Decoding brain calcifications: A single-center descriptive case series and examination of pathophysiological mechanisms

Abstract

Brain calcifications, previously known as Fahr’s disease, is a rare neurological disorder marked by various clinical symptoms, including movement disorders, cognitive impairment, and psychiatric disturbances. Despite its clinical importance, its pathophysiology is unclear and there are no specific treatments. We present four cases of brain calcifications from our tertiary care center, with three female patients (75%) and an average age of 63 years. Our cohort featured both genetic and endocrine etiologies, including one primary familial brain calcification case with a c.852del frameshift mutation in the SLC20A2 gene, and two endocrinopathy-related cases. One patient had an acute stroke which may have been contributed by brain calcifications. Computerized tomography and magnetic resonance imaging scans revealed basal ganglia and dentate nucleus calcifications. Treatment involved physical and occupational therapy in all patients. Hypoparathyroidism-related brain calcifications were treated with oral supplementation with calcitriol, calcium, and vitamin D. Three patients showed improvement or stability of their symptoms. This case series underscores the diverse clinical presentations and etiologies of brain calcifications. The complex pathophysiology involves disrupted Ca⁺²-PO₄^3- homeostasis, deficient cellular PO₄^3- transport, and vascular irregularities in genetic etiologies. Future research should focus on identifying novel genetic mutations, understanding molecular pathways, and refining diagnostic techniques. Integrating multidisciplinary approaches may improve diagnosis, management, and prognosis for patients with this intricate neurological disorder.

Introduction

Brain calcifications (previously Fahr’s disease) is a rare and poorly understood neurological disorder that is characterized by abnormal calcification of the basal ganglia and other areas of the brain. It typically presents with a wide range of symptoms, including movement disorders, cognitive impairment, and psychiatric disturbances, and can have a significant impact on the quality of life of patients. ¹ Despite its clinical importance, the pathophysiology of brain calcifications remains poorly understood, and currently, there are no specific treatments for the condition. ² We present a descriptive case series from our tertiary care center. We will also examine the pathophysiological mechanisms associated with the central nervous system calcifications observed in various endocrine and genetic diseases.

Case series

A summary of all the included cases is provided in Table 1. Neuroimaging findings including computerized tomography (CT) and (MRI) of the brain are provided in Figure 1.

Table 1.

Clinical summary of the participants included in the case series.

Case No.	Age (years)	Gender	Clinical presentation	Etiology	Management	Outcomes
1	66	F	A 3-year history of right-hand resting tremor, memory loss, visual hallucinations, and 6 months of unsteady gait and bradykinesia.	Pseudohypoparathyroidism	Physical and occupational therapy	Lost to follow-up.
2	75	F	7 years of gait difficulties and 2 years of cognitive changes and urinary incontinence	Mutation of the SLC20A2 gene	Physical and occupational therapy	Mild improvement at 6 months.
3	75	F	Acute-onset dysarthria, left facial droop, and chronic left-hand tremor	Hypoparathyroidism	Oral calcium calcitriol and calcium supplementation	Stability of the disease at 1 year of follow-up.
4	36	M	Few months of progressive gait instability, dysarthria, and subjective weakness of the right lower extremity.	Idiopathic or radiation related	Physical and occupational therapy	Stability of the disease at 3 months of follow-up.

Figure 1.

(a) Case 1: Magnetic resonance imaging (MRI) of the brain susceptibility-weighted imaging (SWI) sequence with hypointensities signifying extensive subcortical calcifications involving the basal ganglia. (b) Case 2: Computerized tomography (CT) of the head showing calcifications of the basal ganglia and thalamic pulvinar. (c) Case 3: CT of the head with calcifications affecting the bilateral corona radiata. (d) Case 3: MRI brain diffusion-weighted imaging (DWI) sequence depicts diffusion restriction (hyperintensities) within the right corona radiata consistent with an acute ischemic infarct. (e–f) Case 4: CT of the head with dense calcifications affecting the basal ganglia and cerebellar hemispheres.

Case 1

A 66-year-old woman with a medical history of pseudohypoparathyroidism (GNAS1 mutation carrier) and hypertension presented to the neurology clinic with a 3-year history of right-hand resting tremor and 6 months of unsteady gait and bradykinesia. She also reported problems with short-term memory. There was no reported family history of a movement disorder or brain calcifications. On examination, asymmetric Parkinsonism with notable rigidity was observed. The Montreal Cognitive Assessment (MoCA) score was 20. ³ The patient was prescribed a levodopa–carbidopa trial and the patient was lost to follow-up before the brain MRI was completed.

Three years later, the patient presented to the emergency department (ED) with acute left-sided hemiplegia. A CT head scan revealed a small intraparenchymal hematoma within the posterior right frontal centrum semiovale, as well as diffuse chronic calcifications within the bilateral basal ganglia and bilateral cortical and cerebellar sulci (Figure 1(a)). At that time, she also endorsed delusions and visual hallucinations. Serum laboratory testing was significant for hypocalcemia (8.3 mg/dL [8.5–10.0]), hyperphosphatemia 4.9 mg/dL [2.5–4.5]), and elevated parathyroid hormone (PTH; 80 pg/mL [10–65 pg/mL]). The patient was discharged to rehab on vitamin D and calcium supplementation but unfortunately was lost to follow-up. Written informed consent was obtained from the patient for the publication of this case series.

