Fahr Syndrome

Etiology

Fahr disease is most commonly found to be inherited in an autosomal dominant pattern with incomplete and age-related penetrance, but it may also be transmitted as an autosomal recessive trait or occur sporadically. Some studies have reported the phenomenon of anticipation in this disease.[2] 

There are four genes which have been implicated as the molecular basis of Fahr disease i.e., loss of function mutation in the gene SLC20A2 encoding type 3 sodium-dependent phosphate transporter 2 (PiT2) on chromosome 8p (40%), a mutation in gene XPR1 that encodes for a retroviral receptor with phosphate export function on chromosome 1q (2%), a mutation in the gene which encodes the receptor for members of the platelet-derived growth factor family- gene PDGFRB on chromosome 5q (2%), and gene PDGFB on chromosome 22q (11%). 46% of cases have some unknown gene mutations. Other loci that have been linked to Fahr disease include IBGC1 locus at chromosome 14q, a locus at chromosome 2q, and another one at chromosome 8.[3] 

Since, some genes have been implicated in Fahr disease, the term idiopathic basal ganglia calcification, used previously, should be avoided.

Epidemiology

Fahr disease is reported to commonly affect people in their 40s and 50s. Patients are usually in good health in their youth and tend to develop this progressive neurodegenerative disease later in adulthood. The prevalence of this disease is more or less unknown due to insufficient investigations of first-degree relatives of the patients.

Pathophysiology

Abnormal calcium deposition is hypothesized to be due to either abnormal brain calcium metabolism or metastatic deposition due to locally altered blood-brain barrier. Defective iron transport and free radical production cause tissue damage, which initiates calcification around a nidus composed of mucopolysaccharides and related substances. The calcium deposition starts within the vessel wall and perivascular space and slowly extends to involve the entire neuron. Progressive calcification compresses nearby vessels reducing blood flow and hence continuing the vicious cycle of decreased blood flow, tissue injury, and mineral deposition.[3] 

High levels of copper, zinc, magnesium, iron, and altered glucose metabolism in basal ganglia have also been reported. An increase in CSF levels of CNS-specific peptide, homocarnosine, and low histidine levels have been found in some cases.

Histopathology

On gross pathologic examination, granular deposits and solid nodules deposited in the involved area and mild cortical atrophy are seen.

On histological examination, concentric calcium deposited along the walls of small ad medium-sized arteries is seen with less common involvement of veins. Sometimes, droplet calcifications can be observed. Ischemic changes and diffuse gliosis can be observed in the surroundings of large deposits.

On electron microscopy, calcium appears as amorphous or crystalline material surrounded by a basal membrane. In the cytoplasm of neuronal and glial cells, calcium granules can be seen.

History and Physical

Clinical Features 

(A) Movement disorder like features:[4]

• Signs and symptoms resembling parkinsonism, such as bradykinesia, rigidity, tremor, hypophonia, hypomimia, mask-like facies, shuffling gait
• Clumsiness
• Fatigability
• Gait dysfunction
• Choreoathetosis
• Dystonia
• Slurred speech
• Muscle cramping
• Pyramidal or cerebellar symptoms (rarely)

(B) Neuropsychiatric features [5]

• Depression
• Apoplexia
• Dementia, mostly fronto-executive type resembling subcortical dementia in Wilson disease and Huntington disease
• Concentration deficits
• Behavioral changes

(C) Other CNS features [6][3]

• Loss of consciousness
• Tetany
• Seizures
• Spasticity
• Speech impairment
• Myoclonus
• Coma
• Papilledema
• Chronic headache
• Vertigo
• Urinary urgency or incontinence
• Impotence
• Severe hypertension

In a study done by Batla et al., a clinical correlation with genomic abnormalities (genotype-phenotype relationship) was established after reviewing 137 cases. Those with SLC20A2 mutations were more commonly observed to have parkinsonism and involvement of the thalamus and dentate nucleus. Those with PDGFB mutations were observed to have a headache more commonly and cysts in white matter.[7]

Physical Examination

• General physical examination
• Complete neurological examination
• Mental health screening
• Memory and cognitive assessment
• Functional outcome measures
  • Functional independence measure (FIM)
  • Dynamic gait index
  • Timed up and go test (TUG)
  • Fullerton advanced balance scale (FAB)

Evaluation

Diagnostic criteria of Fahr disease (adapted from Moskowitz et al. and Ellie et al.)[8][9]

• Progressive neurologic dysfunction with onset at any age
• Radiographic evidence of bilateral calcification of basal ganglia and some other regions of the brain
• Absence of biochemical abnormalities suggestive of endocrinopathies, mitochondrial or other systemic disorders
• Absence of infections, toxin or trauma
• Family history with autosomal dominant inheritance

To meet the diagnostic criteria, the following investigations are usually done to exclude other causes of brain calcifications.

