The effects of etidronate on brain calcifications in Fahr's disease or syndrome: rationale and design of the randomised, placebo-controlled, double-blind CALCIFADE trial.

BACKGROUND: Fahr's disease and syndrome are rare disorders leading to calcification of the small arteries in the basal ganglia of the brain, resulting in a wide range of symptoms comprising cognitive decline, movement disorders and neuropsychiatric symptoms. No disease-modifying therapies are available. Studies have shown the potential of treatment of ectopic vascular calcifications with bisphosphonates. This paper describes the rationale and design of the CALCIFADE trial which evaluates the effects of etidronate in patients with Fahr's disease or syndrome. METHODS: The CALCIFADE trial is a randomised, placebo-controlled, double-blind trial which evaluates the effects of etidronate 20 mg/kg during 12 months follow-up in patients aged ≥ 18 years with Fahr's disease or syndrome. Etidronate and placebo will be administered in capsules daily for two weeks on followed by ten weeks off. The study will be conducted at the outpatient clinic of the University Medical Center Utrecht, the Netherlands. The primary endpoint is the change in cognitive functioning after 12 months of treatment. Secondary endpoints are the change in mobility, neuropsychiatric symptoms, volume of brain calcifications, dependence in activities of daily living, and quality of life. RESULTS: Patient recruitment started in April 2023. Results are expected in 2026 and will be disseminated through peer-reviewed journals as well as presentations at national and international conferences. CONCLUSIONS: Fahr's disease and syndrome are slowly progressive disorders with a negative impact on a variety of health outcomes. Etidronate might be a new promising treatment for patients with Fahr's disease or syndrome. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05662111. Registered 22 December 2022, https://clinicaltrials.gov/ct2/show/NCT01585402 .

Fahr's disease in a patient with recurrent pneumonias, parkinsonism and dementia.

Fahr's disease is a rare condition characterised by the presence of idiopathic familial bilateral basal ganglia calcifications, transmitted in an autosomal-dominant fashion. Diagnosis is based on clinical features of neuropsychiatric and somatic symptoms in conjunction with radiological findings. Our patient, a man in his early 50s, presented with pneumonia. History was significant for five admissions in the last 2 years for pneumonia and falls, with gradual cognitive and motor decline since his late 30s. Hypophonia, bradykinesia and dementia were noted on examination. CT of the brain revealed bilateral thalamic calcinosis, consistent with Fahr's syndrome. Further investigations and retrospective history taking, and similar radiological findings within first-degree and second-degree relatives with early deaths, transitioned the diagnosis from Fahr's syndrome to Fahr's disease. We present this case of Fahr's disease to emphasise the value of collaboration among multidisciplinary professionals to improve quality of care for such patients.

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.

TREX-1 related Aicardi-Goutières syndrome improved by Janus kinase inhibitor.

Aicardi-Goutières syndrome (AGS) is a genetic interferonopathy classically characterized by early onset of severe neurologic injury with basal ganglia calcifications, white matter abnormalities, and progressive cerebral atrophy, along with lymphocytosis and raised interferon alpha (INFα) in the cerebrospinal fluid (CSF). Here, we report a 31/2 year-old patient born with prenatal onset AGS, first manifesting as intra-uterine growth retardation. Cranial ultrasonography and cerebral MRI revealed ventriculomegaly and periventricular and basal ganglia calcifications, along with cerebral atrophy. Perinatal infections and known metabolic disorders were excluded. Both CSF lymphocytosis and raised INFα were present. Molecular analysis disclosed two already described compound heterozygous pathogenic variants in TREX1 (c. 309dup, p.(Thr104Hisfs*53) and c. 506G > A, p.(Arg169His)). The evolution was marked by severe global developmental delay with progressive microcephaly. Promptly, the patient developed irritability, quadri-paretic dyskinetic movements, and subsequently tonic seizures. Sensorineural hearing loss was detected as well as glaucoma. Initially, he was symptomatically treated with trihexyphenidyl followed by levetiracetam and topiramate. At age 22 months, baricitinib (0.4 mg/kg/day) was introduced, leading to normal serum INFα levels. Clinically, dyskinetic movements significantly decreased as well as irritability and sleep disturbance. We confirmed that baricitinib was a useful treatment with no major side effect.

