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.

Frequency-Specific Changes of Amplitude of Low-Frequency Fluctuations in Patients with Acute Basal Ganglia Ischemic Stroke.

Objective: The purpose of this study was to investigate the characteristics of different frequency bands in the spontaneous brain activity among patients with acute basal ganglia ischemic stroke (BGIS). Methods: In the present study, thirty-four patients with acute BGIS and forty-four healthy controls were examined by resting-state functional magnetic resonance imaging (rs-fMRI) from May 2019 to December 2020. Two amplitude methods including amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) calculated in three frequency bands (conventional frequency band: 0.01-0.08 Hz; slow-5 frequency band: 0.01-0.027 Hz; and slow-4 frequency band: 0.027-0.073 Hz) were conducted to evaluate the spontaneous brain activity in patients with acute BGIS and healthy controls (HCs). Gaussian Random Field Theory (GRF, voxel p < 0.01 and cluster p < 0.05) correction was applied. The correlation analyses were performed between clinical scores and altered metrics values. Results: Compared to HCs, patients with acute BGIS showed decreased ALFF in the right supramarginal gyrus (SMG) in the conventional and slow-4 bands, increased fALFF in the right middle frontal gyrus (MFG) in the conventional and slow-4 bands, and increased fALFF in the bilateral caudate in the slow-5 frequency band. The fALFF value of the right caudate in the slow-5 frequency band was negatively correlated with the clinical scores. Conclusion: In conclusion, this study showed the alterations in ALFF and fALFF in three frequency bands between patients with acute BGIS and HCs. The results reflected that the abnormal LFO amplitude might be related with different frequency bands and promoted our understanding of pathophysiological mechanism in acute BGIS.

Novel splicing-site mutation in DCAF17 gene causing Woodhouse-Sakati syndrome in a large consanguineous family.

BACKGROUND: Woodhouse-Sakati syndrome is a rare autosomal recessive disease with endocrine and neuroectodermal aberrations with heterogeneous phenotypes and disease course. The most common phenotypes of the disease are progressive sensorineural hearing loss and alopecia, mild-to-moderate mental retardation and hypogonadism. The disease results from mutations in the DCAF17 gene. METHOD: Here, we reported a large consanguineous pedigree with multiple affected individuals with Woodhouse-Sakati syndrome phenotypes. Laboratory tests confirmed the endocrine perturbance in affected individuals. To find out the underlying genetic change, whole-exome sequencing was carried out. RESULT: Analysis of the exome data identified a splicing-site deletion NM_025000.3:c.1423-1_1425delGACA in DCAF17 gene. Sanger sequencing confirmed the co-segregation of the variant with the disease phenotypes in the family. CONCLUSION: The variant is predicted to cause aberrant splicing, i.e., exon skipping, resulting in the translation of a truncated functionless protein which results in appearance of typical phenotypic features and clinical laboratory findings of Woodhouse-Sakati syndrome in affected members of the family.

CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors.

CalDAG-GEFI (CDGI) is a protein highly enriched in the striatum, particularly in the principal spiny projection neurons (SPNs). CDGI is strongly down-regulated in two hyperkinetic conditions related to striatal dysfunction: Huntington's disease and levodopa-induced dyskinesia in Parkinson's disease. We demonstrate that genetic deletion of CDGI in mice disrupts dendritic, but not somatic, M1 muscarinic receptors (M1Rs) signaling in indirect pathway SPNs. Loss of CDGI reduced temporal integration of excitatory postsynaptic potentials at dendritic glutamatergic synapses and impaired the induction of activity-dependent long-term potentiation. CDGI deletion selectively increased psychostimulant-induced repetitive behaviors, disrupted sequence learning, and eliminated M1R blockade of cocaine self-administration. These findings place CDGI as a major, but previously unrecognized, mediator of cholinergic signaling in the striatum. The effects of CDGI deletion on the self-administration of drugs of abuse and its marked alterations in hyperkinetic extrapyramidal disorders highlight CDGI's therapeutic potential.

First pediatric case with primary familial brain calcification due to a novel variant on the MYORG gene and review of the literature.