Laboratory Investigations: Routine lab results are within normal limits in a patient with Fahr disease. Any abnormality should prompt further investigations to rule out secondary causes of brain calcifications.

• Routine hemogram and complete metabolic panel
• Blood and urine heavy metal levels 
• Serum calcium, phosphorus, magnesium, alkaline phosphatase (ALP), calcitonin, vitamin D, parathyroid hormone (PTH)
• Cerebrospinal fluid analysis for bacteria, virus, and parasites
• Ellsworth Howard test (following 200 U PTH injection, 10 to 20 fold increase in urinary cAMP levels)

Imaging studies: Bilateral basal ganglia calcification is visualized in both Fahr disease and secondary causes.

• Brain CT scan: Most sensitive modality in localizing and assessing the extent of calcium deposits. The most commonly affected area is the lenticular nucleus, especially the internal globus pallidus. Other areas where the calcifications have been observed include putamen, caudate, dentate nucleus, thalamus, centrum semiovale, subcortical white matter, cerebellum, and brain stem.

• MRI Brain: MRI provides better anatomic details but is less sensitive than a CT scan. Usually, calcified deposits give low-intensity signals on T2-weighted images and low to high-intensity signals on T-1 weighted images, but a study by Kozic et al. revealed that MRI had heterogeneous signal intensities for calcifications in some subjects which led to misinterpretations.

• FDG-PET: May show decreased F-FDG uptake, especially in basal ganglia.

• Plain skull radiograph: Calcifications can be visualized on a radiograph but is less sensitive than CT scan.

Molecular Genetic Testing:

This is done in an index case that meets the diagnostic criteria to establish the diagnosis of Fahr disease. There are three approaches to genomic testing:

• Serial gene testing: Sequentially testing for genes one at a time, based on the frequency of causation

            SLC20A2>PDGFB>PDGFRB>XPR1

• Multigene panel: One-time analysis of all the four implicated pathogenic variants (SLC20A2, PDGFB, PDGFRB, XPR1) and other genes to rule out secondary syndromes

• Comprehensive genomic testing

Treatment / Management

To this date, no definitive cure is available for Fahr disease, as with other neurodegenerative disorders, and management is focused primarily on symptomatic relief.

(A) Symptomatic Management

• Antileptic therapy for seizures
• Pain killers for headaches
• Anticholinergic for urinary urgency or incontinence
• SSRIs for depression, obsessive-compulsive behaviors, and anxiety
• Neuroleptics for movement disorders

(B) Caution

The use of carbamazepine, benzipenes, and barbiturates in patients with Fahr disease can lead to increased gait dysfunction. Psychiatrists and neurologists should implement great caution with the use of anti-depressants and anxiolytics as the threshold for side effects with these drugs is low in patients with Fahr disease. Lithium has been known to increase seizure risk in the patients, and neuroleptics can exacerbate extrapyramidal symptoms. 

(C) Physical Rehabilitation [10]

• Maintaining range of motion and prevention of contractures with the range of motion exercises, passive and facilitated stretching
• Strengthening underutilized muscle: Usually, antigravity extensors muscles are at risk of weakening in neurological disease. A general conditioning program and using exercise machines may be helpful.
• Improving postural stability: Correcting sitting postures, patients with basal ganglia dysfunction can do balance training while doing activities of using stairs, reaching out, etc., and progressive activities from wide to a narrow base, static to dynamic or low to higher cognition.
• Gait dysfunction: Assess for assisted devices, auditory cues like counting, or visual cues like laser attached to canes.
• Symptomatic improvement: Relaxation techniques for anxiety, deep brain stimulation for hyperkinetic disorders, soft tissue release for spasticity, or sensory stimulation in basal ganglia dysfunction. 

(D) Genetic Counseling

The disease is transmitted in an autosomal dominant fashion. The family history is not fully conclusive. Sometimes the family history of a patient is negative because of the early death of a parent before the disease became evident, or it may have a late-onset in the parent or reduced penetrance.

