Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits.

The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures. In Alzheimer\u27s disease (AD) and epilepsy, both of which are accompanied by recurrent seizures, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG). However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood. Here we report an epigenetic mechanism through which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that ΔFosB, a highly stable transcription factor, is induced in the hippocampus in mouse models of AD and seizures, in which it binds and triggers histone deacetylation at the promoter of the calbindin gene (Calb1) and downregulates Calb1 transcription. Notably, increasing DG calbindin levels, either by direct virus-mediated expression or inhibition of ΔFosB signaling, improves spatial memory in a mouse model of AD. Moreover, levels of ΔFosB and calbindin expression are inversely related in the DG of individuals with temporal lobe epilepsy (TLE) or AD and correlate with performance on the Mini-Mental State Examination (MMSE). We propose that chronic suppression of calbindin by ΔFosB is one mechanism through which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures

GARS- related disease in infantile spinal muscular atrophy: Implications for diagnosis and treatment

The majority of patients with spinal muscular atrophy (SMA) identified to date harbor a biallelic exonic deletion of SMN1. However, there have been reports of SMA- like disorders that are independent of SMN1, including those due to pathogenic variants in the glycyl- tRNA synthetase gene (GARS1). We report three unrelated patients with de novo variants in GARS1 that are associated with infantile- onset SMA (iSMA). Patients were ascertained during inpatient hospital evaluations for complications of neuropathy. Evaluations were completed as indicated for clinical care and management and informed consent for publication was obtained. One newly identified, disease- associated GARS1 variant, identified in two out of three patients, was analyzed by functional studies in yeast complementation assays. Genomic analyses by exome and/or gene panel and SMN1 copy number analysis of three patients identified two previously undescribed de novo missense variants in GARS1 and excluded SMN1 as the causative gene. Functional studies in yeast revealed that one of the de novo GARS1 variants results in a loss- of- function effect, consistent with other pathogenic GARS1 alleles. In sum, the patients’ clinical presentation, assessments of previously identified GARS1 variants and functional assays in yeast suggest that the GARS1 variants described here cause iSMA. GARS1 variants have been previously associated with Charcot- Marie- Tooth disease (CMT2D) and distal SMA type V (dSMAV). Our findings expand the allelic heterogeneity of GARS- associated disease and support that severe early- onset SMA can be caused by variants in this gene. Distinguishing the SMA phenotype caused by SMN1 variants from that due to pathogenic variants in other genes such as GARS1 significantly alters approaches to treatment.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154914/1/ajmga61544_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154914/2/ajmga61544.pd

Avengers Assemble! - Video

A five-year-old otherwise healthy boy presented with a two-week history of behavioral changes, nausea, vomiting, headache, and subacute vision loss bilaterally. Six weeks prior to presentation to our hospital, he had presented to an outside hospital with esotropia and blurred vision in both eyes. At that time, he had bilateral 4+ optic nerve edema. MRI demonstrated a right mesiotemporal lobe arachnoid cyst. Opening pressure on lumbar puncture was elevated, and the patient underwent an arachnoid cyst fenestration. He improved clinically for two weeks but subsequently had a rapid decline in vision and mental status. Repeat MRI showed global enhancement of the leptomeninges, especially of the right mesiotemporal lobe near the arachnoid cyst, and enhancement of both optic nerves and the optic chiasm. Repeat lumbar puncture showed an opening pressure >55cm H2O. He was transferred to our hospital for further care. Initial ophthalmologic examination at our hospital revealed 20/400 visual acuity in the right eye and 20/800 visual acuity in the left eye. Visual fields were constricted to approximately 10-degree nasal islands bilaterally. Motility and alignment were normal. Ophthalmoscopy revealed bilateral 4+ optic disc edema with surrounding peripapillary retinal edema. Given the significant bilateral vision loss, an optic nerve sheath fenestration was attempted, but engorgement of the ophthalmic vessels prevented completion of the procedure. Repeat lumbar puncture showed an opening pressure again of >55cm H2O. An extraventricular drain was placed and dura was biopsied, revealing benign dense connective tissue. An infectious, autoimmune, and paraneoplastic laboratory work-up was unrevealing, and CSF cytology was negative for malignancy and infection. Repeat MRI brain and spine revealed a possible primary tumor involving the right mesiotemporal lobe and hippocampus and multifocal areas of leptomeningeal enhancement outlining the spinal cord conus, raising a question of metastatic disease. Spinal cord arachnoid biopsy was performed, showing histiocytic infiltration with reactive changes. An additional procedure was performed

