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Familial Idiopathic Basal Ganglia Calcification

[FIBGC, Familial Cerebrovascular Ferrocalcinosis, Familial Idiopathic Cerebral Calcinosis, Familial Striopallidodentate Calcification]

Summary

Disease characteristics.  Familial idiopathic basal ganglia calcification (FIBGC) 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 third to fifth decades with a gradual progression of neuropsychiatric and movement disorders. The first manifestations often include clumsiness, fatigability, unsteady gait, slow or slurred speech, dysphagia, involuntary movements, or muscle cramping. Seizures of various types occur frequently. 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.

Diagnosis/testing.  The diagnosis of FIBGC relies upon visualization of bilateral calcification of the basal ganglia on neuroimaging; presence of progressive neurological dysfunction; metabolic, infectious, toxic, or traumatic cause; and a family history consistent with autosomal dominant inheritance. The gene or genes responsible for FIBGC are unknown. Linkage to chromosome 14q has been established in one family. Such testing is available on a research basis only.

Genetic counseling.  Familial idiopathic basal ganglia calcification is inherited in an autosomal dominant manner. The proportion of cases caused by new gene mutations is unknown. Offspring of an affected individual have a 50% risk of being affected. Prenatal testing is not available.

Diagnosis

Familial idiopathic basal ganglia calcification (FIBGC*) is a neurodegenerative disorder with characteristic calcium deposits in the basal ganglia and other brain areas visualized on neuroimaging. Metabolic, infectious, toxic, and traumatic causes must be ruled out, as well as mitochondrial disorders or other inherited conditions associated with brain calcifications. A locus ( IBGC1) for FIBGC was recently identified on chromosome 14. The gene(s) causing FIBGC is currently unknown. Molecular genetic testing by linkage analysis may be pursued in selected families on a research basis.

* FIBGC is the preferred term for this condition. The term Fahr's disease is often used to designate either familial idiopathic basal ganglia calcification or idiopathic basal ganglia calcification without a positive family history. It is unknown if these non-familial cases represent the same disease entity as FIBGC. The term Fahr's disease is ambiguous and should be avoided. In addition, Fahr did not first describe basal ganglia calcification nor did he contribute to the recognition of familial forms.

Clinical Diagnosis

Since the first description of familial idiopathic basal ganglia calcification (FIBGC) [Foley et al 1951], reports of over 20 affected kindreds support its existence as a separate entity [Manyam et al 2001]. Neither the symptoms nor the extent of calcium deposits are diagnostic of familial idiopathic basal ganglia calcification. The diagnosis of FIBGC is supported by the following criteria [modified from Moskowitz et al 1971 and Ellie et al 1989]:

1. Bilateral calcification of the basal ganglia visualized on neuroimaging. Other brain regions may also be affected.
2. Progressive neurological 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.
3. Absence of biochemical abnormalities and somatic features suggestive of a metabolic disease or other systemic disorder.
4. Absence of an infectious, toxic, or traumatic cause.
5. Positive family history consistent with autosomal dominant inheritance.

Rarely, symptomatic individuals within families with FIBGC do not show calcification [Larsen et al 1985 , Geschwind et al 1999]. Thus, in some instances, the diagnosis can be established in the absence of criterion #1 or #2, but not both, providing the remaining criteria are fulfilled.

Testing

Neuroimaging.  Brain CT scan, which easily detects calcium, is the preferred method to localize and assess the extent of cerebral calcifications. The calcifications in FIBGC are not distinguishable from those secondary to hypoparathyroidism or other causes. Most frequently affected is the lenticular nucleus, especially the internal globus pallidus. Calcifications in the putamen, thalami, caudate, and dentate nuclei are common. Cerebellar gyri, the brainstem, centrum semiovale, and subcortical white matter may also be affected [Ellie et al 1989 , Manyam et al 1992]. Occasionally, calcifications begin or predominate in regions outside the basal ganglia [Smits et al 1983]. Diffuse atrophic changes with dilatation of the subarachnoid space and/or ventricular system may coexist with calcifications. Calcification seems to be progressive, since calcifications are generally more extensive in older patients and an increase in calcification can sometimes be documented on follow-up of affected subjects.

