas et al 2013].

Penetrance

Incomplete and age-related penetrance is reported in PFBC, but the factors that influence the clinical manifestations are unknown. The degree of penetrance may depend on whether affectation is considered at an anatomic (positive neuroimaging) level or at a clinical level (presence of clinical symptoms).

Although penetrance may vary among and within families, analysis of reported pedigrees indicates about 95% penetrance by age 50 years or older.

No reliable correlations exist between age of onset, extent of calcium deposits, and neurologic deficit. Although most individuals with calcifications eventually develop neurologic dysfunction, the type or severity of clinical symptoms cannot be predicted from the pattern of calcification.

Anticipation

Anticipation has been occasionally observed in kindreds with PFBC [Geschwind et al 1999, Shirahama et al 2010, Maeda et al 2012].

Nomenclature

Familial idiopathic basal ganglia calcification (FIBGC) was until recently the preferred term for this condition. Manyam [2005] lists 35 different names used in the literature for this disorder. After the recent discoveries of the first genes in which mutation is causative, it is the authors’ opinion that the term "primary" – as opposed to calcifications secondary to infectious, inflammatory, toxic, or other causes – should now be used instead of "idiopathic." Also, because the calcium deposits are not limited to the basal ganglia but can also be seen in other brain areas (as described above), the designation “primary familial brain calcification” (PFBC) is suggested.

Although the term Fahr's disease is often used to designate either familial or sporadic basal ganglia calcification, it is unknown whether the non-familial cases represent the same disease. The term Fahr's disease is ambiguous and should be avoided.

Prevalence

The prevalence of PFBC is unknown; approximately 50 kindreds have been reported. However, the disorder is probably under-recognized because of insufficient investigation of other family members of individuals presenting with calcification of the basal ganglia.

Differential Diagnosis

See Basal Ganglia Calcification, Idiopathic: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

Autosomal recessive forms of primary familial brain calcification have been reported [Longman et al 2003]; however, some of these families have childhood or infantile onset, and somatic or endocrinologic abnormalities, raising the possibility that these early reports actually include some of the disorders discussed in this section, or previously undescribed disorders.

Symmetric calcification of the basal ganglia identified radiographically occurs in a variety of familial and non-familial conditions.

  • Congenital or early-onset findings, intellectual disability, or presence of systemic involvement should alert to the possibility of an alternative diagnosis.
  • Electromyogram and nerve conduction velocity studies may discover latent tetany, myopathic changes, or polyneuropathy. These abnormalities, as well as alterations in somatosensory responses, brain stem auditory evoked responses, or visual evoked responses, should prompt the consideration of parathyroid dysfunction, mitochondrial disease, or other disorders associated with brain calcifications.
  • Basal ganglia calcifications occurring early in infancy or with associated ophthalmologic abnormalities should lead to the consideration of infectious causes or other diagnostic possibilities.

Parathyroid Disorders

Hypoparathyroidism (HP), idiopathic or postsurgical, is the most common cause of symmetric calcification of the basal ganglia [Illum & Dupont 1985]. HP usually begins in childhood or adolescence (i.e., earlier than is observed in PFBC). In individuals with HP, decreased serum concentration of PTH results in hypocalcemia and hyperphosphatemia and their clinical manifestations (i.e., tetany, muscle weakness, paresthesia, seizures, and intellectual disability). Additional features include cataracts, dry hair, alopecia, dental dysplasia, caries, and predisposition to moniliasis. Because treatment of HP may lead to marked clinical improvement, it is appropriate to evaluate individuals with calcification of the basal ganglia for HP.

Pseudohypoparathyroidism (PHP) and pseudo-pseudohypoparathyroidism (PPHP) are the phenotypic spectrum caused by mutations in GNAS, encoding the alpha subunit of a G-protein, which is involved in signal transduction. PHP and PPHP can occur in the same family. Occasionally, variants of PHP (types IB and II) or PPHP may have few or no somatic abnormalities, making diagnosis on clinical grounds difficult.

PHP results from end-organ unresponsiveness to PTH. The biochemical hallmarks are hypocalcemia and hyperphosphatemia with an elevated serum concentration of PTH. The baseline rate of excretion of urinary cAMP is below normal; after infusion of exogenous PTH, the increase in urinary excretion of phosphate and cAMP is generally subnormal. PHP type II is a variant of PHP with normal cAMP response; cases of PHP with normal serum calcium concentration have also been reported.