[Neurological manifestations of hypoparathyroidism: diagnostic difficulties. Case report].

Hypoparathyroidism is a rare condition characterized by reduced production of parathyroid hormone or tissue resistance which leads to hypocalcemia and hyperphosphatemia. Neurological manifestations often occur as the first symptoms of hypoparathyroidism and are characterized by a wide variety of symptoms of both the central and peripheral nervous systems dysfunction, which requires a differential diagnosis with a wide range of neurological diseases. Two clinical cases illustrating the features of subacute and chronic hypoparathyroidism are presented. In the case of subacute hypoparathyroidism, a young woman presented with severe tetany involving the oculomotor muscles (paroxysmal strabismus), laryngeal muscles (respiratory stridor), body muscles (opisthotonus, «obstetrician's hand¼) and the development of secondary myopathy. In another case with a long-term chronic course of postoperative hypoparathyroidism, the patient's adaptation to severe hypocalcemia was noted; the clinical features were dominated by cerebral syndromes due to brain structures calcification (Fahr's syndrome). Possible reasons for late diagnosis of hypoparathyroidism, the importance of active detection of symptoms of neuromuscular hyperexcitability and laboratory testing of phosphorus and calcium metabolism are discussed.

Fahr's syndrome associated with hypoparathyroidism: A case report.

Fahr's syndrome affects fewer than 1 in 100,000 people. It is an inherited neurological disorder, which is distinguished by atypical calcium deposition in the movement-controlling areas of brain, that is thalamus, dentate nucleus, basal ganglia, cerebellum, cerebral cortex, hippocampus and subcortical white matter. The majority of patients often experience extrapyramidal symptoms, cerebellar signs, speech difficulty, dementia and neuropsychiatric manifestations. This disease's molecular genetics have not been thoroughly investigated. Typically, young to middle-aged adults are affected though basal ganglia calcification in hypoparathyroidism is quite uncommon. Laboratory results and radiographic brain imaging helps in reaching the diagnosis. The treatment is mainly symptomatic. We present a case of Fahr's syndrome associated with hypoparathyroidism.

Biotin-thiamine responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of cases in Kuwait with novel variants.

BACKGROUND: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare autosomal recessive neurometabolic disorder that is caused by biallelic pathogenic SLC19A3 variants and is characterized by subacute encephalopathy associated with confusion, convulsions, dysphagia, dysarthria, or other neurological manifestations. METHODS: A retrospective review of the data registry in Kuwait Medical Genetics Center for all cases diagnosed clinically and radiographically and confirmed genetically with BTBGD. RESULTS: Twenty one cases from 13 different families were diagnosed with BTBGD in Kuwait. Most cases (86%) presented with confusion, dystonia, convulsions, or dysarthria, while three individuals were diagnosed pre-symptomatically during familial targeted genetic screening. Symptoms resolved completely within 2-week of treatment in two-thirds of the symptomatic cases but progressed in six of them to a variety of severe symptoms including severe cogwheel rigidity, dystonia and quadriparesis due to delayed presentation and management. Neuroradiological findings of the symptomatic cases revealed bilateral central changes in the basal ganglia. Two novel homozygous missense SLC19A3 variants were detected in a Kuwaiti and a Jordanian individuals, in addition to the previously reported Saudi founder homozygous variant, c.1264A > G; p.(Thr422Ala) in the remaining cases. Age of diagnosis ranged from newborn to 32 years, with a median age of 2-3 years. All cases are still alive receiving high doses of biotin and thiamine. CONCLUSION: This is the first study reporting the phenotypic and genotypic spectrum of 21 individuals with BTBGD in Kuwait and describing two novel SLC19A3 variants. BTBGD is a treatable neurometabolic disease that requires early recognition and treatment initiation. This study highlights the importance of performing targeted molecular testing of the founder variant in patients presenting with acute encephalopathy in the region.

The Genetics of Primary Familial Brain Calcification: A Literature Review.