On 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 due to reactive gliosis or degenerating tissue within the calcified areas [Avrahami et al 1994 , Ellie et al 1989].

On 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 [Boller et al 1977]. 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.

Laboratory investigation.  Serum concentration of calcium, phosphorus, magnesium, alkaline phosphatase, calcitonin, and parathyroid hormone (PTH) are within normal limits. Routine hematologic and biochemical investigations, as well as workup for metabolic, inflammatory, and infectious conditions, do not disclose specific abnormalities.

Determination of urinary excretion of phosphorus and cyclic-AMP at baseline and after administration of exogenous PTH (Ellsworth Howard test) must be done to evaluate for parathyroid disorders. Patients with FIBGC show normal PTH responsiveness with a 10-20 fold increase of urinary cAMP excretion following stimulation with 200µ of PTH [Moskowitz et al 1971 , Boller et al 1977 , Ellie et al 1989].

Cerebrospinal fluid (CSF) study is usually normal, although slight increase in protein has been described [Boller et al 1977]. CSF bacterial, viral, and parasitological investigations are always negative.

Neurophysiology.  Neurophysiologic studies are generally normal. Epilepsy is a frequent manifestation of FIBGC, which may be reflected in an abnormal EEG pattern.

Neuropathology.  Gross pathological 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 frequent. Histological examination of affected areas shows concentric calcium deposits within the walls of small and medium size arteries and, less frequently, veins [Norman et al 1960 , Cervos-Navarro et al 1995]. Droplet calcifications can be observed along capillaries. These deposits may eventually obliterate the lumina of vessels. The pallidal deposits stain positive for iron [Cervos-Navarro et al 1995]. 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 [Cervos-Navarro et al 1995].

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by at least one US CLIA-certified laboratory or a clinical laboratory outside the US. GeneTests does not independently verify information provided by laboratories and does not warrant any aspect of a laboratory's work; listing in GeneTests does not imply that laboratories are in compliance with accreditation, licensure, or patent laws. Clinicians must communicate directly with the laboratories to verify information. —ED.

The gene or genes responsible for FIBGC are unknown. Linkage studies in one family revealed linkage to chromosome 14q ( IBGC1) [Geschwind et al 1999]. Absence of linkage to the IBGC1 locus in at least three families provides evidence of at least one other locus and genetic heterogeneity in this condition [Sobrido et al 2000]. Linkage analysis may be available on a research basis in informative families with more than one affected family member who belong to different generations.

Clinical Description

Most affected individuals are in good health during childhood and young adult life, presenting in the third to fifth decades with a gradual progression of neuropsychiatric and movement disorders. It should be noted that individuals who are clinically asymptomatic may have calcifications on neuroimaging. Although premorbid psychomotor development is generally normal, mild delay in motor or intellectual milestones during school age and low IQ are described.

The first manifestations of the disease often include clumsiness, fatigability, unsteady gait, slow or slurred speech, dysphagia, involuntary movements, or muscle cramping [Moskowitz et al 1971 , Boller et al 1977 , Manyam et al 1992]. Seizures of various types occur frequently. Some patients experience chronic headache [Ellie et al 1989 , Geschwind et al 1999]. Urinary urgency or incontinence and impotence may be present [Manyam et al 1992 , Tokoro et al 1993].

Neurologic evaluation generally discloses 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 [Foley et al 1951 , Moskowitz et al 1971 , Boller et al 1977 , Ellie et al 1989]. Patients may also show pyramidal or cerebellar signs and in some cases, the cerebellar picture predominates [Aiello et al 1981]. Dystonia is prominent in a few families [Caraceni et al 1974 , Larsen et al 1985]. Strength and sensation are generally intact.

