Novel tau filament fold in corticobasal degeneration.

Corticobasal degeneration (CBD) is a neurodegenerative tauopathy-a class of disorders in which the tau protein forms insoluble inclusions in the brain-that is characterized by motor and cognitive disturbances1-3. The H1 haplotype of MAPT (the tau gene) is present in cases of CBD at a higher frequency than in controls4,5, and genome-wide association studies have identified additional risk factors6. By histology, astrocytic plaques are diagnostic of CBD7,8; by SDS-PAGE, so too are detergent-insoluble, 37 kDa fragments of tau9. Like progressive supranuclear palsy, globular glial tauopathy and argyrophilic grain disease10, CBD is characterized by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats11-15. This distinguishes such '4R' tauopathies from Pick's disease (the filaments of which are made of three-repeat (3R) tau isoforms) and from Alzheimer's disease and chronic traumatic encephalopathy (CTE) (in which both 3R and 4R isoforms are found in the filaments)16. Here we use cryo-electron microscopy to analyse the structures of tau filaments extracted from the brains of three individuals with CBD. These filaments were identical between cases, but distinct from those seen in Alzheimer's disease, Pick's disease and CTE17-19. The core of a CBD filament comprises residues lysine 274 to glutamate 380 of tau, spanning the last residue of the R1 repeat, the whole of the R2, R3 and R4 repeats, and 12 amino acids after R4. The core adopts a previously unseen four-layered fold, which encloses a large nonproteinaceous density. This density is surrounded by the side chains of lysine residues 290 and 294 from R2 and lysine 370 from the sequence after R4.

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.

Fahr's disease with neuropsychiatric symptoms and intermittent course: a case report.

Fahr's disease is a rare neurodegenerative disorder with brain calcifications and neuropsychiatric symptoms. It can have variable phenotypic expression and intermittent symptomatology, making diagnosis challenging. In this report, we describe a young female patient presenting with symptoms of psychosis and confusion, which could be indicative of a delirium superimposed on the cerebral vulnerability associated with Fahr's disease. Notably, about two years prior, she experienced multiple episodes of tonic-clonic seizures that spontaneously resolved without pharmacological intervention. She had no previous psychiatric history. Following comprehensive investigations, other organic causes were ruled out, and Fahr's disease was diagnosed based on bilateral symmetrical brain calcifications seen on a head CT scan. Her treatment regimen encompassed antipsychotics and anticonvulsants. This case highlights the importance of considering Fahr's disease as a differential diagnosis in patients with new-onset neuropsychiatric symptoms. The case also explores the atypical early onset and intermittent nature of symptoms in the absence of a positive family history, highlighting the complexity of Fahr's disease. A multidisciplinary approach and regular follow-up are crucial for optimizing patient care and monitoring disease progression. Further research is needed to enhance our understanding of Fahr's disease and develop standardized treatment strategies for this rare condition.

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.

Biotin Homeostasis and Human Disorders: Recent Findings and Perspectives.

Biotin (vitamin B7, or vitamin H) is a water-soluble B-vitamin that functions as a cofactor for carboxylases, i.e., enzymes involved in the cellular metabolism of fatty acids and amino acids and in gluconeogenesis; moreover, as reported, biotin may be involved in gene regulation. Biotin is not synthesized by human cells, but it is found in food and is also produced by intestinal bacteria. Biotin status/homeostasis in human individuals depends on several factors, including efficiency/deficiency of the enzymes involved in biotin recycling within the human organism (biotinidase, holocarboxylase synthetase), and/or effectiveness of intestinal uptake, which is mainly accomplished through the sodium-dependent multivitamin transporter. In the last years, administration of biotin at high/"pharmacological" doses has been proposed to treat specific defects/deficiencies and human disorders, exhibiting mainly neurological and/or dermatological symptoms and including biotinidase deficiency, holocarboxylase synthetase deficiency, and biotin-thiamine-responsive basal ganglia disease. On the other hand, according to warnings of the Food and Drug Administration, USA, high biotin levels can affect clinical biotin-(strept)avidin assays and thus lead to false results during quantification of critical biomarkers. In this review article, recent findings/advancements that may offer new insight in the abovementioned research fields concerning biotin will be presented and briefly discussed.