The average age of onset of PHP is eight to ten years. Most clinical manifestations are related to hypocalcemia and thus similar to those in hypoparathyroidism, with intellectual disability being somewhat more common in PHP. Affected individuals may have other manifestations of Albright hereditary osteodystrophy, including short stature, round facies, obesity, soft tissue calcification, short metacarpals or metatarsals, and other hormone resistance, resulting in hypothyroidism and/or hypogonadism.

PPHP, in contrast, is characterized by the physical findings of Albright hereditary osteodystrophy with normal serum concentration of calcium and phosphorus and normal response to PTH stimulation.

Kenny-Caffey syndrome type 1, characterized by growth delay, cortical thickening of the long bones, hypocalcemia, hypoparathyroidism, and calcification of the basal ganglia, is caused by mutations in TBCE, the gene encoding a chaperone protein required for proper folding of alpha-tubulin subunits and the formation of alpha-beta-tubulin heterodimers [Parvari et al 2002]. Inheritance is autosomal recessive.

Mitochondrial Disorders

Mineral deposits in the basal ganglia and other brain structures are observed in mitochondrial diseases (see Mitochondrial Disorders Overview). Some mitochondrial disorders only affect a single organ (such as the eye in Leber hereditary optic neuropathy), but many involve multiple organ systems and often present with prominent neurologic and myopathic features. Many individuals with mitochondrial abnormalities have a discrete clinical syndrome such as Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), neurogenic weakness with ataxia and retinitis pigmentosa (NARP), or Leigh syndrome (LS). However, clinical variability is considerable and many do not fit neatly into a recognized syndrome.

Infectious Diseases

Intrauterine or perinatal infection with toxoplasmosis, rubella, cytomegalovirus, or herpes simplex virus may result in calcification of the basal ganglia and dentate nucleus, as well as irregular masses of calcium distributed throughout the brain. CNS infection should be considered when clinical onset occurs soon after birth, especially in the presence of chorioretinitis, microcephaly, or neurologic abnormalities.

Non-congenital, active viral encephalitis should also be considered in some individuals with brain calcifications and negative family history [Morita et al 1998]. In AIDS, either opportunistic infections or inflammatory changes may cause symmetric calcified lesions in the basal ganglia, mostly in children.

Bacterial or parasitic infections such as brucellosis, toxoplasmosis, or cysticercosis should be considered, although the appearance and distribution of calcific deposits are generally quite different from FPFBC.

  • Brucellosis. Although cerebral calcification is rare, the detection of basal ganglia calcification in individuals residing in endemic areas should raise the possibility of CNS brucellar infection.
  • Toxoplasmosis. The basal ganglia are affected in up to 75% of cases.
  • Parenquimatous cysticercosis. Calcifications are a manifestation of death of the larvae and are generally rounded, less symmetric, and scattered within the grey matter or grey-white matter junction, sometimes in the basal ganglia or in the deep matter. This diagnostic possibility should be borne in mind in regions in which cysticercal infection is common. MRI is more sensitive than CT scan in identifying the parasitic cysts.

Adult-Onset Neurodegenerative Conditions

Pantothenate kinase-associated neurodegeneration (PKAN; formerly called Hallervorden-Spatz syndrome) is a form of neurodegeneration with brain iron accumulation (NBIA). PKAN is characterized by progressive dystonia and basal ganglia iron deposition with onset that usually occurs before age ten years. Commonly associated features include dysarthria, rigidity, and pigmentary retinopathy. About 25% of affected individuals have an 'atypical' presentation with later onset (age >10 years), prominent speech defects, psychiatric disturbances, and more gradual progression of disease. Approximately 50% of individuals given a clinical diagnosis of NBIA have identifiable mutations in PANK2. To date, all individuals with NBIA who are found to have the 'eye-of-the-tiger' sign on T2-weighted magnetic resonance imaging have been found to have at least one mutation in PANK2. Inheritance is autosomal recessive.

Neuroferritinopathy, another form of NBIA, typically presents with progressive adult-onset chorea or dystonia and subtle cognitive deficits. The movement disorder involves additional limbs within five to ten years and becomes more generalized within 20 years. Cognitive deficits, behavioral issues, and dysphagia are major problems with time. The diagnosis of neuroferritinopathy is based on clinical findings, including adult-onset chorea or dystonia and MRI or CT showing excess iron storage or cystic degeneration in the putamina. FTL, the ferritin light channel gene, is the only gene currently known to be associated with neuroferritinopathy. Inheritance is autosomal dominant.