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 [Francis et al 1979 , Cummings et al 1983 , Geschwind et al 1999]. It has been suggested that patients who become symptomatic early in adulthood are more likely to have psychosis [Cummings et al 1983]. The pattern of dementia includes frequent frontal-executive dysfunction and resembles that occurring in other disorders affecting subcortical structures, including Wilson disease and Huntingtondisease [Cummings et al 1983 , Geschwind et al 1999].

The onset age, clinical presentation, and severity of FIBGC is highly variable, both among and within families. Although penetrance may vary among families, analysis of reported pedigrees indicates about 95% penetrance by age 50 years or older. No reliable correlation exists among age, extent of calcium deposits, and neurological deficits. Although most patients with calcifications eventually develop neurologic dysfunction, the type or severity of clinical symptoms cannot be predicted from the pattern of calcification. In some kindreds, earlier appearance of symptoms in successive generations has been observed, a finding that suggests anticipation [Geschwind et al 1999]. In some instances, calcifications precede the clinical manifestations by several years; characteristic changes can be observed on CT scan in individuals who are in their thirties or younger with no neurologic abnormalities [Ellie et al 1989 , Manyam et al 1992]. The converse is also possible: young symptomatic individuals with no changes observed on CT scan later develop radiologically visible calcification [Larsen et al 1985 , Geschwind et al 1999].

The clinical manifestations of FIBGC are limited to the nervous system. General medical examination, growth and facial appearance are normal. Specifically, no abnormalities are detected in the skull, hands, teeth, nails, or skin and there is no evidence of a parathyroid disorder. Severe hypertension has been reported in two sisters with basal ganglia calcification with no other neurologic or systemic abnormalities [Puvanendran et al 1980]; whether this represents a random association, a rare manifestation of FIBGC or another, distinct, genetic disorder with basal ganglia calcification is unknown.

Genotype-Phenotype Correlations

Only one kindred with linkage to the IBGC1 locus has been identified to date and the causal gene is still unknown. The clinical presentation of the family with IBGC1 does not differ significantly from other FIBGC kindreds reported in the literature. The identification of families that are not linked to the IBGC1 locus demonstrate that there are genetically different conditions underlying a similar phenotype [Sobrido et al 2000]; the other loci are yet to be identified.

Prevalence

The prevalence of FIBGC is unknown; about 30 kindreds have been reported. However, this disorder is probably under-recognized due to insufficient investigation of other family members of individuals presenting with calcification of the basal ganglia.

Differential Diagnosis

Autosomal recessive forms of familial idiopathic basal ganglia calcification have been reported [Fritzsche et al 1935 , Matthews et al 1957 , Sala et al 1959 , Bruyn et al 1964 , Smits et al 1983]. However, some of these families have childhood or infantile onset, and somatic or endocrinologic abnormalities, raising the possibility that these early reports actually describe some of the disorders discussed in this section.

Symmetric calcification of the basal ganglia identified radiographically occur in a variety of conditions, both familial and non-familial. Congenital or early-onset findings, mental retardation, or presence of systemic involvement should alert to the possibility of an alternative diagnosis. Electromyogram (EMG) and nerve conduction velocity (NCV) studies may discover latent tetany, myopathic changes, or polyneuropathy. These abnormalities, as well as alterations in somatosensory responses, brainstem auditory evoked responses (BAER), or visual evoked responses (VER) should prompt the consideration of paraythyroid dysfunction, mitochondrial disease, or other disorders associated with brain calcifications. Basal ganglia calcifications occurring early in infancy or with associated ophthalmologic abnormalities should prompt the consideration of infectious causes or other diagnostic possibilities.

Parathyroid Disorders

Hypoparathyroidism (HP), idiopathic or postsurgical, is the most common pathologic cause of symmetric calcification of the basal ganglia [Bennett et al 1959 , Illum et al 1985]. Spontaneous hypoparathyroidism usually occurs in childhood or adolescence, a younger age of presentation than that of familial idiopathic basal ganglia calcification. In patients with hypoparathyroidism, decreased PTH production results in hypocalcemia and hyperphosphatemia, leading to tetany, muscle weakness, paresthesias, seizures, and mental retardation. Additional systemic features include cataracts, dry hair, alopecia, dental dysplasia, caries, and predisposition to moniliasis. Since adequate treatment of HP may lead to marked clinical improvement, serum concentration of calcium, phosphorus, and PTH must be determined in all patients with calcification of the basal ganglia to rule out hypoparathyroidism. Kenny-Caffey syndrome, a rare inherited condition with growth delay, medullary stenosis of the tubular bones, and calcification of the basal ganglia, is thought to be a type of primary hypoparathyroidism [Lee et al 1983].

