Familial encephalopathy with neuroserpin inclusion bodies

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a disorder that causes progressive dysfunction of the brain (encephalopathy). This condition is characterized by a loss of intellectual functioning (dementia) and seizures.

The first signs of intellectual impairment in individuals with FENIB may be problems with attention and concentration. Affected individuals may have trouble regulating their thoughts or speech. As the condition progresses, personality changes develop, and judgment, insight, and memory become impaired. Affected individuals lose the ability to perform the activities of daily living, and most eventually require comprehensive care.

People with FENIB have seizures that involve a sudden, involuntary muscle jerking or twitching (myoclonus). Many also experience at least one other form of seizure, typically generalized seizures that involve a loss of consciousness, muscle rigidity, and convulsions. In rare cases, people with FENIB have prolonged episodes of seizure activity that last several minutes (status epilepticus). In most people with FENIB, anti-seizure medications are not effective. Many people with FENIB have other types of involuntary movement (dyskinesia).

The signs and symptoms of FENIB can appear at any age, and they vary in severity. In severe cases, dementia can appear in childhood or adolescence and is often the first sign of the condition. Less severe cases are characterized by a progressive decline in intellectual functioning that begins in mid- to late adulthood.

People with FENIB have a shortened life expectancy. The earlier the signs and symptoms appear, the greater the impact on life expectancy. Causes of death in people with FENIB include status epilepticus and pneumonia.

FENIB appears to be very rare. The condition was first described in 1999 and at least 13 affected individuals have been reported worldwide. 

FENIB is caused by variants (also called mutations) in the SERPINI1 gene. This gene provides instructions for making a protein called neuroserpin, which is found primarily in nerve cells (neurons). This protein helps neurons divide and mature so they can take on specific functions (differentiation). The connections between neurons (synapses) also need neuroserpin to function properly, which suggests that this protein may be important for learning and memory. 

SERPINI1 gene variants can cause cells to produce an abnormally shaped, unstable form of neuroserpin. Within neurons, these altered neuroserpin proteins attach to one another and form chains (neuroserpin polymers) that clump together to form neuroserpin inclusion bodies. These inclusion bodies disrupt the normal functioning of neurons and ultimately lead to cell death. Additionally, the formation of neruoserpin polymers likely increases the release of calcium ions into the cell. This can lead to certain neurons becoming more active than usual, which may trigger the abnormal brain activity that is associated with seizures in people with FENIB. 

The encephalopathy and dementia in people with FENIB occur as neuroserpin inclusion bodies accumulate in the brain, causing the gradual loss of neurons. Larger numbers of inclusion bodies cause more severity of the neurological problems. People with severe FENIB tend to have more widespread neuron loss than those with milder cases of FENIB. 

Genetic Testing Information

• Genetic Testing Registry: Familial encephalopathy with neuroserpin inclusion bodies

Genetic and Rare Diseases Information Center

• Familial encephalopathy with neuroserpin inclusion bodies

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• ENCEPHALOPATHY, FAMILIAL, WITH NEUROSERPIN INCLUSION BODIES; FENIB

Scientific Articles on PubMed

• PubMed

• Bradshaw CB, Davis RL, Shrimpton AE, Holohan PD, Rea CB, Fieglin D, Kent P, Collins GH. Cognitive deficits associated with a recently reported familial neurodegenerative disease: familial encephalopathy with neuroserpin inclusion bodies. Arch Neurol. 2001 Sep;58(9):1429-34. doi: 10.1001/archneur.58.9.1429. Citation on PubMed
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• Gourfinkel-An I, Duyckaerts C, Camuzat A, Meyrignac C, Sonderegger P, Baulac M, Brice A. Clinical and neuropathologic study of a French family with a mutation in the neuroserpin gene. Neurology. 2007 Jul 3;69(1):79-83. doi: 10.1212/01.wnl.0000265052.99144.b5. Citation on PubMed
• Hagen MC, Murrell JR, Delisle MB, Andermann E, Andermann F, Guiot MC, Ghetti B. Encephalopathy with neuroserpin inclusion bodies presenting as progressive myoclonus epilepsy and associated with a novel mutation in the Proteinase Inhibitor 12 gene. Brain Pathol. 2011 Sep;21(5):575-82. doi: 10.1111/j.1750-3639.2011.00481.x. Epub 2011 Mar 24. Citation on PubMed
• Miranda E, MacLeod I, Davies MJ, Perez J, Romisch K, Crowther DC, Lomas DA. The intracellular accumulation of polymeric neuroserpin explains the severity of the dementia FENIB. Hum Mol Genet. 2008 Jun 1;17(11):1527-39. doi: 10.1093/hmg/ddn041. Epub 2008 Feb 11. Citation on PubMed or Free article on PubMed Central
• Yang X, Fang Z, Yan L, He X, Luo H, Han Z, Gui J, Cheng M, Jiang L. Role of SERPINI1 pathogenic variants in familial encephalopathy with neuroserpin inclusion bodies: A case report and literature review. Seizure. 2022 Dec;103:137-147. doi: 10.1016/j.seizure.2022.11.008. Epub 2022 Nov 13. Citation on PubMed
• Yepes M, Lawrence DA. Neuroserpin: a selective inhibitor of tissue-type plasminogen activator in the central nervous system. Thromb Haemost. 2004 Mar;91(3):457-64. doi: 10.1160/TH03-12-0766. Citation on PubMed