Avengers Assemble! - Path PPT

A five-year-old otherwise healthy boy presented with a two-week history of behavioral changes, nausea, vomiting, headache, and subacute vision loss bilaterally. Six weeks prior to presentation to our hospital, he had presented to an outside hospital with esotropia and blurred vision in both eyes. At that time, he had bilateral 4+ optic nerve edema. MRI demonstrated a right mesiotemporal lobe arachnoid cyst. Opening pressure on lumbar puncture was elevated, and the patient underwent an arachnoid cyst fenestration. He improved clinically for two weeks but subsequently had a rapid decline in vision and mental status. Repeat MRI showed global enhancement of the leptomeninges, especially of the right mesiotemporal lobe near the arachnoid cyst, and enhancement of both optic nerves and the optic chiasm. Repeat lumbar puncture showed an opening pressure >55cm H2O. He was transferred to our hospital for further care. Initial ophthalmologic examination at our hospital revealed 20/400 visual acuity in the right eye and 20/800 visual acuity in the left eye. Visual fields were constricted to approximately 10-degree nasal islands bilaterally. Motility and alignment were normal. Ophthalmoscopy revealed bilateral 4+ optic disc edema with surrounding peripapillary retinal edema. Given the significant bilateral vision loss, an optic nerve sheath fenestration was attempted, but engorgement of the ophthalmic vessels prevented completion of the procedure. Repeat lumbar puncture showed an opening pressure again of >55cm H2O. An extraventricular drain was placed and dura was biopsied, revealing benign dense connective tissue. An infectious, autoimmune, and paraneoplastic laboratory work-up was unrevealing, and CSF cytology was negative for malignancy and infection. Repeat MRI brain and spine revealed a possible primary tumor involving the right mesiotemporal lobe and hippocampus and multifocal areas of leptomeningeal enhancement outlining the spinal cord conus, raising a question of metastatic disease. Spinal cord arachnoid biopsy was performed, showing histiocytic infiltration with reactive changes. An additional procedure was performed

Avengers Assemble! - Presentation PPT

A five-year-old otherwise healthy boy presented with a two-week history of behavioral changes, nausea, vomiting, headache, and subacute vision loss bilaterally. Six weeks prior to presentation to our hospital, he had presented to an outside hospital with esotropia and blurred vision in both eyes. At that time, he had bilateral 4+ optic nerve edema. MRI demonstrated a right mesiotemporal lobe arachnoid cyst. Opening pressure on lumbar puncture was elevated, and the patient underwent an arachnoid cyst fenestration. He improved clinically for two weeks but subsequently had a rapid decline in vision and mental status. Repeat MRI showed global enhancement of the leptomeninges, especially of the right mesiotemporal lobe near the arachnoid cyst, and enhancement of both optic nerves and the optic chiasm. Repeat lumbar puncture showed an opening pressure >55cm H2O. He was transferred to our hospital for further care. Initial ophthalmologic examination at our hospital revealed 20/400 visual acuity in the right eye and 20/800 visual acuity in the left eye. Visual fields were constricted to approximately 10-degree nasal islands bilaterally. Motility and alignment were normal. Ophthalmoscopy revealed bilateral 4+ optic disc edema with surrounding peripapillary retinal edema. Given the significant bilateral vision loss, an optic nerve sheath fenestration was attempted, but engorgement of the ophthalmic vessels prevented completion of the procedure. Repeat lumbar puncture showed an opening pressure again of >55cm H2O. An extraventricular drain was placed and dura was biopsied, revealing benign dense connective tissue. An infectious, autoimmune, and paraneoplastic laboratory work-up was unrevealing, and CSF cytology was negative for malignancy and infection. Repeat MRI brain and spine revealed a possible primary tumor involving the right mesiotemporal lobe and hippocampus and multifocal areas of leptomeningeal enhancement outlining the spinal cord conus, raising a question of metastatic disease. Spinal cord arachnoid biopsy was performed, showing histiocytic infiltration with reactive changes. An additional procedure was performed

