Fahr's Disease Research Articles

Traumatic Brain Injury in the Setting of Fahr Syndrome

Fahr syndrome, or bilateral striatopallidodentate calcinosis, is a rare syndrome that can confound interpretation of traumatic brain injury seen on computed tomography of the head (CTH). Understanding that this syndrome presents with diffuse calcified lesions will assist clinicians unfamiliar with Fahr syndrome when evaluating diffuse hyperdensities seen on CTH in the setting of trauma between traumatic acute blood versus calcification. We present a unique image that demonstrates how a traumatic brain injury patient can present with traumatic acute hemorrhage and Fahr syndrome. We highlight 2 methods within the CTH images that can be used to assist in these diagnoses, which will better inform neurosurgeons and other clinicians when encountering this unique and rare presentation for the first time.

Teaching Neuro Images : Fahr syndrome caused by hypoparathyroidism

A 57-year-old woman with a remote history of thyroidectomy but no prior neurologic symptoms developed seizures, fever, and coma. Limited evaluation at her local hospital in rural Haiti demonstrated serum hypocalcemia (4 mg/dL) and extensive bilateral subcortical calcification in the cerebral and cerebellar hemispheres on CT (figure). This pattern of calcification can occur in inherited conditions such as familial idiopathic basal ganglia calcification (Fahr disease) and acquired conditions (referred to as Fahr syndrome) including parathyroid dysfunction and intrauterine infection.1,2 Given our patient's severe hypocalcemia, Fahr syndrome was attributed to presumed hypoparathyroidism related to prior thyroidectomy in her case.

Case Report : Fahr’s Disease With Acute Double Hemiparese Manifestation

Fahr's disease is a very rare disease with a prevalence of 1/1,000,000 individuals. We present a case report of a male with sudden double hemiparese and basal ganglia calcification leading to the diagnosis of Fahr's disease. A 59 years old male presented to the emergency department with a chief complaint of unable to move his upper and lower extremities in a sudden. The complaint begins with weakness of the right side of the body, followed by weakness of the left side of the body the day after. The serum levels of calcium, magnesium, phosphorus, and Parathyroid Hormonal (PTH) have not been measured due to the patient’s financial problems. CT scan of the brain showed bilateral, symmetrical, wide areas of calcification over the fossa posterior, basal ganglia, periventricular, and parietal area, which were suggested as Fahr’s disease. The patient is being treated with the injection of neuroprotectant, antibiotic, vitamin, neuropathic analgesia, and fluids. He is also being consulted with medical rehabilitation to get some physical treatments. Treatment goals include: increase and or maintain ROM, prevent contractures, strengthens weak muscles that may be underutilized, improvement and maintenance of postural stability in static postures and during mobility, and fall prevention. Our case highlight sudden double hemiparese which different from previous literature which says that neurological deficit symptoms appear with a chronic nature and the importance of combining pharmacological therapy and physical therapy as in this patient to reduce the patient's morbidity.

The clinical and genetic spectrum of primary familial brain calcification

Primary familial brain calcification (PFBC), formerly known as Fahr’s disease, is a rare neurodegenerative disease characterized by bilateral progressive calcification of the microvessels of the basal ganglia and other cerebral and cerebellar structures. PFBC is thought to be due to an altered function of the Neurovascular Unit (NVU), where abnormal calcium-phosphorus metabolism, functional and microanatomical alterations of pericytes and mitochondrial alterations cause a dysfunction of the blood–brain barrier (BBB) and the generation of an osteogenic environment with surrounding astrocyte activation and progressive neurodegeneration. Seven causative genes have been discovered so far, of which four with dominant (SLC20A2, PDGFB, PDGFRB, XPR1) and three with recessive inheritance (MYORG, JAM2, CMPK2). Clinical presentation ranges from asymptomatic subjects to movement disorders, cognitive decline and psychiatric disturbances alone or in various combinations. Radiological patterns of calcium deposition are similar in all known genetic forms, but central pontine calcification and cerebellar atrophy are highly suggestive of MYORG mutations and extensive cortical calcification has been associated with JAM2 mutations. Currently, no disease-modifying drugs or calcium-chelating agents are available and only symptomatic treatments can be offered.

T-cell infiltration in the central nervous system and their association with brain calcification in Slc20a2-deficient mice.