Variants in the myogenesis-regulating glycosidase (MYORG) gene which is known as the first autosomal recessive gene that has been associated with primary familial brain calcification (AR-PFBC). Although adult patients have been reported, no pediatric case has been reported until now. Herein, we review the clinical and radiological features of all AR- PFBC patients with biallelic variants in the MYORG gene who were reported until now, and we report the youngest patient who has a novel homozygous variant. Since the first identification of the MYORG gene in 2018, 74cases of MYORG variants related to AR-PFBC were evaluated. The ages of symptom onset of the patients ranged between 7.5 and 87 years. The most frequent clinical courses were speech impairment, movement disorder and cerebellar signs. All patients showed basal ganglia calcification usually bilaterally with different severities. Conclusion; herein, we reported the first pediatric patient in the literature who had a novel homozygous variant in the MYORG gene with mild clinic findings.

Extrapyramidal signs and Alzheimer's disease prognosis in a multiethnic, community-based sample of demented elders.

INTRODUCTION: Extrapyramidal signs (EPS) are a common feature of Alzheimer's disease associated with worse outcomes in observational studies of dementia. Less research has been conducted on ethnic minority and non-clinic-based populations. METHODS: One hundred and forty-two multiethnic community-dwelling participants with dementia were selected. Adjusted Cox models were fitted for mortality, cognitive (Mini Mental State Examination ≤10), functional (Blessed Dementia Rating Scale ≥10), and dependency (needs full-time care) endpoints with baseline EPS as predictor. RESULTS: Thirty-seven participants (26.06%) had EPS at baseline. EPS predicted more rapid time to death (hazard ratio [HR] = 2.76, 95% confidence interval [CI] = 1.49, 5.42), and functional endpoint (HR = 3.88, 95% CI = 1.75, 8.62) but not cognitive and dependency endpoints. No evidence of interaction by ethnicity, age, sex, education, or apolipoprotein E ε4 polymorphism was found. DISCUSSION: Our results partially confirm previous studies on predominantly White, clinic-based samples. Further research is needed to better understand the etiological role of EPS in AD.

Fahr's syndrome due to hypoparathyroidism revisited: A case of parkinsonism and a review of all published cases.

INTRODUCTION: Fahr's syndrome due to hypoparathyroidism refers to bilateral basal ganglia (BG) calcifications and manifests with movement disorders, seizures, cognitive and behavioral symptoms. CASE PRESENTATION: We report a case of a 74-year-old woman, who presented with parkinsonism due to post-surgical hypoparathyroidism and normal DaT scan, despite extensive calcifications of the BG, periventricular white matter, and cerebellum. METHODS: A comprehensive literature review of all reported cases of Fahr's syndrome due to hypoparathyroidism was conducted in the electronic databases PubMed and Web of science. Moreover, demographic and clinical characteristics of the patients overall were calculated and associated with radiological findings. RESULTS: We reviewed a total of 223 cases with Fahr's syndrome due to hypoparathyroidism (124 female, 99 male). Mean age on presentation was 44.6 ± 17.7 years. Thirty nine percent of patients had idiopathic hypoparathyroidism, 35.4 % acquired and 25.6 % pseudohypoparathyroidism. Almost half of the patients had tetany, seizures or a movement disorder and approximately 40 % neuropsychiatric symptoms. The patients with a movement disorder had a 2.23 likelihood of having neuropsychiatric symptoms as well (OR 2.23, 95 % CI 1.29-3.87). Moreover, there was a statistically significant association between the phenotype severity (i.e. the presence of more than one symptom) and the extent of brain calcifications (χ2 = 32.383, p = 0.009). CONCLUSION: Fahr's syndrome is a rare disorder, which nonetheless manifests with several neurological symptoms. A head CT should be considered for patients with hypoparathyroidism and neurological symptoms. More studies using DaT scan are needed to elucidate the effects of calcifications on the dopaminergic function of the BG.

Continuous epileptiform discharges during sleep as an evolutionary pattern in patients with congenital Zika virus syndrome.