Pseudohypoparathyroidism (PHP) and Pseudo-pseudohypoparathyroidism (PPHP).  PHP results from end-organ unresponsiveness to PTH. The biochemical hallmarks of PHP are hypocalcemia and hyperphosphatemia with an elevated serum concentration of PTH. As in HP, the baseline rate of excretion of urinary cAMP in PHP is below normal. After infusion of exogenous PTH, the increase in urinary excretion of phosphate and cAMP is generally subnormal. The average age of onset is eight to ten years of age. Most clinical manifestations of PHP are related to hypocalcemia and thus similar to those in HP, with mental retardation being somewhat more frequent in PHP. In addition to PHP, patients may have other manifestations of Albright's hereditary osteodystrophy (short stature, round facies, obesity, soft tissue calcification, and short metacarpals or metatarsals) [Aurbach et al 1971]. Resistance to other hormones may be present, resulting in hypothyroidism or hypogonadism. In contrast, patients with PPHP exhibit the characteristic features of Albright's osteodystrophy, but have normal serum concentration of calcium or phosphorus and normal response to PTH stimulation [Mann et al 1962 , Aurbach et al 1971].

Occasionally variants of PHP (types IB and II) or PPHP may present with few or no somatic abnormalities. The recognition of a variant of PHP with normal cAMP response (PHP type II) as well as cases of PHP with normal serum calcium concentration may make it difficult to establish the diagnosis [Balachandar et al 1975]. These parathyroid abnormalities are often familial and the coexistence of PHP and PPHP in the same family is not rare [Mann et al 1962 , Aurbach et al 1971].

Other Metabolic Disorders

Wilson disease is an autosomal recessive disorder of copper metabolism that can present with hepatic, neurological, or psychiatric disturbances, or a combination of these, in individuals ranging in age from three years to over 50 years. Neurological presentations include movement disorders (tremors, poor coordination, loss of fine-motor control, chorea, choreoathetosis) or rigid dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement). Psychiatric disturbance includes depression, neurotic behaviors, disorganization of personality, and, occasionally, intellectual deterioration. The most common findings on neuroimaging are atrophy of the caudate and brainstem. Sometimes symmetric hypodense lesions can be seen in striatum, dentate, and brainstem. Basal ganglia calcifications, although occasionally encountered, do not show the pattern and extension of those in FIBGC [Harik et al 1981]. However, given that clinical symptoms and findings on neuroimaging in both conditions are somewhat overlapping and given the possibility of effective therapy for Wilson disease with copper chelating agents or zinc, the latter should always be included in the differential diagnosis of basal ganglia calcification. Diagnosis of Wilson disease depends upon the detection of low serum copper and ceruloplasmin concentrations and increased urinary copper excretion. Molecular genetic testing of the ATP7B gene (chromosomal locus 13q14-q21), for a limited number of mutations, is available clinically for diagnostic purposes.

Renal tubular acidosis. These individuals generally also have defects in bone formation and osteoporosis. Both the abnormalities of bone development and the brain calcifications may be due to mild parathyroid hormone (PTH) resistance, although serum concentration of calcium, phosphate, and PTH is usually normal as is response to PTH stimulation. Arterial blood gases, concentration of serum and urine electrolytes, and urine acidification tests provide the basis for this diagnosis [Whyte et al 1980].