Primary familial brain calcification (PFBC), also known as Fahr's disease, is a rare inherited disorder characterized by bilateral calcification in the basal ganglia according to neuroimaging. Other brain regions, such as the thalamus, cerebellum, and subcortical white matter, can also be affected. Among the diverse clinical phenotypes, the most common manifestations are movement disorders, cognitive deficits, and psychiatric disturbances. Although patients with PFBC always exhibit brain calcification, nearly one-third of cases remain clinically asymptomatic. Due to advances in the genetics of PFBC, the diagnostic criteria of PFBC may need to be modified. Hitherto, seven genes have been associated with PFBC, including four dominant inherited genes (SLC20A2, PDGFRB, PDGFB, and XPR1) and three recessive inherited genes (MYORG, JAM2, and CMPK2). Nevertheless, around 50% of patients with PFBC do not have pathogenic variants in these genes, and further PFBC-associated genes are waiting to be identified. The function of currently known genes suggests that PFBC could be caused by the dysfunction of the neurovascular unit, the dysregulation of phosphate homeostasis, or mitochondrial dysfunction. An improved understanding of the underlying pathogenic mechanisms for PFBC may facilitate the development of novel therapies.

New Evidence Suggests a Much Complex Classification for the Genetic Pattern of Inheritance in Primary Brain Calcification.

Primary familial brain calcification (PFBC), often called Fahr's disease, is a condition in which calcium phosphate accumulates in the brain, mainly in the basal ganglia, thalamus, and cerebellum, and without the association of any metabolic or infectious cause. Patients present a variety of neurological and psychiatric disorders, usually during adulthood. The disease is caused by autosomal dominant pathogenic variants in genes such as SLC20A2, PDGFRB, PDGFB, and XPR1. MYORG and JAM2 are the other genes linked to homozygous patterns of inheritance. Here, we briefly discuss the recent cases reported by Ceylan et al. (2022) and Al-Kasbi et al. (2022), which challenge the current association with two previous genes and a clear pattern of inheritance. Ceylan et al. report a new biallelic variant related to a pathogenic variant in the SLC20A2 gene, which is typically associated with a heterozygous mutation pattern. The affected siblings displayed a severe and early onset of the disease, revealing a phenotype similar to that seen in CMV infections, often named as pseudo-TORCH. Furthermore, a study of genes related to intellectual disability conducted by Al-Kasbi et al. demonstrated that the biallelic manifestation of the XPR1 gene was associated with early symptoms, leading to the belief that the homozygous pattern of genes responsible for causing PFBC with an autosomal dominant pattern may also be linked to early-onset manifestations of PFBC. Further studies might explore the variety of clinical presentations linked to PFBC genes, especially if we pay attention to complex patterns of inheritance, reinforcing the need for a more detailed bioinformatic analysis.

[Autoimmune Parkinsonism and Related Disorders].

Autoimmune parkinsonism and related disorders are immune-mediated central nervous system disorders that present with extrapyramidal signs such as involuntary movements, hypokinesia, and rigidity. Patients commonly have neurological signs other than the extrapyramidal signs. Some patients show a slowly progressive clinical course with neurological symptoms resembling those of neurodegenerative disorders. Occasionally, specific autoantibodies targeting the basal ganglia or related sites are detected in their serum or cerebrospinal fluid. These autoantibodies are important diagnostic markers for these disorders.

PSEN1/SLC20A2 double mutation causes early-onset Alzheimer's disease and primary familial brain calcification co-morbidity.

Primary familial brain calcification (PFBC; formerly Fahr's disease) and early-onset Alzheimer's disease (EOAD) may share partially overlapping pathogenic principles. Although the heterozygous loss-of-function mutation c.1523 + 1G > T in the PFBC-linked gene SLC20A2 was detected in a patient with asymmetric tremor, early-onset dementia, and brain calcifications, CSF ß-amyloid parameters and FBB-PET suggested cortical ß-amyloid pathology. Genetic re-analysis of exome sequences revealed the probably pathogenic missense mutation c.235G > A/p.A79T in PSEN1. The SLC20A2 mutation segregated with mild calcifications in two children younger than 30 years. We thus describe the stochastically extremely unlikely co-morbidity of genetic PFBC and genetic EOAD. The clinical syndromes pointed to additive rather than synergistic effects of the two mutations. MRI data revealed the formation of PFBC calcifications decades before the probable onset of the disease. Our report furthermore exemplifies the value of neuropsychology and amyloid PET for differential diagnosis.

Slovenian Version of the Drug-Induced Extrapyramidal Symptoms Scale: Evaluation of Interrater and Test-Retest Reliability.