Case 2

A 75-year-old woman with a medical history of hypertension and hyperlipidemia presented with 7 years of gait difficulties, 2 years of cognitive changes and urinary incontinence. One year before coming to our clinic, she underwent a ventricular shunt for normal pressure hydrocephalus, which resulted in only a slight temporary improvement in her symptoms. On presentation to our clinic, the patient had a smooth saccadic break, mild postural and intention tremor bilateral upper extremities, and a magnetic gait. Her tone was normal. Family members reported that she had delusions and impairment of short-term memory, executive functions, and calculations. There was no family history of brain calcifications or psychiatric disorders.

A review of previous CT head scans showed extensive mineralization of both cerebellar hila, basal ganglia, thalamic pulvinar, and deep white matter (Figure 1(b)). Serum calcium and phosphorus levels were normal. Genetic testing confirmed a pathogenic variant of the SLC20A2 gene with the variant allele c.852del (p.lle285Sers*33), which is associated with autosomal dominant primary familial brain calcification (PFBC). This specific mutation results in premature termination of the codon, resulting in a truncated or absent protein. There was no reported family history of movement disorder or brain calcifications. Serum calcium, phosphate, and PTH were within range. The patient had no family history of neurological disorders. The patient showed mild improvement at a 6-month follow-up appointment with both physical and occupational therapy. Written informed consent was obtained from the patient for the publication of this case series.

Case 3

A 75-year-old woman with a medical history of hypertension and chronic, untreated hypoparathyroidism secondary to a thyroidectomy when she was a teenager presented to the ED with acute-onset dysarthria, left facial droop, and left-hand dysmetria. Upon further history, the patient reported a right-hand tremor for the past 10 years and chronic, slowly progressing gait instability. There were no cognitive symptoms. There was no family history of brain calcifications or psychiatric disorders.

Detailed examination revealed a right-side intention and postural tremor, as well as weakness in the flexion of the right hip with a clonus of the right ankle. The gait was spastic. Her CT of the head demonstrated bilateral symmetric calcifications within the basal ganglia, thalami, and dentate nuclei (Figure 1(c)). An MRI of the brain showed an area of diffusion restriction (hyperintensity) on the diffusion-weighted imaging sequence within the right corona radiata consistent with an acute ischemic infarct (Figure 1(d)). Serum laboratory testing was significant for hypocalcemia (7.8 mg/dL [8.5–10.0]), hyperphosphatemia 5.1 mg/dL [2.5–4.5]), and decreased PTH (8 pg/mL [10–65 pg/mL]). Genetic testing was negative for common genes causing idiopathic basal ganglia calcifications including SLC20A2, PDGFRB, PDGFB, XPR1, and MYORG. The patient was discharged with oral calcitriol and calcium. Aspirin 81 mg daily was started for her stroke. We observed stability in her symptoms at the 1-year follow-up. Written informed consent was obtained from the patient for the publication of this case series.

Case 4

A 36-year-old male with a medical history of hypertension, hyperlipidemia, and pineal blastoma resected at the age of 6 years, with subsequent chemotherapy with cisplatin/etoposide, radiation therapy, and placement of a ventriculoperitoneal shunt, presented with a few months of progressive gait instability, dysarthria, and subjective weakness of the right lower extremity. Upon examination, mild dysarthria, bilateral hip flexion, knee extension weakness (4/5), bilateral upgoing toes, and a slender gait were observed. There was also a decrease in vibrational sense in the lower extremities with a positive Romberg test. ⁴ CT of the head demonstrated bilateral basal ganglia and cerebellar calcifications (Figure 1(e–f)). Serum calcium, phosphorus, and vitamin D levels were normal. Genetic testing was negative for common genes causing idiopathic basal ganglia calcifications including SLC20A2, PDGFRB, PDGFB, XPR1, and MYORG. The patient’s gait instability was believed to be secondary to a combination of peripheral neuropathy and basal ganglia calcifications. He was discharged to an inpatient rehabilitation facility and showed improvement in leg weakness on a 3-month follow-up. Written informed consent was obtained from the patient for the publication of this case series.

Discussion

A series of four cases from our tertiary care center are described. Three out of four (75%) of the cases occurred in women, and the average age was 63 years. Genetic, endocrine, and iatrogenic etiologies were observed in our cohort. Brain calcifications are a rare neurological disorder with an estimated prevalence of 0.02% to 0.05% in the general population. ⁵ It affects both sexes equally and can occur at any age, 50% of patients have an onset after 62 or before 21 years. ⁶ Brain calcifications have a variable clinical presentation that can range from asymptomatic cases to severe neurological manifestations. The most common symptoms include movement disorders, cognitive impairment, and psychiatric disturbances. Movement disorders such as Parkinsonism, chorea, and dystonia can be seen in affected individuals. Cognitive symptoms can include memory loss, executive dysfunction, and behavioral changes. Psychiatric disturbances such as depression, anxiety, and psychosis can also occur. Other symptoms include seizures, ataxia, and dysarthria. ⁷ The severity and progression of symptoms can vary widely among individuals, and the disease can also be observed with other neurological conditions such as subarachnoid hemorrhage. ⁸ In Case 3 we also observed that the tissue surrounding the calcifications may be susceptible to ischemic infarction. The calcified area can restrict cerebral blood flow to surrounding brain tissue, leading to reduced oxygen and nutrient supply. This can cause brain tissue to become ischemic and can cause a new stroke. Second, the presence of calcium deposits can also cause inflammation and damage to blood vessels in the brain. This can further contribute to reduced blood flow and an increased risk of stroke.