Dentatorubro-pallidoluysian atrophy (DRPLA). Bilateral calcification of the globus pallidus has also been reported in individuals with the allelic variant of DRPLA, the Haw-River syndrome, a neurodegenerative disorder described in a large African-American family from North Carolina. Affected individuals show a varied combination of gait ataxia, dysarthria, involuntary movements, seizures, psychosis, and dementia, overlapping with the clinical picture of families with PFBC. The diagnosis of DRPLA rests on positive family history, characteristic clinical findings, and the detection of an expansion of a CAG/polyglutamine tract in DRPLA.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is characterized by fractures resulting from radiologically demonstrable polycystic osseous lesions, frontal lobe syndrome, and progressive presenile dementia beginning in the fourth decade. Bilateral calcifications of the basal ganglia, most often in the putamina, are commonly observed on CT. Calcifications may occur before CNS symptoms appear. TYROBP (DAP12) and TREM2 are the two genes associated with PLOSL. Inheritance is autosomal recessive.

Autosomal dominant dystonia-plus syndrome with brain calcinosis. Baba et al [2005] have updated information on a family with PFBC associated with movement disorders (dystonia, chorea, ataxia), mean age of onset of 19 years, and no linkage to 14q.

Parkinsonism, dystonia, hypermanganesemia, polycythemia, and chronic liver disease. This condition was recently reported to result from homozygous mutations in SLC30A10. Neuroimaging findings in individuals with this condition might mimic those seen in individuals with PFBC [Quadri et al 2012, Tuschl et al 2012].

Inherited Congenital or Early Onset Syndromes

Calcifications in the basal ganglia and other brain structures are encountered in several congenital or early onset syndromes with normal calcium-phosphorus metabolism and frequently associated intellectual disability.

Cockayne syndrome (CS) includes several forms that differ by age of onset:

  • CS type I (the "classic" form) presents with growth and developmental delays in the first two years of life. Progressive impairment of vision, hearing, and central and peripheral nervous system function lead to severe disability, with death typically occurring in the first or second decade. Intracranial calcifications, including of the basal ganglia, are seen in some individuals.
  • CS type II, a more severe form, also known as "connatal" Cockayne syndrome, cerebro-oculo-facial syndrome (COFS), or Pena-Shokeir type II syndrome, exhibits growth failure at birth with little or no postnatal neurologic development, congenital cataracts and other structural eye anomalies, kyphosis/scoliosis and joint contractures, and death usually by age seven years.
  • CS type III is a milder, rare form with late onset.

Cockayne syndrome is diagnosed in classic cases by clinical findings and in "non-classic" cases by assay of DNA repair in skin fibroblasts or lymphoblasts. Mutation in two genes, ERCC6 and ERCC8, is causative. Inheritance is autosomal recessive.

Aicardi-Goutières syndrome is an early-onset encephalopathy characterized by mental and physical handicap associated with calcification of the basal ganglia, particularly the putamen, globus pallidus, and thalamus; leukodystrophy; cerebral atrophy; chronic cerebrospinal fluid (CSF) leukocytosis; and increased concentration of interferon-alpha in the CSF. Onset typically occurs in the first three months of life; normal initial development is followed by loss of acquired skills, progressive microcephaly, irritability, feeding problems, sterile pyrexias, and hypersomnia. About 20%-25% of individuals have generalized tonic-clonic or focal tonic seizures. Six associated genes –RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and TREX1 – have been identified. Inheritance is autosomal recessive.

Tuberous sclerosis complex involves abnormalities of the skin (hypomelanotic macules, facial angiofibromas, shagreen patches, fibrous facial plaques, ungual fibromas), brain (cortical tubers, subependymal nodules, seizures, intellectual disability/developmental delay), kidney (angiomyolipomas, cysts), and heart (rhabdomyomas, arrhythmias). The cerebral hamartomas may be calcified; however, they are mainly periventricular or subcortical. Two associated genes, TSC1 and TSC2, have been identified. Inheritance is autosomal dominant.

Cerebroretinal microangiopathy with calcifications and cysts. This autosomal recessive condition, also named Coats plus syndrome, has been recently found to be due to mutations in CTC1 [Anderson et al 2012]. The spectrum of neurologic manifestations is complex and includes cognitive deterioration, seizures, spastic tetraparesis and cerebellar signs. Neuroimaging features are highly characteristic of an encephalopathy with diffuse intracranial calcifications and formation of parenchymal cysts. Affected individuals also have growth retardation, retinal exudates and skeletal malformations [Linnankivi et al 2006, Briggs et al 2008].

Down syndrome. Reports of basal ganglia calcifications in Down syndrome are abundant.