AIM: The Drug-Induced Extrapyramidal Symptom Scale (DIEPSS) is a multidimensional rating scale for the assessment of drug-induced extrapyramidal symptoms (EPS), developed in 1994. It is suitable for evaluating EPS considering the degree of influence EPS has on daily activities and the subjective distress that it causes. METHOD: This study to evaluate the interrater and test-retest reliability of the DIEPSS Slovenian version conducted at the University Medical Center Maribor in Slovenia in November 2018. RESULTS: Six raters performed the interrater assessment of 135 DIEPSS video clips with recordings of patients with EPS. A second assessment was then performed by 2 raters to evaluate the test-retest reliability, which was high (interclass correlation coefficients from 0.743 to 0.936). CONCLUSIONS: The results for the Slovenian language version of the DIEPSS show high interrater and test-retest reliability, with high concordance rates for all evaluated items (interclass correlation coefficient > 0.8).

Scales for Antipsychotic-Associated Movement Disorders: Systematic Review, Critique, and Recommendations.

BACKGROUND: Antipsychotic-associated movement disorders remain common and disabling. Their screening and assessment are challenging due to clinical heterogeneity and different use of nomenclature between psychiatrists and neurologists. OBJECTIVE: An International Parkinson and Movement Disorder Society subcommittee aimed to rate psychometric quality of severity and screening instruments for antipsychotic-associated movement disorders. METHODS: Following the methodology adopted by previous International Parkinson and Movement Disorders Society subcommittee papers, instruments for antipsychotic-associated movement disorders were reviewed, applying a classification as "recommended," "recommended with caveats," "suggested," or "listed." RESULTS: Our review identified 23 instruments. The highest grade of recommendation reached is "recommended with caveats," assigned to seven severity rating instruments (Extrapyramidal Symptoms Rating Scale, Barnes Akathisia Rating Scale, Abnormal Involuntary Movements Scale, Drug-Induced Extra-Pyramidal Symptoms Scale, Maryland Psychiatric Research Centre involuntary movements scale, Simpson Angus Scale, and Matson Evaluation of Drug Side effects). Only three of these seven (Drug-Induced Extra-Pyramidal Symptoms Scale, Maryland Psychiatric Research Centre, Matson Evaluation of Drug Side effects) were also screening instruments. Their main caveats are insufficient demonstration of psychometric properties (internal consistency, skewing, responsiveness to change) and long duration of administration. Eight "suggested" instruments did not meet requirements for the "recommended" grade also because of insufficient psychometric validation. Other limitations shared by several instruments are lack of comprehensiveness in assessing the spectrum of antipsychotic-associated movement disorders and ambiguous nomenclature. CONCLUSIONS: The high number of instruments "recommended with caveats" does not support the need for developing new instruments for antipsychotic-associated movement disorders. However, addressing the caveats with new psychometric studies and revising existing instruments to improve the clarity of their nomenclature are recommended next steps. © 2023 International Parkinson and Movement Disorder Society.

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.

All in One: Varied Manifestations of Hypocalcemia in the Same Patient.

INTRODUCTION: The calcium ion plays a critical role in normal cellular functioning and signaling neuro muscular signaling, cardiac contractility, hormone secretion and blood coagulation. The extra cellular calcium levels are maintained within a narrow range through a series of feedback mechanisms that involve parathormone and vitamin D. MATERIALS: Herein we present a patient with hypocalcemia who presented with many of its features. A 65 year old female came with complaints of new onset seizures. She was a known case of hypothyroidism since 20 years. She had history of thyroidectomy surgery 25 years back. Shes also hypertensive. On examination she was conscious, oriented. vitals stable. Tone was reduced in all 4 limbs. Blood investigations were normal except for low serum calcium levels. CT brain showed bilateral symmetrical classification in the basal ganglia and cerebellar dentate nuclei. ECG short QT prolongation. Serum parathormone levels were low. Post surgical hypothyroidsm with hypoparathyroidsm led to chronic hypocalcemia and the present features. RESULT: Chvosteks sign Trousseau sign QT prolongation Bilateral basal ganglia calcification- Fahrs syndrome Conclusion: An interesting case of bilateral basal ganglia calcification due to hypocalcemia which also had other features of hypocalcemia.

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.