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Last update 08 May 2025

Familial Encephalopathy With Neuroserpin Inclusion Bodies

Last update 08 May 2025

Basic Info

Synonyms

ENCEPHALOPATHY, FAMILIAL, WITH COLLINS BODIES, ENCEPHALOPATHY, FAMILIAL, WITH NEUROSERPIN INCLUSION BODIES, Encephalopathy, Familial, With Neuroserpin Inclusion Bodies

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Introduction

A rare serpinopathy characterized by progressive myoclonus epilepsy and/or pre-senile dementia with prominent frontal-lobe features and relative sparing of recall memory. In addition, other neurological manifestations like cerebellar symptoms and pyramidal signs may be present. Age of onset is variable, the disease having been reported in children as well as elderly patients. Neuropathological examination reveals the typical neuronal inclusions of mutated neuroserpin (Collins bodies).

Clinical Trials associated with Familial Encephalopathy With Neuroserpin Inclusion Bodies

NCT00916903

/ TerminatedNot ApplicableIIT

Genetic Disease Gene Identification

This is a a study to identify inherited disease genes. The study will use molecular techniques to map genetic diseases using techniques such as Affymetrix SNP chips. The powerful combination of the information generated by the Human Genome Project and technical advances such as microarrays enables attempts to identify genes responsible for inherited disorders more possible than ever before. Starting with even modest pedigrees of only a few individuals, or even single individuals, it is possible to identify the gene(s) involved. It is proposed to collect up to 20 ml of peripheral blood and/or buccal cell samples from subjects and relevant family members. Currently the following disorders are approved for investigation.
The current list of disorders:
Aarskog-Scott syndrome, Café-au-Lait spots, Cerebral cavernous malformation, delXp, del2q, del10p, del11q, del12p, del13q, del14q, del16q, del17q, del18q, del Xp21, Choreoathetosis, Congenital Vertical Talus (CVT), Clubfoot, Tarsal coalition and other congenital limb deformities, Cystic Fibrosis (CF)-like disease, Desbuquois syndrome, Droopy Eyelid syndrome (Ptosis), Fanconi-Bickel syndrome (FBS), FENIB (familial encephalopathy with neuroserpin inclusion bodies), FG syndrome, Idiopathic generalised epilepsy (IGE), Renpenning syndrome, transient neonatal diabetes with 6q UPD, translocation (13;14), translocation (3;8), translocation (2;18), Uncharacterized familial dementia and X-linked mental retardation (XLMR).

Start Date01 Oct 2005

Sponsor / Collaborator

SUNY Upstate Medical University

NCT00006176

/ CompletedNot ApplicableIIT

Clinical, Molecular and Biochemical Characterization of Familial Encephalopathy With Neuroserpin Inclusion Bodies

The purpose of this study is to learn more about the medical problems and the genetic factors involved in a recently defined form of inherited dementia called "familial dementia with neuroserpin inclusion bodies (FDNIB)." Abnormal substances in nerve cells of patients with this disease affect brain and nervous system function, causing confusion, memory decline and impaired cognition (thinking ability). Patients also develop movement disorders and, possibly, seizures. Symptoms begin in midlife, between 45 and 55 years of age.
Patients with FDNIB and family members 18 years of age or older at risk for the disease may be eligible for this 3-year study.
Participants will have a medical and family history and review of medical records; interview with a medical geneticist (specialist in genetics); physical, neurological and psychiatric examinations; and the following tests and procedures:
Blood tests to assess general health
Chest and skull X-rays
Electrocardiogram (EKG)-record of the electrical activity of the heart using electrodes placed on the chest
Electroencephalogram (EEG)-record of the electrical activity of the brain using electrodes placed on the head
Ultrasound of the abdomen-imaging of abdominal organs using sound waves
Brain magnetic resonance imaging (MRI)-imaging of the brain using a strong magnetic field and radio waves
Hearing evaluation
Assessment of performance of daily living activities
Single photon emission computed tomography (SPECT)-imaging of brain metabolism and blood flow using a radioactive substance injected into a vein
The evaluation will be done over a 3- to 4-day period. At their completion, participants will meet with a physician and a genetics counselor to discuss the clinically significant findings. Participants may be asked to return for follow-up evaluations every 6 months to a year (depending on the individual's condition) for 3 years.

Start Date10 Aug 2000

Sponsor / Collaborator

National Human Genome Research Institute

100 Clinical Results associated with Familial Encephalopathy With Neuroserpin Inclusion Bodies

100 Translational Medicine associated with Familial Encephalopathy With Neuroserpin Inclusion Bodies

0 Patents (Medical) associated with Familial Encephalopathy With Neuroserpin Inclusion Bodies

Literatures (Medical) associated with Familial Encephalopathy With Neuroserpin Inclusion Bodies

01 Mar 2025·Molecular Therapy Nucleic Acids

Modeling and correction of protein conformational disease in iPSC-derived neurons through personalized base editing

Article

Author: Yang, Qiaoyan ; Devinsky, Orrin ; Zhang, Qinkun ; Konishi, Colin T ; Pressler, Mariel ; Long, Chengzu ; Butola, Tanvi ; Mulaiese, Nancy ; Kagan, Dana ; Basu, Jayeeta ; Dirvin, Brooke G