Other

Calcifications of the basal ganglia may result from the following:

  • Necrosis of neural tissue caused by traumatic, toxic, or physical insults. These include but are not limited to perinatal anoxia, Rh incompatibility, carbon monoxide intoxication, mercury and lead poisoning, exposure to ionizing radiation, and methotrexate therapy.
  • Systemic lupus erythematosus (SLE)
  • Celiac disease. Although intracranial calcifications have been described, the calcium deposits are mainly occipital. Other neurologic manifestations can include cerebellar ataxia, epilepsy, and peripheral neuropathy.
  • Normal aging. Calcification of the basal ganglia is an incidental finding in about 0.3%-1.5% of brain CT scans, especially in aged individuals (age therefore being the most common cause). Microscopic calcifications can be observed in the globus pallidus and dentate nucleus in up to 70% of autopsy series. These calcifications are generally confined to the globus pallidus and do not have associated clinical findings [Forstl et al 1992]. Basal ganglia calcifications in the aged have been associated with psychotic symptoms [Ostling et al 2003].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with primary familial brain calcification (PFBC), thorough neurologic and neuropsychiatric assessment is recommended.

Treatment of Manifestations

The following are appropriate:

  • Pharmacologic treatment to improve anxiety, depression, and obsessive-compulsive behaviors
  • To alleviate dystonia and other associated involuntary movements, pharmacologic therapies as typically used in neurologic practice for the treatment of movement disorders.
  • For urinary urgency or incontinence, oxybutynin or other anticholinergic medications
  • Appropriate antiepileptic drugs (AEDs) for seizures
  • To alleviate migraine headaches, symptomatic and preventive drugs as commonly used for migraine

Surveillance

Thorough neurologic and neuropsychiatric assessment is indicated annually.

Agents/Circumstances to Avoid

Neuroleptic medication should be used cautiously, since it may exacerbate extrapyramidal symptoms [Cummings et al 1983]. A poor response to neuroleptics was obtained in a family with PFBC and mainly psychotic manifestations [Callender 1995].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Anecdotally, a therapeutic trial with sodium etidronate in one affected individual resulted in partial improvement of speech and gait, but not of other neurologic symptoms; no reduction in the amount of calcification was observed [Loeb 1998].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

The response of parkinsonian features to levodopa therapy is generally poor. Manyam et al [2001a] attributed a positive response to levodopa in an affected individual in a family with PFBC to the coexistence of PFBC and idiopathic Parkinson disease.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Primary familial brain calcification (PFBC) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with PFBC have an affected parent as identified either clinically or by brain CT scan. However, the transmitting parent may be clinically asymptomatic or may develop disease manifestations that are later in onset or less severe than those in the proband.
  • No cases have been reported thus far as a result of a de novo gene mutation in SLC20A2. The proportion of cases caused by de novo mutations is unknown. Whether non familial (simplex) cases represent de novo gene mutations (thus placing their children at a 50% risk), incomplete penetrance or non-genetic conditions is also not known.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include physical and neurologic examination and CT scan.

Note: Although most individuals diagnosed with PFBC have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to the sibs of a proband depends on the genetic status of the parents.
  • If one parent is affected, the sibs of the proband are at a 50% risk of being affected.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low and depends on the spontaneous mutation rate of the gene(s) involved and the probability of germline mosaicism in a parent, both of which are currently unknown.

Offspring of a proband. Each child of an individual with PFBC has a 50% chance of inheriting the mutation.

Other family members. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

A thorough discussion of the implications and limitations of clinical genetic testing, particularly in presymptomatic at-risk individuals, is advisable.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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.

Testing of at-risk asymptomatic adults. Since calcium deposits may precede the onset of clinical symptoms by several years, a brain CT scan serves as a presymptomatic test in at-risk individuals. Thus, psychological and ethical considerations in offering such testing should be similar to those applied for other neurodegenerative disorders in which a curative treatment is not currently available, including the caveat regarding testing of at-risk individuals who are younger than age 18 years.

Brain CT scan is not useful in predicting age of onset, severity or type of symptoms, or rate of progression in asymptomatic individuals. Testing for calcium deposits using brain CT scan in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of PFBC, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent (including the possibility of incidental findings on a CT scan and whether such findings will be discussed) should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluations.

Testing of at-risk asymptomatic individuals during childhood. Consensus holds that individuals younger than age 18 years who are at risk for adult-onset disorders for which no curative or preventive treatment exists should not be tested in the absence of symptoms. The principal arguments against testing asymptomatic individuals before age 18 years for PFBC are that such testing removes the individual's future autonomy to make his/her own medical decisions and, because no treatment is currently available, it has no immediate medical benefit. Furthermore, a CT scan will not remove uncertainty in the case of PFBC because penetrance is age dependent, reaching about 95% by age 50 years.