There are no demonstrated medical benefits for screening the relatives. Predictive testing in the form of brain CT scan (calcium deposits precede clinical manifestations by years) and molecular testing (if PDGFB, PDGFRB, XPR1, SLC20A2 pathogenic variant has been identified in proband) can be offered to asymptomatic first-degree relatives (>18 years) after weighing the ethical and psychosocial conditions because no curative treatment is available. Testing individuals >18 years can help them in decision making in regards to their marriage, family planning, career, and finance. Testing is usually not recommended in individuals <18 years considering social issues, discrimination and anxiety in future, negative impact on parent-child or sibling-child relationship, and uncertain CT scan predictability as penetrance is age-dependent.

(E) Prenatal Counseling

Prenatal testing and preimplantation genetic diagnosis are possible for high-risk pregnancy in which PDGFB, PDGFRB, XPR1, SLC20A2 pathogenic variant has been detected in the proband.

(F) Surveillance: Annual neurologic and neuropsychiatric assessment.

Differential Diagnosis

Basal ganglia calcifications occur in several other familial and non-familial conditions that are required to be excluded before making a diagnosis of primary familial basal ganglia calcification.

 1. Endocrine Disorders

Parathyroid hormone (PTH) disturbances are the most common cause of bilateral basal ganglia calcifications. Reduced levels of actions of PTH cause hyperphosphatemia and hypocalcemia, which promotes calcification. In a review of 150 cases of Fahr syndrome, 35 (23.3%) had idiopathic hypoparathyroidism, and 23 (15.3%) had secondary (post-thyroidectomy) hypoparathyroidism.[11][12]  

Hypoparathyroidism: Idiopathic (absence, fatty replacement or atrophy of parathyroid gland) or secondary (due to inadvertent removal during thyroidectomy)

Pseudohypoparathyroidism (PHP) and Pseudo-pseudohypoparathyroidism (PPHP): Both are phenotypic variants with autosomal dominant inheritance with mutation of the GNAS gene. Both have clinical features of Albright hereditary osteodystrophy. In PHP, there is resistance to the action of parathyroid hormone with hypocalcemia, hyperphosphatemia, and elevated PTH levels, but PPHP has no biochemical abnormality with normal calcium and phosphorus levels and a normal response to PTH secretion.

Kenny Caffey syndrome type 1

It is a rare skeletal disorder with a mutation in the TBCE gene and is characterized by dwarfism, cortical thickening and medullary stenosis of long bones, facial dysmorphism, hypocalcemia due to congenital hypoparathyroidism and basal ganglia calcifications.[13]

2. Mitochondrial Myopathy

Basal ganglia calcification is a recognized finding in mitochondriopathy due to abnormal calcium homeostasis.[14] In a study, neuro-radiological findings were studied in six kindreds of 24 subjects with MELAS; bilateral basal ganglia calcification was the commonest radiological finding.

 3. Infectious Diseases

Intrauterine and perinatal infections: Herpes, CMV, rubella, and toxoplasmosis may cause basal ganglia and intracerebral calcification in the newborn and may present with microcephaly, seizures, chorioretinitis, or other CNS features.

Brucellosis: A study by Mousa AM et al. showed 9 (13.8%) out of 65 cases of CNS brucellosis (neuropsychiatric manifestations) had radiologic evidence of basal ganglia calcifications. Three cases had unilateral, 4 cases had bilaterally symmetric, and 2 cases had bilaterally asymmetric calcifications.

Toxoplasmosis: The most commonly affected region (75% cases) is basal ganglia showing multiple ring-enhancing lesions with edema and sometimes calcifications.

Neurocysticercosis: Larval cyst may sometimes occur in basal ganglia and gets calcified.

HIV/AIDS: In a study done for reporting neuropathology in 52 HIV patients, three were found to have basal ganglia calcifications.  

 4. Congenital Disorders

Cockayne syndrome (CS)/Neill-Dingwall Syndrome [15]

It is an autosomal recessive disorder with an underlying defect in DNA repair. CS type 1 is the classic variant in which there is normal development initially, and features develop after first two years of life, such as hearing and visual impairment, CNS and PNS degradation with bilateral basal ganglia calcifications. CS type 2 is a more severe congenital variant, also known as cerebro-oculofacial syndrome or Pena Shokeir type 2 syndrome. There is no postnatal neurological development with associated eye and skeletal anomalies.