Congenital Zika virus syndrome (CZVS) is associated with severe neurological deficits. Clinical characteristics of epilepsy and the electroencephalographic (EEG) pattern in CZVS were documented in infancy. In this study, we aimed to describe the EEG findings observed during the follow-up of children with CZVS. Seventy-six EEGs of 55 children (60% female; mean age = 50 months) with confirmed CZVS were analyzed, considering the background, interictal, and ictal epileptiform discharges. Continuous (or almost continuous) epileptiform discharges during non-rapid eye movement sleep were identified in 22 (40%) patients. In 20 (90.1%) patients, the pattern was symmetrical, with an anterior predominance of the epileptiform activity. All patients with this pattern had epilepsy, which was severe in 15 (68.2%) and demanded polytherapy in 19 (86.4%). Subcortical calcifications (77.3%) and multifocal EEGs (72.8%) in earlier ages occurred more often in patients with this pattern. Other unspecific interictal EEG patterns were focal epileptiform discharges in 23 (41.8%) and multifocal activity in six (10.9%). In CZVS, continuous (or almost continuous) epileptiform discharges during sleep emerge as a pattern after the second year of life. This was associated with severe and drug-resistant epilepsy, but not necessarily with an apparent regression. Subcortical calcifications and multifocal epileptiform discharges in infancy are associated with this pattern.

Effect of Functional BDNF and COMT Polymorphisms on Symptoms and Regional Brain Volume in Frontotemporal Dementia and Corticobasal Syndrome.

OBJECTIVE: The authors examined the effects of two common functional polymorphisms-brain-derived neurotrophic factor (BDNF) Val66Met and catechol-O-methyltransferase (COMT) Val158Met-on cognitive, neuropsychiatric, and motor symptoms and MRI findings in persons with frontotemporal lobar degeneration (FTLD) syndromes. METHODS: The BDNF Val66Met and COMT Val158Met polymorphisms were genotyped in 174 participants with FTLD syndromes, including behavioral variant frontotemporal dementia, primary progressive aphasia, and corticobasal syndrome. Gray matter volumes and scores on the Delis-Kaplan Executive Function System, Mattis Dementia Rating Scale, Wechsler Memory Scale, and Neuropsychiatric Inventory were compared between allele groups. RESULTS: The BDNF Met allele at position 66 was associated with a decrease in depressive symptoms (F=9.50, df=1, 136, p=0.002). The COMT Val allele at position 158 was associated with impairment of executive function (F=6.14, df=1, 76, p=0.015) and decreased bilateral volume of the head of the caudate in patients with FTLD (uncorrected voxel-level threshold of p<0.001). Neither polymorphism had a significant effect on motor function. CONCLUSIONS: These findings suggest that common functional polymorphisms likely contribute to the phenotypic variability seen in patients with FTLD syndromes. This is the first study to implicate BDNF polymorphisms in depressive symptoms in FTLD. These results also support an association between COMT polymorphisms and degeneration patterns and cognition in FTLD.

Proactive interference apraxic agraphia: a writing and drawing disorder associated with corticobasal syndrome.

Proactive interference is when a previously performed task impairs performance on a current task. It is often associated with memory tasks and has not been reported to interfere with writing or drawing. We evaluated a left-handed man diagnosed with corticobasal syndrome who had a two-year history of progressive agraphia. On the sentence writing and clock drawing tasks, he initially wrote letters and numbers correctly but revealed an increase of movement errors as the tasks progressed. We propose the term "proactive interference apraxic agraphia" for this novel disorder. Prefrontal dysfunction may cause an impairment in disengaging from previously activated motor programs.

Bilateral basal ganglia infarcts presenting as rapid onset cognitive and behavioral disturbance.

We describe a rare case of a patient with rapid onset, prominent cognitive and behavioral changes who presented to our rapidly progressive dementia program with symptoms ultimately attributed to bilateral basal ganglia infarcts involving the caudate heads. We review the longitudinal clinical presentation and neuropsychological testing for this patient, and discuss the implicated basal ganglia and frontal lobe neuroanatomy.

Movement Disorders Due to Selective Basal Ganglia Lesions with Uremia.