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.

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.

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.

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).

Aneurysmal subarachnoid hemorrhage with PFBC and beta thalassemia: a case report.

BACKGROUND: Primary familial brain calcification (PFBC), habitually called Fahr's disease, is characterized by bilateral calcification of the basal ganglia, accompanied by extensive calcification of the cerebellar dentate nucleus, brainstem cerebrum, and cerebellum at the grey-white matter junction. However, there are few reports about PFBC with aneurysmal subarachnoid hemorrhage (aSAH) and thalassemia. CASE PRESENTATION: We describe a patient admitted to the hospital with an acute deterioration in the level of consciousness with no history of neuropsychiatric features or movement disorders. After computed tomography (CT) and CT angiography (CTA), the patient was diagnosed with PFBC, accompanied by aneurysmal subarachnoid haemorrhage (aSAH), intracranial haemorrhage (ICH), and hemoglobin electrophoresis suggested beta-thalassemia. This patient underwent craniotomy aneurysm clipping and intracranial hematoma removal. CONCLUSIONS: For patients with PFBC, we should pay attention to their blood pressure and intracranial vascular conditions. The CTA is necessary to clarify the cerebrovascular conditions of the patient, especially when combined with hypertension and persistent headache or other related prodromal symptoms of cerebrovascular disease.

The factor structure of extrapyramidal symptoms evaluated using the Drug-Induced Extrapyramidal Symptoms Scale in patients with schizophrenia: Results from the 2016 REAP AP-4 study.

INTRODUCTION: Drug-induced extrapyramidal syndrome (EPS) remains a major problem in clinical psychiatry. This study aimed to examine the factor structure of drug-induced extrapyramidal symptoms observed in patients with schizophrenia and assessed using the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). METHODS: The participants were 1478 patients with a diagnosis of schizophrenia whose EPS was assessed using the DIEPSS in India, Indonesia, Japan, Malaysia, and Taiwan in the 2016 REAP AP-4 study. The records of the participants were randomly divided into two subgroups: the first for exploratory factor analysis of the eight DIEPSS items, and the second for confirmatory factor analysis. RESULTS: The factor analysis identified three factors: F1 (gait and bradykinesia), F2 (muscle rigidity and tremor), and F3 (sialorrhea, akathisia, dystonia, and dyskinesia). CONCLUSION: The results suggest that the eight individual items of the DIEPSS could be composed of three different mechanisms: acute parkinsonism observed during action (F1), acute parkinsonism observed at rest (F2), and central dopaminergic mechanisms with pathophysiology other than acute parkinsonism (F3).

Cerebellar vermis hypoplasia and bilateral basal ganglia calcification in maternally inherited diabetes and deafness.

Maternally inherited diabetes and deafness (MIDD) is a rare diabetic syndrome mainly caused by a point mutation in the mitochondrial DNA. It affects up to 1% of patients with diabetes but is often unrecognized by physicians. We report a case of MIDD in a 29-year-old man with coexisting imaging of cerebellar vermis hypoplasia and bilateral basal ganglia calcification.

Anterior communicating artery aneurysm in a young patient with Fahr's disease: case presentation.

BACKGROUND AND IMPORTANCE: Fahr disease is an uncommon disorder defined as prominent calcification in basal ganglia, dentate nuclei of cerebellum, pulvinar thalami and subcortical white matter and it has been shown that calcium is the major factor that causes the hyperdensity on computer tomography (CT). Spontaneous subarachnoid hemorrhage from an aneurysm in a patient with Fahr disease was first reported by Al-Jehani et al. in 2012 in a 54-year-old female patient with calcification of basal ganglia and deep cerebellar nuclei and a subarachnoid hemorrhage from a right posterior communicating artery aneurysm. CLINICAL PRESENTATION: We present a 17 years old patient with Fahr disease with an anterior communicating artery aneurysm rupture. CONCLUSION: There are few reports of intracranial hemorrhage with Fahr's disease. It may be suggested that excessive calcium accumulation contributes to aneurysm formation or rupture.