Brain calcifications can be associated with several genetic conditions, including PFBC, autosomal dominant hypocalcemia (ADH), and pseudohypoparathyroidism (PHP). Mutations in the SLC20A2, PDGFB, PDGFRB, MYORG, CMPK2, JAM2, and XPR1 genes have been implicated in the pathogenesis of PFBC, while epivariations in the CASR gene are associated with ADH and PHP. ² A previous review from 2016 determined that SLC20A2 was the most common gene implicated; with 75 out of 137 cases included with PFBC (55%) followed by PDGFB (31%) and PDGFRB (11%). ⁷ Case 2 from our cohort also had a mutation in the SLC20A2 gene (c.852del). Despite advances in genetic diagnostics, many cases of brain calcifications disease are idiopathic, and the genetic mechanisms underlying the disease remain poorly understood. Brain calcifications are associated with several endocrine abnormalities, including hypoparathyroidism, hyperparathyroidism, and pseudohypoparathyroidism. Other endocrine abnormalities, such as abnormalities in vitamin D metabolism and thyroid dysfunction, have also been reported in association with brain calcifications (Figure 2). ⁹ A pedigree tree depicting the autosomal dominant inheritance pattern of PFBC has been illustrated in Figure 3.

Figure 2.

Pathophysiological mechanisms of observed conditions associated with brain calcifications.

Figure 3.

Family pedigree tree depicting hypothetical autosomal dominant inheritance pattern seen in primary familial brain calcification, including SLC20A2 gene mutation as seen in Case 2.

The pathophysiology of these intracranial calcifications is complex and involves abnormal calcium and phosphate metabolism that causes insidious deposition within the basal ganglia and dentate nucleus, among others. These nuclei are implicated because of enhanced metabolic activity. The authors hypothesize that regional cerebral blood flow, anatomical variation, and autoregulatory mechanisms are additional factors that contribute to the preferential deposition within the basal ganglia and dentate nucleus. 18 F-fluorodeoxyglucose positron emission tomography/CT) has shown decreased glucose uptake not only in the putamen but in bilateral parietal and temporal cortices, indicative of widespread cortical network dysfunction in response to the calcifications. ¹⁰ Neuropathological data suggest dysfunction of vascular smooth muscle cells, pericytes, and hypodermal microvascular calcifications. ¹¹ The histopathological examination has shown deposition of zinc, manganese, iron, and aluminum in addition to calcium. ¹² The pathogenesis of ectopic calcification surrounds Ca⁺²-PO₄^3- homeostasis including a low calcium/phosphate [Ca/P] ratio which has been observed in hypoparathyroidism. ⁹ Additionally, prolonged hyperphosphatemia is believed to cause the down regulation of phosphate transporters in the basal ganglia, leading to the precipitation of minerals in the surrounding blood vessels. ¹³ Radiation therapy, while a crucial tool in the management of various cancers, can have several long-term side effects, including brain calcifications. The exact mechanisms behind this are not fully understood, but it is believed to involve radiation-induced injury to the brain’s vasculature and tissues. The damage prompts an inflammatory response, which can lead to the deposition of calcium in the brain tissues over time. ¹⁴

Future research should focus on identifying novel genetic mutations and epigenetic factors using advanced genomic techniques, such as whole genome sequencing and transcriptomics. This may reveal potential therapeutic targets and improve the understanding of the disease mechanism. Investigating the molecular pathways underlying brain calcifications and neurological manifestations, including calcium homeostasis and immune responses, could lead to new therapeutic strategies. Developing advanced neuroimaging techniques and improving the use of biomarkers in blood or cerebrospinal fluid may facilitate early diagnosis and monitoring of disease progression. Additionally, stem cell therapy and gene editing technologies, such as CRISPR/Cas9, may hold promise in treating brain calcifications by directly targeting genetic causes. ⁹

Conclusions

Brain calcifications are a rare neurological disorder characterized by intracranial calcifications and a wide range of clinical manifestations. Our case series highlights the diverse etiologies (e.g., genetic mutations, endocrinopathies) and clinical presentations encountered in practice. Additionally, Cases 1 and 3 may demonstrate the susceptibility of calcified brain tissue to hemorrhagic and ischemic infarction, respectively. Despite advances in genetic diagnostics, many cases remain idiopathic, highlighting the need for further research into the underlying mechanisms. Future investigations should focus on identifying novel genetic and epigenetic factors, exploring molecular pathways, and developing advanced diagnostic and therapeutic approaches.