Aicardi-Gouteres Syndrome

It is a neurodevelopmental disorder characterized by microcephaly, neonatal seizures, cerebral atrophy, encephalopathy, cerebral calcifications typically bilateral, and in basal ganglia, especially putamen and globus pallidus. 

Tuberous Sclerosis Complex

It is an autosomal dominant neurocutaneous syndrome with a mutation in TSC1 and TSC2 genes. It exhibits features involving the skin (ash-leaf macules, shagreen patch, adenoma sebacum, angiofibroma), kidneys (angiomyolipoma), cardiac (rhabdomyosarcoma) and CNS (subependymal nodules, hamartomas, cortical and subcortical tubers which can get calcified). The frequency of calcifications increases with age.

Coats plus syndrome (CRMCC-Cerebroretinal microangiopathy with calcifications and cysts)

Coats disease is a congenital nonhereditary eye disorder characterized by abnormal development of blood vessels behind the retina with resultant complete or partial blindness. Coats plus disease has associated neurologic features with intracerebral calcifications and formation of parenchymal cysts, bone, and gastrointestinal abnormalities.

Down Syndrome: In a study by Takashima et al. in 33 patients of down syndrome, 45% had basal ganglia calcifications, especially located in globus pallidus, and it increased with age.[16]

Others: Immunodeficiency 38 with basal ganglia calcification, PKAN (Pantothenate kinase-associated neurodegeneration)

5. Adult-Onset Disorders

Neuroferritinopathy: Autosomal dominant disease, a variant of NBIA (neurodegeneration with brain iron accumulation), which presents with adult-onset dystonia, cognitive and behavioral changes with radiographic evidence of excessive iron storage and cystic degeneration of putamen.

Spinocerebellar ataxia type 20: Autosomal dominant disease with marked calcifications in the cerebellum (especially dentate nucleus).

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL, Nasu-hakola disease): Autosomal recessive disease which presents with fractures, dementia, and bilateral basal ganglia (esp putamen) calcifications.

Others: DNTC-Diffuse neurofibrillary tangles with calcification (Kosaka- Shibayama disease),[17] DRPLA- Dentatorubral-pallidoluysian atrophy (Haw river syndrome).

6. Dermatological Conditions

Lipoid proteinosis: It is a rare genodermatosis in which amorphous hyaline material accumulates intracellularly in the skin, mucous membranes, and internal organs. Manifestations include alopecia, photosensitivity, dwarfism, seizures, and dementia. Selective brain parenchymal calcifications occur in the amygdala, corpus striatum, hippocampus, and parahippocampal gyrus.[18]

Dyskeratosis Congenita: It is a disorder with a classic triad of dysplastic nails, lacy reticular pigmentation of the upper chest, and oral leukoplakia. Intracranial calcifications have been reported in the Revesz syndrome variant.[19]

 7. Toxins

Neural necrosis has been reported with excess vitamin D, lead, mercury, ionizing radiation, and methotrexate therapy.

 8. Normal Aging

0.3-1.5 % of brain CT scans are incidentally found to have basal ganglia calcifications. In a study done by Forstl et al., about 70% of autopsies had microscopic calcifications in globus pallidus and the dentate nucleus, but patients were usually asymptomatic.[20] In a study done by Ostling et al., basal ganglia calcification was strongly correlated with psychotic symptoms in the elderly.[21]

  9. Others

Some other reported conditions with brain calcifications include biotinidase deficiency, hereditary folate malabsorption, carbonic anhydrase deficiency, celiac disease, cerebral lupus, and tetrahydrobiopterin-deficient hyperphenylalaninemia.[22]

Prognosis

The prognosis of a patient with Fahr disease is variable and unpredictable. There is no correlation between the age of disease onset, symptoms at onset, or extent of calcifications in the brain with the severity of the disease. Penetrance is age-dependent, with a 95% occurrence by the age 50. As such, an asymptomatic disease carrier might present with a negative CT scan at a younger age. Calcifications have been reported to become more extensive with age, as evidenced by follow up scans of confirmed cases.

Complications

Although Fahr disease is a rare disorder it has some crippling complications. Following are some of the complications that the providers should be aware of:

• Depression
• Dementia
• Psychosis
• Speech difficulty
• Epilepsy
• Contractures
• Recurrent falls and orthopedic consequences