BACKGROUND: Basal ganglia (BG) lesions are rarely reported in patients with uremia and may manifest by movement disorders. However, their exact incidence and pathogenesis have not been extensively studied. This study aimed to determine the frequency, types, risk variables (clinical, laboratory, and imaging), and manifestations of BG lesions with uremia and patients' neurologic outcomes. METHODS: This observational study included 70 adults (mean age: 45.87 ± 3.36 years; duration of uremia: 5.5 ± 1.5 years). They underwent extensive evaluations (clinical, laboratory, and neuroimaging) and had prospectively evaluated clinically every 3 months for 2 years. Repeated magnetic resonance imaging (MRI) brains were done to patients with movement disorders and correlated with their neurologic outcomes. RESULTS: BG lesions were found in 15 patients (21.4%) and 6 (8.6%) had movement disorders [Parkinsonism (n = 4), choreo-dystonia (n = 1) and dystonia (n = 1)] after the onset of uremia (mean = 10 months). There were no characteristic risk variables that distinguished patients with movement disorders from those without. Five developed movement disorders prior to the period of the study and one was de novo. The majority was females and had diabetes and higher frequencies of abnormal renal dysfunction, metabolic derangements, and white matter hyperintensities in MRIs. Movement disorders persisted in all patients despite the resolution of neuroimaging in three patients. CONCLUSIONS: There is no clear threshold for renal failure to result in movement disorders due to BG lesions. The clinical outcome is variables depending on each patient's comorbidities and complications. Persistent neuronal damage (due to uremic toxins/metabolic/nutritional and ischemic/microvascular factors) has been suggested as the cause of poor neurologic outcomes.

Alien limb in the corticobasal syndrome: phenomenological characteristics and relationship to apraxia.

Alien limb refers to movements that seem purposeful but are independent of patients' reported intentions. Alien limb often co-occurs with apraxia in the corticobasal syndrome, and anatomical and phenomenological comparisons have led to the suggestion that alien limb and apraxia may be causally related as failures of goal-directed movements. Here, we characterised the nature of alien limb symptoms in patients with the corticobasal syndrome (n = 30) and their relationship to limb apraxia. Twenty-five patients with progressive supranuclear palsy Richardson syndrome served as a disease control group. Structured examinations of praxis, motor function, cognition and alien limb were undertaken in patients attending a regional specialist clinic. Twenty-eight patients with corticobasal syndrome (93%) demonstrated significant apraxia and this was often asymmetrical, with the left hand preferentially affected in 23/30 (77%) patients. Moreover, 25/30 (83%) patients reported one or more symptoms consistent with alien limb. The range of these phenomena was broad, including changes in the sense of ownership and control as well as unwanted movements. Regression analyses showed no significant association between the severity of limb apraxia and either the occurrence of an alien limb or the number of alien limb phenomena reported. Bayesian estimation showed a low probability for a positive association between alien limb and apraxia, suggesting that alien limb phenomena are not likely to be related to severity apraxia. Our results shed light on the phenomenology of these disabling and as yet untreatable clinical features, with relevance to theoretical models of voluntary action.

Improved Mobility, Cognition, and Disease Severity in Corticobasal Degeneration of an African American Man After 12 Weeks of Adapted Tango: A Case Study.

Corticobasal degeneration (CBD) has no available treatment to slow disease progression and generally resists drug therapy. Corticobasal degeneration has symptoms and decreased quality of life similar to Parkinson disease. Adapted Tango, a successful rehabilitation for Parkinson, may address CBD. A 63-yr-old African American man with CBD (alias: YD; CBD duration = 2 yrs) was evaluated for motor, cognitive, and psychosocial function before, immediately after, 1 mo after, and 6 mos after 12 wks of 20, biweekly 90-min adapted-tango lessons. After intervention, disease-related motor symptoms improved and YD reported fewer problems in nonmotor experiences of daily living, which include mood, cognition, pain, fatigue, etc. Motor symptoms remained above baseline at 6-mo posttest. YD's balance confidence improved after intervention but declined below baseline at 6-mo posttest. Quality of life was maintained despite worsened depression. YD improved or maintained executive function, and visuospatial function and attention at posttest and 1-mo posttest. At posttest, YD maintained mobility and improved on dynamic balance. At 1-mo posttest, most mobility measures had improved relative to baseline. However, YD showed executive function and overall motor decline 6 mos after intervention. Adapted tango may have temporarily slowed disease progression and improved or maintained mobility and cognition. Gains were poorly maintained after 6 mos. Further study is warranted.