Primary familial brain calcification (PFBC) is a rare neurodegenerative and neuropsychiatric disorder characterized by bilateral symmetric intracranial calcification along the microvessels or inside neuronal cells in the basal ganglia, thalamus, and cerebellum. Slc20a2 homozygous (HO) knockout mice are the most commonly used model to simulate the brain calcification phenotype observed in human patients. However, the cellular and molecular mechanisms related to brain calcification, particularly at the early stage much prior to the emergence of brain calcification, remain largely unknown. In this study, we quantified the central nervous system (CNS)-infiltrating T-cells of different age groups of Slc20a2-HO and matched wild type mice and found CD45+CD3+ T-cells to be significantly increased in the brain parenchyma, even in the pre-calcification stage of 1-month-old -HO mice. The accumulation of the CD3+ T-cells appeared to be associated with the severity of brain calcification. Further immunophenotyping revealed that the two main subtypes that had increased in the brain were CD3+ CD4- CD8- and CD3+ CD4+ T-cells. The expression of endothelial cell (EC) adhesion molecules increased, while that of tight and adherents junction proteins decreased, providing the molecular precondition for T-cell recruitment to ECs and paracellular migration into the brain. The fusion of lymphocytes and EC membranes and transcellular migration of CD3-related gold particles were captured, suggesting enhancement of transcytosis in the brain ECs. Exogenous fluorescent tracers and endogenous IgG and albumin leakage also revealed an impairment of transcellular pathway in the ECs. FTY720 significantly alleviated brain calcification, probably by reducing T-cell infiltration, modulating neuroinflammation and ossification process, and enhancing the autophagy and phagocytosis of CNS-resident immune cells. This study clearly demonstrated CNS-infiltrating T-cells to be associated with the progression of brain calcification. Impairment of blood-brain barrier (BBB) permeability, which was closely related to T-cell invasion into the CNS, could be explained by the BBB alterations of an increase in the paracellular and transcellular pathways of brain ECs. FTY720 was found to be a potential drug to protect patients from PFBC-related lesions in the future.

Bilateral striopallidodentate calcinosis due to primary hypoparathyroidism presenting with chorea and seizure

Abstract Bilateral striopallidodentate calcinosis (BSPDC) is a rare genetic neurodegenerative disorder. There are multiple causes of BSPDC; however, primary hypoparathyroidism is the most common cause of secondary BSPDC. BSPDC can present with various neurological conditions, including movement disorders such as parkinsonism, chorea, and dystonia. Here, we report the case of a 48-year-old man who had a past history of seizure and presented to our department with chorea (predominant right hemichorea). On detailed evaluation, he was found to have low calcium, high phosphate, and low parathormone, suggestive of primary hypoparathyroidism. There was remarkable improvement in chorea with treatment. We suggest that hypoparathyroidism should be suspected in all cases of BSPDC and movement disorders.

Fahr and beyond: Anesthesia for obstetric emergency in a patient with fahr's syndrome

Fahr and beyond: Anesthesia for obstetric emergency in a patient with fahr's syndrome

Vrednosti kalcitonina u pseudohipoparatiroidizmu

Pseudohypoparathyroidism type 1A is a rare endocrine disorder caused by GNAS mutation and the resulting hormone resistance at the receptor level, i.e. the activation of the intracellular pathway of the Gs alpha subunit is not possible. This disorder is most often characterized by resistance to the parathyroid hormone. However, it can also be characterized by resistance to other hormones, such as thyroid-stimulating hormone, gonadotropins (luteinizing and follicle-stimulating hormones), growth hormone-releasing hormone, and calcitonin. In this article, we describe the case of a patient diagnosed with pseudohypoparathyroidism based on phenotypic features of hereditary Albright osteodystrophy. Due to the progressive decline in intellectual functions and changing behavior, neurological examination confirmed calcifications of the CNS as part of Fahr's syndrome. During hospitalization, higher levels of thyroid-stimulating hormone and calcitonin were observed, probably as a result of resistance at the level of the receptor and its intracellular pathway. Hypercalcitoninemia occurs sporadically in cases involving pseudohypoparathyroidism type 1-a and type 1-b. Elevated levels of calcitonin should be evaluated by means of anamnesis and clinical examination involving morphological and functional tests, considering that a highly specific tumor is a marker of medullary carcinoma of the thyroid gland, as well as some neuroendocrine tumors. Some authors recommend fine needle aspiration biopsy in order to minimize the risk of medullary thyroid cancer.

Fahr's syndrome and optic nerve head calcification in young: A rare consortium

Fahr's syndrome and optic nerve head calcification in young: A rare consortium

Intracranial Calcinosis: Fahr's Syndrome.

Intracranial Calcinosis: Fahr's Syndrome.

Pharmacology of Mammalian Na+-Dependent Transporters of Inorganic Phosphate.