In addition, testing of individuals during childhood runs the risk of causing psychological harm to the child by altering self-image, disturbing parent-child or sibling-sibling relationships, increasing anxiety and guilt, and stigmatizing the child. Moreover, the child could be discriminated against as an adult through denial of health insurance coverage.

Symptomatic individuals who are younger than age 18 years who are tested usually benefit from having a specific diagnosis established. See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

A normal brain CT scan does not completely eliminate the possibility of PFBC, especially in younger individuals.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in a family member, prenatal testing for pregnancies at increased risk is possible either through a clinical laboratory or a laboratory offering custom prenatal testing.

Interpretation of results of prenatal testing may be complicated by incomplete information on pathogenicity of certain genetic variants and on penetrance of some mutations. This should lead to special caution when prenatal testing is planned for adult-onset conditions that have manifestations of variable severity.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • Parkinson's Disease Foundation (PDF)
    1359 Broadway
    Suite 1509
    New York NY 10018
    Phone: 800-457-6676 (Toll-free Helpline); 212-923-4700
    Fax: 212-923-4778
    Email: info@pdf.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Primary Familial Brain Calcification: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Primary Familial Brain Calcification (View All in OMIM)

158378SOLUTE CARRIER FAMILY 20 (PHOSPHATE TRANSPORTER), MEMBER 2; SLC20A2
173410PLATELET-DERIVED GROWTH FACTOR RECEPTOR, BETA; PDGFRB
213600BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 1; IBGC1
606656BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 2; IBGC2
615007BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 4; IBGC4

SLC20A2

Normal allelic variants. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. The longest transcript NM_001257180.1 has 11 exons.

Pathogenic allelic variants. Mutations in SLC20A2 have been reported in seven families with PFBC [Wang et al 2012]. One was a frameshift mutation (one base deletion), one was an in-frame 3-bp deletion, and the remaining were missense mutations. In a large-scale screen Chan Hsu and collaborators reported a Swedish family with the p.Ser601Leu mutation that had previously been reported in a Chinese family [Wang et al 2012, Hsu et al 2013]. Another missense mutation affecting the same residue (p.Ser601Trp) was found in a different family with PFBC from China [Wang et al 2012]. Additionally, Hsu and colleagues reported 13 variants in SLC20A2 in PFBC: two frameshift, four nonsense, four missense, three splice site, and one rare synonymous variant [Hsu et al 2013]. Several of the missense mutations reported in different studies are within the N-terminal and C-terminal ProDom domains shared by all PiT transporters [Bøttger & Pedersen 2011].

Table 2. SLC20A2 Pathogenic Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.1802C>Tp.Ser601LeuNM_001257180​.1
NP_001244109​.1
c.1802C>Gp.Ser601Trp

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The longest transcript encodes a protein of 652 amino acids (NP_001244109.1)

Abnormal gene product. Functional studies suggest that the disorder is caused by haploinsufficiency of the protein product (sodium-dependent phosphate transporter 2) rather than a dominant negative effect.

PDGFRB

Normal allelic variants. The PDGFRB transcript has 23 exons.

Pathogenic allelic variants. Two missense mutations have been reported in PDGFRB in two French kindreds [Nicolas et al 2013].

Table 3. PDGFRB Pathogenic Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.1973T>Cp.Leu658ProNM_002609​.3
NP_002600​.1
c.2959C>Tp.Arg987Trp

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. PDGFRB on chromosome 5 encodes the platelet derived growth factor receptor beta, a class III tyrosine kinase receptor. The canonical transcript NM_002609.3, codes for a 1106-amino acid protein.

Abnormal gene product. PDGFRB is expressed in the brain, where it plays a role in angiogenesis and in the maintenance of the blood brain barrier. PDGFRB-deficient mice lack pericytes and have increased vascular permeability [Daneman et al 2010]. It has also been suggested that mutations in PDGFRB originate brain calcifications through interference with phosphate homeostasis [Nicolas et al 2013].

References

Published Guidelines/Consensus Statements

  1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 11-14-13. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2012. Accessed 11-14-13.

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Chapter Notes

Revision History

  • 27 June 2013 (me) Comprehensive update posted live
  • 20 September 2007 (me) Comprehensive update posted to live Web site
  • 9 June 2004 (me) Comprehensive update posted to live Web site
  • 18 April 2002 (me) Review posted to live Web site
  • 28 September 2001 (ms) Original submission
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