Mitochondrialdiseases.  Mineral deposits in the basal ganglia and other brain structures have been frequently recognized in disorders of this group [Markesbery et al 1979 , Robertson et al 1979]. Some mitochondrial disorders only affect a single organ (such as the eye in Leber hereditary opticneuropathy), but many involve multiple organ systems and often present with prominent neurological and myopathic features. Mitochondrial disorders may present at any age. Many patients display a cluster of clinical features that fall into a discrete clinical syndrome such as the 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, there is often considerable clinical variability and many patients do not fit neatly into one particular category. Common clinical features of mitochondrial disease include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. The central nervous system is often involved with features such as a fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. Some individuals with mitochondrial disease present with a characteristic phenotype and the diagnosis can be confirmed by molecular genetic testing of DNA extracted from a blood sample. In many individuals this is not the case, and the further investigation of suspected mitochondrial disease can involve a range of different clinical tests, including muscle biopsy and molecular genetic testing on muscle mtDNA.

Infectious diseases.  Intracranial calcifications may result from intrauterine or perinatal CNS infections, most frequently toxoplasmosis, rubella, cytomegalovirus, or herpes simplex virus [Bennett et al 1959]. CNS infection should be considered when clinical onset occurs soon after birth, especially if chorioretinitis, microcephaly, or neurological abnormalities coexist. Although the cerebral calcifications may involve the basal ganglia and dentate nucleus, additional irregular masses of calcium are generally distributed throughout the brain.

Non-congenital, active viral encephalitis should also be considered in some patients 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 [Belman et al 1986]. In some cases, bacterial or parasitic infections such as toxoplasmosis, cysticercosis, or brucellosis should be considered, although the appearance and distribution of the calcific deposits are generally quite different from that in FIBGC. For instance, the basal ganglia are affected in up to 75% of cases of toxoplasmosis. In the parenquimatous form of cysticercosis , calcification is a manifestation of death of the larvae and are generally rounded, less symmetrical, 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 [Rodriguez-Carbajal et al 1983]. Although cerebral calcification in brucellosis is rare, the detection of basal ganglia calcification in patients residing in endemic areas should raise the possibility of CNS brucellar infection [Mousa et al 1987].

Adult-Onset Neurodegenerative Conditions

Hallervorden-Spatz disease (renamed neurodegeneration with brain iron accumulation type 1 [NBIA 1] and also known as pantothenate kinase-associated neurodegeneration [PKAN]) is a rare autosomal recessive neurodegenerative disorder that usually presents as a childhood, adolescent, or adult-onset disorder with a constellation of dystonia, rigidity, choreoathetosis, corticospinal tract dysfunction, optic nerve atrophy, and intellectual impairment. Some of the patients with this syndrome have been found to have a 7bp deletion mutation and other mutations in the PANK2 gene on 20p12.3-p13 in the coding sequence of gene PANK2 with homology to pantothenate kinase [Zhou et al 2001].

Dentatorubro-pallidoluysian atrophy (DRPLA).  Bilateral calcification of the globus pallidus has also been reported in patients 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 FIBGC [Farmer et al 1991]. The diagnosis of DRPLA rests on positive family history, characteristic clinical findings, and the detection of an expansion of a CAG/polyglutamine tract in the DRPLA gene (chromosomal locus 12p13). The CAG repeat length in patients with DRPLA ranges from 49 to 79.

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 mental retardation.

• Cockayne syndrome , inherited in an autosomal recessive manner, has a classic form with onset after age two years and a connatal form present at birth. Patients have a leukodystrophy on MRI and often have basal ganglia calcification. Patients have progressive growth failure, characteristic facies, behavioral and intellectual deterioration, deafness, and retinitis pigmentosa. Classic Cockayne syndrome is diagnosed by clinical findings and the connatal form is diagnosed by assay of DNA repair in skin fibroblasts or lymphoblasts.
• Aicardi-Goutieres syndrome is a form of leukodystrophy presenting as an encephalopathy with microcephaly, calcification of the basal ganglia, and CSF lymphocytosis inherited in an autosomal recessive manner [Aicardi et al 1984].
• Tuberous sclerosis , inherited in an autosomal dominant manner, involves abnormalites of the skin (hypomelanotic macules, facial angiofibromas, shagreen patches, fibrous facial plaques, ungual fibromas), brain (cortical tubers, subependymal nodules, seizures, mental retardation/developmental delay), kidney (angiomyolipomas, cysts), and heart (rhabdomyomas, arrhythmias). The cerebral hamartomas may be calcified; however, they are mainly periventricular or subcortical [Fitz et al 1974].
• Reports of basal ganglia calcifications in Down syndrome are abundant [Wisniewski et al 1982].
• Brain calcifications are also associated with other rare disorders such as dyskeratosis congenita, hidrotic ectodermal dysplasia, and Coat's syndrome.