Inorganic phosphate (Pi) is an essential component of many biologically important molecules such as DNA, RNA, ATP, phospholipids, or apatite. It is required for intracellular phosphorylation signaling events and acts as pH buffer in intra- and extracellular compartments. Intestinal absorption, uptake into cells, and renal reabsorption depend on a set of different phosphate transporters from the SLC20 (PiT transporters) and SLC34 (NaPi transporters) gene families. The physiological relevance of these transporters is evident from rare monogenic disorders in humans affecting SLC20A2 (Fahr's disease, basal ganglia calcification), SLC34A1 (idiopathic infantile hypercalcemia), SLC34A2 (pulmonary alveolar microlithiasis), and SLC34A3 (hereditary hypophosphatemic rickets with hypercalciuria). SLC34 transporters are inhibited by millimolar concentrations of phosphonoformic acid or arsenate while SLC20 are relatively resistant to these compounds. More recently, a series of more specific and potent drugs have been developed to target SLC34A2 to reduce intestinal Pi absorption and to inhibit SLC34A1 and/or SLC34A3 to increase renal Pi excretion in patients with renal disease and incipient hyperphosphatemia. Also, SLC20 inhibitors have been developed with the same intention. Some of these substances are currently undergoing preclinical and clinical testing. Tenapanor, a non-absorbable Na+/H+-exchanger isoform 3 inhibitor, reduces intestinal Pi absorption likely by indirectly acting on the paracellular pathway for Pi and has been tested in several phase III trials for reducing Pi overload in patients with renal insufficiency and dialysis.

Rare case of Fahr's syndrome with dissociative amnesia

Background: Fahr's syndrome (FS) is a movement and psychiatric disorder characterized by symmetrical and bilateral calcification of the basal ganglia. Dissociative amnesia is a rare psychiatric disorder that occurs after stressful events and is classified as a dissociative disorder. In addition, dissociation is the process by which the mind conceals stressful events from consciousness. Several neuropsychiatric manifestations in FS have been reported. However, due to their rarity, FS and dissociative amnesia can be misdiagnosed. Case: A 43-year-old female presented with Parkinsonian symptoms and an inability to recall important personal information. FS and dissociative amnesia were diagnosed after a thorough medical, psychiatric, and diagnostic investigation. Subsequently, correction of calcium and phosphate levels by α-hydroxy-vitamin-73 D3 and psychotherapy were administered for two-months until there were no neuropsychiatric symptoms reported. Conclusion: This research highlights a rare case of FS with dissociative amnesia which pathophysiology is not completely understood due to limited research.

FAHR's Disease and MCA Aneurysm Bleeding Case Report

Fahr's disease is named after the German neurologist Karl Theodor Fahr, who first reported it in 1930. This is a rare neurological condition characterized by abnormal idiopathic calcification of the basal ganglia and is usually inherited in autosomal dominant manner.

Golgi damage caused by dysfunction of PiT-2 in primary familial brain calcification

The Golgi apparatus is vital for protein modification and molecular trafficking. It is essential for nerve development and activity, and damage thereof is implicated in many neurological diseases. Primary familial brain calcification (PFBC) is a rare inherited neurodegenerative disease characterized by multiple brain calcifications. SLC20A2, which encodes the inorganic phosphate transporter 2 (PiT-2) protein, is the main pathogenic gene in PFBC. The PiT-2 protein is a sodium-dependent phosphate type III transporter, and dysfunction leads to a deficit in the cellular intake of inorganic phosphate (Pi) and calcium deposits. Whether the impaired Golgi apparatus is involved in the PFBC procession requires elucidation. In this study, we constructed induced pluripotent stem cells (iPSCs) derived from two PFBC patients with different SLC20A2 gene mutations (c.613G > A or del exon10) and two healthy volunteers as dependable cell models for research on pathogenic mechanism. To study the mechanism, we differentiated iPSCs into neurons and astrocytes in vitro. Our study found disruptive Golgi structure and damaged autophagy in PFBC neurons with increased activity of mTOR. We also found damaged mitochondria and increased apoptosis in the PFBC dopaminergic neurons and astrocytes. In this study, we prove that dysfunctional PiT-2 leads to an imbalance of cellular Pi, which may disrupt the Golgi apparatus with impaired autophagy, mitochondria and apoptosis in PFBC. Our study provides a new avenue for understanding nerve damage and pathogenic mechanism in brain calcifications.