Disentangling brain functional network remodeling in corticobasal syndrome - A multimodal MRI study.

OBJECTIVE: The clinical diagnosis of corticobasal syndrome (CBS) represents a challenge for physicians and reliable diagnostic imaging biomarkers would support the diagnostic work-up. We aimed to investigate the neural signatures of CBS using multimodal T1-weighted and resting-state functional magnetic resonance imaging (MRI). METHODS: Nineteen patients with CBS (age 67.0 ± 6.0 years; mean±SD) and 19 matched controls (66.5 ± 6.0) were enrolled from the German Frontotemporal Lobar Degeneration Consortium. Changes in functional connectivity and structure were respectively assessed with eigenvector centrality mapping complemented by seed-based analysis and with voxel-based morphometry. In addition to mass-univariate statistics, multivariate support vector machine (SVM) classification tested the potential of multimodal MRI to differentiate patients and controls. External validity of SVM was assessed on independent CBS data from the 4RTNI database. RESULTS: A decrease in brain interconnectedness was observed in the right central operculum, middle temporal gyrus and posterior insula, while widespread connectivity increases were found in the anterior cingulum, medial superior-frontal gyrus and in the bilateral caudate nuclei. Severe and diffuse gray matter volume reduction, especially in the bilateral insula, putamen and thalamus, characterized CBS. SVM classification revealed that both connectivity (area under the curve 0.81) and structural abnormalities (0.80) distinguished CBS from controls, while their combination led to statistically non-significant improvement in discrimination power, questioning the additional value of functional connectivity over atrophy. SVM analyses based on structural MRI generalized moderately well to new data, which was decisively improved when guided by meta-analytically derived disease-specific regions-of-interest. CONCLUSIONS: Our data-driven results show impairment of functional connectivity and brain structure in CBS and explore their potential as imaging biomarkers.

The Effects of Lee - Silverman Voice Treatment on Voice and Swallowing Functions in a Case with Bilateral Striopallidodentate Calcinosis.

BACKGROUND: Bilateral striopallidodentate calcinosis (BSPDC) is a rare neurodegenerative disorder characterized by abnormal calcium accumulation in the basal ganglia, dentate nucleus, and semioval center. Speech, voice, and swallowing abnormalities can be associated with the disease. However, there are a limited number of studies regarding the speech and swallowing characteristics of this disease in the literature. Lee-Silverman voice therapy (LSVT-LOUD) is a structured speech therapy method that can be used to treat neurogenic conditions. AIMS: The main purpose of this article was to document the effects of LSVT-LOUD on voice and swallowing functions in a case of BSPDC. DESIGN: Case report. METHODS: A comprehensive voice and swallowing evaluation, including objective methods, was conducted before therapy and at post-therapy follow-ups (FU) after 3 months and 6 months. RESULTS: The voice and swallowing parameters were substantially improved at the 3-month FU; at the 6-month FU, the improvement in swallowing function was still preserved; however, the improvement in voice function had regressed. CONCLUSION: LSVT-LOUD may improve the voice and swallowing functions of patients with BSPDC. However, long-term retention of the effects of LSVT-LOUD should be investigated in future studies.

Corticobasal degeneration.

Corticobasal degeneration (CBD) is a rare neurodegenerative disease characterized by the predominance of pathological 4 repeat tau deposition in various cell types and anatomical regions. Corticobasal syndrome (CBS) is one of the clinical phenotypes associated with CBD pathology, manifesting as a progressive asymmetric akinetic-rigid, poorly levodopa-responsive parkinsonism, with cerebral cortical dysfunction. CBD can manifest as several clinical phenotypes, and similarly, CBS can also have a pathologic diagnosis other than CBD. This chapter discusses the clinical manifestations of pathologically confirmed CBD cases, the current diagnostic criteria, as well as the pathologic and neuroimaging findings of CBD/CBS. At present, therapeutic options for CBD remain symptomatic. Further research is needed to improve the clinical diagnosis of CBD, as well as studies on disease-modifying therapies for this relentlessly progressive neurodegenerative disorder.