Other.  Calcifications of the basal ganglia may result from 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 [Harwood-Nash et al 1970 , Peylan-Ramu et al 1977 , Illum et al 1980].

Intracranial calcifications may be associated with systemic lupus erythematosus (SLE) [Anderson et al 1981]. Coeliac disease exhibits diverse neurological manifestations, including cerebellar ataxia, epilepsy, and peripheral neuropathy. Although intracranial calcifications have been described in this condition, the calcium deposits are mainly occipital [Gobbi et al 1992].

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) [Sachs et al 1979 , Harrington et al 1981], and microscopic calcifications can be observed in the globus pallidus and dentate nucleus in up to 70% of autopsy series [Slager et al 1956]. These calcifications are generally confined to the globus pallidus, and do not have associated clinical findings.

Management

No curative therapy is currently available for FIBGC; treatment is symptomatic. Management of behavioral and neuropsychiatric manifestations is often the main concern.

• Appropriate pharmacological treatment may improve anxiety, depression, and obsessive-compulsive behaviors.
• Neuroleptic medication should be used cautiously, since it may potentiate extrapyramidal symptoms [Cummings et al 1983]. A poor response to neuroleptics was obtained in a family with FIBGC and mainly psychotic manifestations [Callender et al 1995].
• The response of parkinsonian features to levodopa therapy is generally poor [Klawans et al 1976 , Berendes et al 1978]. Manyam et al (2001) attributed a positive response to levodopa in an affected individual in a family with FIBGC to the coexistence of IBGC and idiopathic Parkinson disease [Manyam et al 2001].
• Symptomatic treatment may alleviate dystonia and other associated involuntary movements.
• Oxybutynin may be tried for urinary incontinence.
• Patients with seizures should be treated with appropriate antiepileptic drugs.
• Anecdotically, a therapeutic trial with sodium etidronate in one patient resulted in partial improvement of speech and gait, but not other neurologic symptoms; no reduction in the amount of calcification was observed [Loeb 1998].

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 or cultural issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Familial idiopathic basal ganglia calcification (FIBGC) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband.  In most cases, the affected parent can be 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 of the proband. In addition, a proband with FIBGC may have the disorder as the result of a new gene mutation. The proportion of cases caused by new gene mutations is unknown. Whether non-familial cases represent de novo gene mutations (thus placing their children at a 50% risk) or non-genetic conditions is also not known. The parents of a child with apparent idiopathic basal ganglia calcification and no known family history of idiopathic basal ganglia calcification should be informed that the disease may show no or minor clinical manifestations and thus they may be unaware of their affectation status. They should make an informed decision about whether or not to undergo a physical and neurological exam as well as a CT scan. If the clinical and/or image findings are positive, the discussed work-up to rule out a metabolic disorder should be undertaken.

Sibs of a proband.  The risk to sibs depends on the genetic status of the parents. If one parent is affected, the sibs of the proband have a 50% risk of being affected. If a proband has a new gene mutation, the risk to the sibs of a proband depends on the spontaneous mutation rate of FIBGC and the probability of germline mosaicism, both of which are currently unknown.

Offspring of a proband.  Offspring of the proband have a 50% risk of being affected. Every child of an individual with FIBGC has a 50% chance of inheriting the mutation.

