A case report of a patient with primary familial brain calcification with a PDGFRB genetic variant.

Fahr's disease, or primary familial brain calcification (PFBC), is a rare genetic neurologic disease characterized by abnormal calcification of the basal ganglia, subcortical white matter and cerebellum. Common clinical features include parkinsonism, neuropsychiatric symptoms, and cognitive decline. Genes implicated in Fahr's disease include PDGFB, PDGFRB, SLC20A2, XPR1, MYORG, and JAM2. We present the case of a 51-year-old woman who developed subacute cognitive and behavioral changes primarily affecting frontal-subcortical pathways and parkinsonism in association with extensive bilateral calcifications within the basal ganglia, subcortical white matter, and cerebellum on neuroimaging. Relevant family history included a paternal aunt with parkinsonism at age 50. Normal parathyroid hormone and calcium levels in the patient's serum ruled out hypoparathyroidism or pseudohypoparathyroidism as causes for the intracranial calcifications. Genetic panel sequencing revealed a variant of unknown significance in the PDGFRB gene resulting in a p.Arg919Gln substitution in the tyrosine kinase domain of PDGFRB protein. To our knowledge this is the first report of a p.Arg919Gln variant in the PDGFRB gene associated with PFBC. Although co-segregation studies were not possible in this family, the location of the variant is within the tyrosine kinase domain of PDGFRB and pathogenicity calculators predict it is likely to be pathogenic. This report adds to the list of genetic variants that warrant functional analysis and could underlie the development of PFBC, which may help to further our understanding of its pathogenesis and the development of targeted therapies for this disorder.

Pontine stroke in a patient with Chronic Progressive External Ophthalmoplegia (CPEO): a case report.

BACKGROUND: Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease with slowly progressive bilateral ptosis and symmetric ophthalmoplegia due to a genetic mutation that results in defective oxidative phosphorylation. Common genes that are implicated in CPEO include POLG, RRM2B, ANT1 and PEO1/TWNK. Here, we report a case of a patient diagnosed with CPEO caused by a novel mutation in PEO/TWNK after suffering a right pontine stroke. CASE PRESENTATION: A 70-year-old man with history of chronic progressive bilateral ptosis and ophthalmoplegia, as well as similar ocular symptoms in his father and grandfather, presented with acute onset of right hemifacial weakness and dysarthria. Brain MRI revealed an acute ischemic stroke in the right dorsal pons. The patient did not experience diplopia due to severe baseline ophthalmoplegia. Creatine kinase was elevated to 6,080 U/L upon admission and normalized over the course of one week; electromyography revealed a myopathic process. Genetic testing revealed a novel mutation c.1510G > A (p. Ala504Thr) in a pathogenic "hot spot" of the C10ORF2 gene (TWNK/PEO1), which is associated with CPEO. The mutation appears to be deleterious using several pathogenicity prediction tools. CONCLUSIONS: This case report describes a patient with late-onset CPEO caused by a novel, likely pathogenic, mutation in the TWNK gene. Although the patient presented with a pontine stroke, it manifested with solely new onset facial palsy, as he had a severe underlying ophthalmoplegia secondary to his CPEO.

99m Technetium-pyrophosphate bone scan: A potential biomarker for the burden of transthyretin amyloidosis in skeletal muscle: A preliminary study.

INTRODUCTION/AIMS: Transthyretin amyloidosis (ATTR) proteins can infiltrate skeletal muscle and infrequently cause a myopathy. 99m Technetium-pyrophosphate (99m Tc-PYP) is a validated biomarker for cardiac involvement in variant and wild-type ATTR (ATTRv and ATTRwt, respectively). The aim of this study was to test the hypothesis that 99m Tc-PYP is a biomarker for muscle burden of ATTR. METHODS: Radioisotope uptake in the deltoid muscles of patients with ATTR was compared to uptake in control subjects without amyloidosis in a retrospective study. 99m Tc-PYP scans were evaluated in 11 patients with ATTR (7 ATTRv, 4 ATTRwt) and 14 control subjects. Mean count (MC) values were measured in circular regions of interest (ROIs) 2.5-3.8 cm2 in area. Tracer uptake was quantified in the heart, contralateral chest (CC), and deltoid muscles. RESULTS: Tracer uptake was significantly higher over the deltoids and heart but not the CC, in patients with ATTR than in control subjects. MC values were 120.1 ± 43.7 (mean ± SD) in ATTR patients and 78.9 ± 20.4 in control subjects over the heart (p = 0.005), 73.3± 21.0 and 63.5 ± 14.4 over CC (p = 0.09), and 37.0 ± 11.7 and 26.0 ± 7.1 averaged over both deltoid muscles (p = 0.014). DISCUSSION: 99m Tc-PYP is a potential biomarker for ATTR amyloid burden in skeletal muscle.