Role of phosphate transporter PiT-2 in the pathogenesis of primary brain calcification

Primary brain calcification (PBC), also known as idiopathic basal ganglia calcification (IBGC), primary familial brain calcification (PFBC) and so on, is a rare intractable disease characterized by abnormal mineral deposits, including mostly calcium in the basal ganglia, thalamus, and cerebellum. The causative gene of familial PBC is SLC20A2, which encodes the phosphate transporter PiT-2. Despite this knowledge, the molecular mechanism underlying SLC20A2-associated PBC remains unclear. In the present study, we investigated whether haploinsufficiency or a dominant-negative mechanism reduced Pi uptake in two PiT-2 variants (T115 M and R467X). We demonstrated that the presence of T115 M or R467X had no dominant-negative effect on Pi transport activity of wild-type (WT). In addition, the subcellular localization of R467X completely differed from that of WT, indicating that there is no interaction between R467X and WT. Conversely, T115 M and WT showed almost the same localization. Therefore, we examined the interaction between T115 M and WT using the bioluminescence resonance energy transfer (BRET) method. Although WT and T115 M interact with each other, T115 M does not inhibit WT's Pi transport activity. These results suggest that the role of SLC20A2 in the pathogenesis of PBC may involve decreased intracellular Pi uptake by a haploinsufficiency mechanism rather than a dominant-negative mechanism; agents promoting PiT-2 dimerization may be promising potential therapeutic agents for PBC.

SLC20A2-Associated Idiopathic basal ganglia calcification (Fahr disease): a case family report

BackgroundIdiopathic basal ganglia calcification (IBGC) is a genetic disorder of the nervous system commonly known as Fahr disease. IBGC patients with a genetic background are considered to have primary familial brain calcification (PFBC), also known as familial basal ganglia calcification (FBGC), or familial Fahr disease. It is a rare degenerative neurological disorder characterized by extensive bilateral basal ganglia calcification that can lead to a range of extrapyramidal symptoms and neuropsychiatric manifestations. Studies have suggested that more than 50 variants of SLC20A2 gene mutations account for approximately 50% of IBGC cases. There is a wide spectrum of mutation types, including frameshift, nonsense, and splice site mutations in addition to deletion and missense mutations. Here we report a case of familial basal ganglia calcification caused by a frameshift mutation in the SLC20A2 gene. We identified a heterozygous mutation in the SLC20A2 gene, c.1097delG (p.G366fs*89). To our knowledge, this mutation site has not been reported before.Case presentationA 57-year-old male patient was admitted to the hospital with “unstable walking and involuntary movements between the eyes and eyebrows for 6 months”. Based on the patient’s family history, symmetrical calcification foci in the bilateral caudate nucleus head, thalamus, cerebellum and parietal lobe indicated by head CT, and gene test results, the diagnosis of familial Fahr disease caused by mutations in the SLC20A2 gene, c.1097delG p.G366fs*89) was confirmed.ConclusionFor the first time, we identified c.1097delG (p.G366fs*89) as a frameshift mutation in the IBGC family. This frameshift mutation caused the condition in this family of patients. This mutation not only broadens the range of known SLC20A2 mutations but also aids in the genetic diagnosis of IBGC.

Vertical Supranuclear Gaze Palsy in Primary Familial Brain Calcification Associated with a Novel SLC20A2 Mutation.

Vertical Supranuclear Gaze Palsy in Primary Familial Brain Calcification Associated with a Novel SLC20A2 Mutation.

Fahr syndrome due to hypoparathyroidism presenting in a comatous patient: A Case Report

Fahr syndrome due to hypoparathyroidism presenting in a comatous patient: A Case Report

The primary familial brain calcification-associated protein MYORG is an α-galactosidase with restricted substrate specificity.

Primary familial brain calcification (PFBC) is characterised by abnormal deposits of calcium phosphate within various regions of the brain that are associated with severe cognitive impairments, psychiatric conditions, and movement disorders. Recent studies in diverse populations have shown a link between mutations in myogenesis-regulating glycosidase (MYORG) and the development of this disease. MYORG is a member of glycoside hydrolase (GH) family 31 (GH31) and, like the other mammalian GH31 enzyme α-glucosidase II, this enzyme is found in the lumen of the endoplasmic reticulum (ER). Though presumed to act as an α-glucosidase due to its localization and sequence relatedness to α-glucosidase II, MYORG has never been shown to exhibit catalytic activity. Here, we show that MYORG is an α-galactosidase and present the high-resolution crystal structure of MYORG in complex with substrate and inhibitor. Using these structures, we map detrimental mutations that are associated with MYORG-associated brain calcification and define how these mutations may drive disease progression through loss of enzymatic activity. Finally, we also detail the thermal stabilisation of MYORG afforded by a clinically approved small molecule ligand, opening the possibility of using pharmacological chaperones to enhance the activity of mutant forms of MYORG.

Teaching NeuroImage: Primary Familial Brain Calcification in SLC20A2 Genotype.

Teaching NeuroImage: Primary Familial Brain Calcification in SLC20A2 Genotype.