Altered protein conformation can cause incurable neurodegenerative disorders. Mutations in SERPINI1, the gene encoding neuroserpin, can alter protein conformation resulting in cytotoxic aggregation leading to neuronal death. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare autosomal dominant progressive myoclonic epilepsy that progresses to dementia and premature death. We developed HEK293T and induced pluripotent stem cell (iPSC) models of FENIB, harboring a patient-specific pathogenic SERPINI1 variant or stably overexpressing mutant neuroserpin fused to GFP (MUT NS-GFP). Here, we utilized a personalized adenine base editor (ABE)-mediated approach to correct the pathogenic variant efficiently and precisely to restore neuronal dendritic morphology. ABE-treated MUT NS-GFP cells demonstrated reduced inclusion size and number. Using an inducible MUT NS-GFP neuron system, we identified early prevention of toxic protein expression allowed aggregate clearance, while late prevention halted further aggregation. To address several challenges for clinical applications of gene correction, we developed a neuron-specific engineered virus-like particle to optimize neuronal ABE delivery, resulting in higher correction efficiency. Our findings provide a targeted strategy that may treat FENIB and potentially other neurodegenerative diseases due to altered protein conformation such as Alzheimer's and Huntington's diseases.

01 Feb 2025·Drug Development Research

An Inducible Neural Stem Progenitor Cell Model for Testing Therapeutic Interventions Against Neurodegeneration FENIB

Article

Author: Bonato, Francesca ; Seneci, Pierfausto ; Passarella, Daniele ; Serangeli, Ilaria ; Sabato, Valentina ; Giustini, Alessandro ; Miranda, Elena ; Quintiliani, Anna ; Lupo, Giuseppe ; Maiocchi, Alice ; Pedrini, Martina

ABSTRACTFamilial encephalopathy with neuroserpin inclusion bodies (FENIB) is a neurodegenerative pathology caused by accumulation of mutant neuroserpin (NS) polymers inside the endoplasmic reticulum (ER) of neurons, leading to cellular toxicity and neuronal death. To date, there is no cure for FENIB, and only palliative care is available for FENIB patients, underlining the urgency to develop therapeutic strategies. The purpose of this work was to create a cellular system designed for testing small molecules able to reduce the formation of NS polymers. Our results show the generation and characterisation of a novel cell culture model for FENIB based on neural stem progenitor cells (NPCs) with inducible expression of either wild type (WT) or G392E NS, a variant that causes severe FENIB. We also report the use of these novel cell lines to explore the effects of four different proteolysis targeting chimaera (PROTAC) compounds, small bivalent molecules engineered to bind to the E3 ubiquitin ligase cereblon, and to NS through a recruiting motif based on the small molecule embelin. This approach aims to enhance the degradation of mutant NS after retro‐translocation to the cytosol by facilitating its targeting to the proteasome. Our results show little toxicity and no variation in NS levels with any of the compounds tested. In conclusion, this work sets the basis for future attempts to identify molecules able to prevent NS accumulation inside the ER of cultured cells.

22 Dec 2022·Bioscience Reports

Strand 1A variant in neuroserpin shows increased aggregation and no loss of inhibition: implication in ameliorating polymerization to retain activity

Article

Author: Fatima, Sana ; Ahmad, Tahif ; Jairajpuri, Mohamad Aman ; Khan, Yasmeen ; Ansari, Shoyab ; Ahamad, Shahzaib ; Khan, Abdul Burhan ; Gupta, Dinesh

AbstractNeuroserpin (NS) is predominantly expressed in the brain and is the primary inhibitor of tissue plasminogen activator (tPA). NS variants are associated with the neurogenerative disease termed familial encephalopathy with neuroserpin inclusion bodies (FENIB). The disease is characterized by variable age of onset and severity. The reactive center loop (RCL) insertion-based inhibitory mechanism of NS requires a coordinated conformational change leading to a shift in the strands of the β-sheet A and movement of helix F. Strand 1A is connected to the helix F at its C terminal end and with the strand 2A at its N terminal, both these domain move for accommodating the inserting loop; therefore, a variant that influences their movement may alter the inhibition rates. A molecular dynamic simulation analysis of a H138C NS variant from strand 1A showed a large decrease in conformational fluctuations as compared with wild-type NS. H138 was mutated, expressed, purified and a native-PAGE and transmission electron microscopy (TEM) analysis showed that this variant forms large molecular weight aggregates on a slight increase in temperature. However, a circular dichroism analysis showed its secondary structure to be largely conserved. Surprisingly, its tPA inhibition activity and complex formation remain unhindered even after the site-specific labeling of H138C with Alexa fluor C5 maleimide. Further, a helix F-strand 1A (W154C-H138C) double variant still shows appreciable inhibitory activity. Increasingly, it appears that aggregation and not loss of inhibition is the more likely cause of shutter region-based variants phenotypes, indicating that hindering polymer formation using small molecules may retain inhibitory activity in pathological variants of NS.

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Familial Encephalopathy With Neuroserpin Inclusion Bodies

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