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

Specific risk issues.  Typically, the age of onset with FIBGC is between 30 and 60 years of age. Children or adolescents may show calcification of the basal ganglia and may or may not be symptomatic. Anticipation has been observed in one family with FIBGC [Geschwind et al 1999]. In light of these observations, the possibility of affected parents or grandparents in previous generations should be considered when obtaining a family history.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation.  When the parents of a proband with an autosomal dominant condition are unaffected, possible non-medical explanations include alternate paternity or undisclosed adoption.

Family planning.  The optimal time for determination of genetic risk is before pregnancy.

The following specific counseling issues regarding FIBGC should be addressed [Hopfer et al, manuscript in preparation]:

Rule out other known causes of hereditary IBGC in the initial assessment of a patient when FIBGC is suspected. Ruling out hereditary metabolic diseases, which are listed in Differential Diagnosis (parathyroid disorders) may be done by ordering specific biochemical tests (see Laboratory Investigation). Optimally, patients should be referred to an endocrinologist for these tests.

Family history.  Obtaining a complete and accurate family medical history poses challenges related to variable expressivity of symptoms and unawareness of the condition. Symptomatic family members either may have been misdiagnosed in the past or may not be in the habit of seeing a physician when symptoms do not disable their daily activities. To be familiar with the symptoms of FIBGC in conducting a directed medical-genetic family history query, see Clinical Description .

Age-dependent penetrance and variable expressivity.  Although penetrance may vary among and within families, analysis of reported pedigrees indicates about 95% penetrance by age 50 years or older. Thus, affected individuals in whom the disorder has gone unrecognized may exist. There are no reliable correlations among age, extent of calcium deposits, and neurological deficit. Although most patients with calcifications eventually develop neurologic dysfunction, the type or severity of clinical symptoms cannot be predicted from the pattern of calcification.

Presymptomatic diagnosis.  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 in other neurodegenerative disorders in which a curative treatment is not currently available, including a special consideration of testing children at risk.

If CT scan testing is offered to asymptomatic at-risk family members, the testee should be counseled that interpretation of results is limited because clinical prognosis cannot be predicted. The testee should be counseled about the possibility of incidental findings on a CT scan and whether such findings will be discussed. Obtaining informed consent for family members (whether or not they are currently symptomatic) is an essential part of proper health care management. Disclosure of the benefits and limitations of testing is an obligation of the professional providing care.

Testing of at-risk asymptomatic children.  Consensus holds that children at risk for adult-onset disorders should not be tested in the absence of symptoms and/or a treatment. The principal reasons against testing asymptomatic children for FIBGC include removal of the child's future autonomy to make his/her own medical decisions, lack of immediate medical benefits of having testing, and lack of currently available treatment. Additionally, having a CT scan will not remove uncertainty in the case of FIBGC since penetrance is age dependent, reaching about 95% by age 50 years. Testing children on the other hand, runs the risk of procuring psychological harm to a 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 stigmatized as an adult through denial of health insurance coverage [Bloch & Hayden 1990 , Harper & Clarke 1990].

Symptomatic children who are tested usually benefit from having a specific diagnosis established. The policy in support of opposing predictive testing to asymptomatic children abides by the ethical principle applicable to health care management "above all do no harm." (See also the National Society of Genetic Counselors statement on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider on genetic testing of children.)

A normal brain CT scan does not completely rule out the presence of FIBGC, especially in younger individuals. On the other hand, family members with abnormal imaging may have no symptoms.

Because establishing the diagnosis of FIBGC often depends upon CT examination of additional family members, it is recommended that other family members be provided genetic counseling prior to undergoing testing to ensure informed decision making.

DNA banking.  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, particularly in situations in which molecular genetic testing is available on a research basis only. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Prenatal testing is not available because molecular genetic testing is on a research basis only.

Molecular Genetics

Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

References

Published Statements and Policies Regarding Genetic Testing

• American Society of Human Genetics and American College of Medical Genetics (1995) Points to consider : ethical, legal, and psychosocial implications of genetic testing in children and adolescents
• National Society of Genetic Counselors (1995) Resolution on prenatal and childhood testing for adult-onset disorders

Literature Cited

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