Avengers Assemble! - Abstract

A five-year-old otherwise healthy boy presented with a two-week history of behavioral changes, nausea, vomiting, headache, and subacute vision loss bilaterally. Six weeks prior to presentation to our hospital, he had presented to an outside hospital with esotropia and blurred vision in both eyes. At that time, he had bilateral 4+ optic nerve edema. MRI demonstrated a right mesiotemporal lobe arachnoid cyst. Opening pressure on lumbar puncture was elevated, and the patient underwent an arachnoid cyst fenestration. He improved clinically for two weeks but subsequently had a rapid decline in vision and mental status. Repeat MRI showed global enhancement of the leptomeninges, especially of the right mesiotemporal lobe near the arachnoid cyst, and enhancement of both optic nerves and the optic chiasm. Repeat lumbar puncture showed an opening pressure >55cm H2O. He was transferred to our hospital for further care. Initial ophthalmologic examination at our hospital revealed 20/400 visual acuity in the right eye and 20/800 visual acuity in the left eye. Visual fields were constricted to approximately 10-degree nasal islands bilaterally. Motility and alignment were normal. Ophthalmoscopy revealed bilateral 4+ optic disc edema with surrounding peripapillary retinal edema. Given the significant bilateral vision loss, an optic nerve sheath fenestration was attempted, but engorgement of the ophthalmic vessels prevented completion of the procedure. Repeat lumbar puncture showed an opening pressure again of >55cm H2O. An extraventricular drain was placed and dura was biopsied, revealing benign dense connective tissue. An infectious, autoimmune, and paraneoplastic laboratory work-up was unrevealing, and CSF cytology was negative for malignancy and infection. Repeat MRI brain and spine revealed a possible primary tumor involving the right mesiotemporal lobe and hippocampus and multifocal areas of leptomeningeal enhancement outlining the spinal cord conus, raising a question of metastatic disease. Spinal cord arachnoid biopsy was performed, showing histiocytic infiltration with reactive changes. An additional procedure was performed

A Myel-In, a Long Way to Go (Video)

A 9-year-old previously healthy female with two recent admissions for presumed diagnosis of ADEM re-presented with persistent headache and ataxic gait. During her initial admissions, she presented with fever, acute onset of ataxia, facial asymmetry and abnormal eye movements. Inpatient ocular exam showed normal vision and fundus in both eyes, but her motility exam revealed right 6th and 7th nerve palsy. MRI showed dorsal brainstem and right cerebellar lesions concerning for ADEM, and additional lesions extending to the 4th ventricle with associated mass effect. After extensive negative infectious disease/rheumatology work ups, she was treated with a course of IVIG and steroids during each admission, and both times demonstrated considerable clinical response with near total resolution of her ataxia and cranial nerve deficits. Four days after 2nd discharge, she presented with symptoms of slurred speech, diplopia, ataxia and severe occipital headache. On examination, she had 20/20 vision and full visual fields bilaterally. She was noted to have new horizontal nystagmus, and right 4th, 6th and 7th nerve palsy. MRI demonstrated worsening of brainstem/cerebellar lesions, new diffusion restriction in the pons concerning for ischemic infarction, and an acute communicating hydrocephalus requiring emergent EVD placement. These new findings shifted the diagnostic focus to potential etiologies of stroke including CLIPPERS, CNS vasculitis, infection, and rheumatologic disease, though extensive work up was unrevealing, including cerebral and conventional angiogram which were normal. Given the uncertainty of diagnosis, a novel plasma detection test for microbial cell-free DNA (cfDNA) identified free DNA from Cladophialophora bantiana fungi. A brain biopsy was performed with gross visualization of intraventricular pus and black, web-like material. Histopathology confirmed branching hyphae, and fungal PCR testing was positive for Cladophialophora bantiana, which validated the cfDNA test. Anti-fungal treatment was initiated aystemically, and locally with novel intraventricular approach to directly target the ventricular fungal burden