Fahr's disease associated with anaplastic ependymoma: a case report and review of the literature.

Fahr's disease, also known as familial idiopathic basal ganglia calcification or bilateral strio-pallido-dentate calcinosis, is a rare entity characterized by abnormal vascular calcium depositionin the thalamus, basal ganglia, cerebral cortex and the dentate nuclei of the cerebellum. Intracranial ependymomas comprise approximately 2% to 9% of all neuroepithelial tumors. It is reported that supratentorial ependymoma constitute 30% to 50% of all intracranial ependymal tumors. Among supratentorial ependymomas, approximately 50% of them are located extraventricular and demonstrate no relationship with the ventricularsystem.The association of brain tumor with Fahr's disease is a rare entity and has been reported several times before. Whereas, to best our knowledge, the association of Fahr's disease and supratentorial anaplastic ependymoma is described in the present study for the first time.

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.

Basal ganglia calcifications: No association with cognitive function.

BACKGROUND AND PURPOSE: Basal ganglia calcifications (BGC), a form of vascular calcification, are a common brain computed tomography (CT) finding. We investigated whether BGC are associated with cognitive function and examined the association between vascular risk factors and BGC. MATERIAL AND METHODS: Patients who visited a memory clinic of a Dutch general hospital between April 2009 and April 2015 were included. The patients underwent a standard diagnostic work up including cognitive tests (Cambridge Cognitive Examination, including the Mini Mental State Examination) and brain CT. Vascular risk factors such as hypertension, diabetes mellitus, hyperlipidemia and smoking were assessed. CTs were analyzed for presence and severity (absent, mild, moderate or severe) of BGC. Multivariable logistic regression was used to identify risk factors for BGC and linear regression for the association between BGC and cognitive function. RESULTS: Of the 1992 patients, 40.3% was male. The median age was 80 years and 866 patients (43.5%) had BGC. BGC was associated with female gender (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.06-1.53, p 0.011), and inversely associated with hypertension (OR 0.74, 95% CI 0.60-0.89, p 0.002) and use of antihypertensive drugs (OR 0.79, 95% CI 0.64-0.98, p 0.031). No association was found between presence and severity of BGC and cognitive function or other vascular risk factors. CONCLUSIONS: No association with cognitive function was found. Risk factors for BGC were female gender, while hypertension and antihypertensive drug use were associated with a lower risk of BGC.

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.

[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.

Identification of a 5 bp duplicate in the AP1S2 gene of an individual with X-linked intellectual disability.

Adaptor-related protein complex 1 subunit sigma 2 (AP1S2) is a subunit of AP1 that is crucial for the reformation of the synaptic vesicle. Variants in AP1S2 have been reported to cause a rare neurodevelopmental disorder, Pettigrew syndrome (PGS) (OMIM: 304,340), which is characterized by walking delay, abnormal speech, mild to profound X-linked intellectual disability (XLID), and abnormal brain, and behaviors. Here, we describe a 2-year- and 5-month-old male patient who presented with global developmental delay (GDD). Trio whole exome sequencing (WES) revealed a 5 bp duplicate in the AP1S2 gene (NM_003916.5: exon 2: c.96_100dup, p. Leu34Glnfs*8) predicted to cause early termination of translation, which was inherited from the unaffected mother. The clinical features of our patient were consistent with previous reports. This is the second case in the Chinese family and the eleventh variant found in AP1S2-related XLID. Our findings expand the AP1S2 variant spectrum in neurodevelopmental disorders and provide evidence for the application of WES in PGS diagnosis.

Reassessing models of basal ganglia function and dysfunction.

The basal ganglia are a series of interconnected subcortical nuclei. The function and dysfunction of these nuclei have been studied intensively in motor control, but more recently our knowledge of these functions has broadened to include prominent roles in cognition and affective control. This review summarizes historical models of basal ganglia function, as well as findings supporting or conflicting with these models, while emphasizing recent work in animals and humans directly testing the hypotheses generated by these models.