EEG background frequency is associated with discharge outcomes in non-ICU hospitalized patients with COVID-19.

Objective: To assess risk factors for encephalopathy in non-ICU hospitalized patients with COVID-19 and the effect of encephalopathy on short-term outcomes. Methods: We collected clinical and electrophysiological characteristics of fifty patients with COVID-19 infection admitted to a ward service and who had an electroencephalogram (EEG) performed. Associations with short-term outcomes including hospital length of stay and discharge disposition were determined from univariate and multivariate statistical analysis. Results: Clinical delirium was associated with encephalopathy on EEG, cefepime use was associated with increased length of stay, and of all factors analyzed, background frequency on EEG alone was correlated with discharge disposition. Conclusion: Encephalopathy is one of the major determinants of short-term outcomes in hospitalized non-ICU patients with COVID-19.

A Novel TBK1 Variant (Lys694del) Presenting With Corticobasal Syndrome in a Family With FTD-ALS Spectrum Diseases: Case Report.

Several variants of the TANK-Binding Kinase 1 (TBK1) gene have been associated with frontotemporal dementia - amyotrophic lateral sclerosis (FTD-ALS) spectrum diseases. Corticobasal syndrome (CBS) is characterized by asymmetric limb rigidity, dystonia or myoclonus, in association with speech or limb apraxia, cortical sensory deficit, and/or alien limb. It can result from a variety of underlying pathologies and although typically sporadic, it has been occasionally associated with MAPT and GRN variants. We describe here the proband of a family with multiple occurrences of FTD-ALS spectrum disease who developed an isolated right-sided primary asymmetric akinetic-rigid syndrome and subsequent speech and cognitive dysfunction associated with contralateral anterior temporal lobe atrophy on MRI and corresponding hypometabolism by FDG-PET. Genetic testing revealed a novel Lys694del variant of the TBK1 gene and Type A TDP-43 pathology in a predominantly frontotemporal distribution contralateral to the affected side. To our knowledge this is the first report of CBS as the initial expression of a TBK1 variant. This case emphasizes the importance of considering TBK1 genetic screening in patients with CBS, as this may be an underrepresented population on the spectrum of genetic FTD-ALS.

Progressive Multiple Mononeuropathy in a Patient With Familial Transthyretin Amyloidosis After Liver Transplantation.

ABSTRACT: Valine 122 isoleucine (V122I) is the most common mutation associated with familial transthyretin-related amyloidosis (fATTR) in the metropolitan United States. V122I-related fATTR usually presents with cardiomyopathy. When polyneuropathy is encountered, it is usually mild, distal, and axonal in nature. Although liver transplantation improves survival for fATTR neuropathy patients, neuropathy may progress post liver transplantation because of the deposition of wild-type transthyretin. We report a patient with homozygous V122I mutation who presented with asymmetrical, upper limb predominant neuropathy rather early in his disease course, which progressed for a period of 5 years after liver transplantation before stabilization with the initiation of patisiran.

Challenging Cases of Neurocognitive Disorders.

Dementia is broadly defined by DSM-V as cognitive decline from a previous level that impacts the patient's functioning at work or play. This broad definition does not provide information about the underlying disease process, an aspect of clinical care that is of increasing importance, as therapeutic development inches closer to effective disease-modifying treatments. The most common neurodegenerative dementias include Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, and Parkinson's disease dementia. Although rare, the prion diseases constitute an important group of dementias that should be routinely considered in the evaluation. Over the last two decades, advances in neuroimaging, biomarker development, and neurogenetics have not only led to a better understanding of the biology of these diseases, but they have improved our awareness of less common clinical subtypes of dementia. As such, to best define the disease process, the evaluation of a patient with cognitive decline requires attention to a myriad of disease aspects, such as the primary symptom at onset (memory, language, visual perception, praxis, etc.), the age at onset (younger or older than 65 years), the rate of disease progression (weeks to months or years), the cognitive and behavioral profile (neuropsychological assessment), and involvement of physical findings. We present here three cases that highlight the decision-making process in the evaluation of patients with atypical presentations of dementia.