NORD gratefully acknowledges Richard L. Davis MD, PhD, Assistant Professor of Pathology, SUNY Upstate Medical University, for assistance in the preparation of this report.
Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare genetic degenerative disorder affecting the brain and spinal cord, or central nervous system (neurodegenerative disorder). Affected individuals display poor attention and concentration, declining work or academic performance, and language difficulties. Eventually, they experience a global decline in their intellectual abilities (dementia). Memory, however, is relatively well-preserved early in the course of the disease compared to the severe memory deficits that are typical of Alzheimer's disease. Some affected individuals develop additional symptoms such as uncontrolled, irregular muscle contractions and seizures. Changes in mood, such as apathy, depression, or anger frequently occur. Eventually, affected individuals require comprehensive medical care.
The age of onset, rate of progression, and severity of FENIB varies depending on the specific mutation in the neuroserpin gene. All individuals with a given mutation tend to become symptomatic at approximately the same age and to have similar clinical manifestations. The symptoms of FENIB may become apparent as early as the first decade or as late as the fifth or sixth decade of life. Our knowledge of FENIB is limited by the fact that only a few families with FENIB have been described.
When FENIB begins in the fifth or sixth decade, affected individuals typically experience declining cognitive function that affects their ability to work, often resulting in job loss. In addition to deficits in attention, concentration, and language usage, they may develop an impaired ability to judge the spatial relationship between objects (poor visuospatial skills). A striking finding is perseveration, a condition marked by uncontrolled, repetitive behaviors such as continually repeating a word, phrase or gesture. Daily living skills are gradually lost and they become increasingly dependent on family or other care givers. Eventually, most will require comprehensive care in a skilled nursing facility. Other symptoms may include tremor, motor restlessness, dystonia (sustained muscle contractions associated with abnormal, uncontrolled movements and postures) and occasionally seizures. The rate of decline is relatively slow, and with adequate supportive care, patients may survive for many years or even decades.
When FENIB begins earlier in life, from the first to third decade, there are additional neurological symptoms and the disease may progress quite rapidly. Seizures may be the first manifestation, including a syndrome called progressive myoclonic epilepsy (PME). The seizures may be difficult to control with medication, and episodes of status epilepticus, or persistent, repetitive seizures may occur, sometimes resulting in death. In general, an earlier age of onset is associated with more severe symptoms, and the patient may survive for only a few years.
FENIB is caused by mutations of the serine protease inhibitor 1 (SERPINI1) gene. This genetic mutation is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. Most, if not all individuals who carry the mutant SERPINI1 gene will eventually become symptomatic (high penetrance).
Investigators have determined that the SERPINI1 gene is located on the long arm (q) of chromosome 3 (3q26).
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 3q26” refers to band 26 on the long arm of chromosome 3. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The SERPINI1 gene contains instructions for creating (encoding) a protein known as neuroserpin. Neuroserpin is normally found in nerve cells and, although its exact function is not fully understood, it is believed to play a vital role in the development, repair, and maintenance of the central nervous system. In FENIB, mutant neuroserpin proteins link together (a process called polymerization) to form long chains that entangle and aggregate. Microscopically, these aggregates are observed as distinct inclusions called Collins bodies within the nerve cells. Collins bodies are believed to disrupt the normal functioning of affected nerve cells, eventually causing the symptoms of FENIB. As the disorder progresses, more Collins bodies are formed and a greater portion of the central nervous system is affected. The relationship between the accumulation and deposition of neuroserpin in the form of Collins bodies in individuals with FENIB and the subsequent development of characteristic symptoms is not fully understood. More research is necessary to determine exactly how Collins bodies may damage or injure nerve cells.
FENIB affects males and females in equal numbers. Only a few families with this disorder have been reported in the medical literature. FENIB was originally described in the medical literature in 1999. The incidence of FENIB in the general population is unknown. The age of onset of FENIB can be as early as the first decade or as late as the fifth or sixth
A diagnosis of FENIB may be suspected based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms and a variety o. specialized tests that can rule out other conditions. Such tests may include brain imaging studies such as magnetic resonance imaging (MRI), computed tomography (CT) scans, a test that measures the electrical activity of the brain (electroencephalogram [EEG]), and neuropsychological assessment. The diagnosis of FENIB is usually confirmed by a physician who specializes in the treatment of neurological disorders. The principal confirmatory test is genetic analysis to identify the causative mutation in the SERPINI1 gene or more rarely the identification of Collins bodies in a brain tissue biopsy specimen.
The treatment of FENIB is directed toward the specific symptoms that are apparent in each individual. Individuals with progressive dementia often experience frustration, anxiety, and depression due to their decreasing ability to function in certain aspects of their lives. These frustrations may be minimized by maintaining a stable home environment and a structured routine that does not place excessive demands on the affected individual.
Eventually, most individuals with FENIB require comprehensive medical care as provided in a nursing home. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Miranda E, MacLeod I, Davies MJ, et al. The intracellular accumulation of polymeric neuroserpin explains the severity of the dementia FENIB. Hum Mol Genet. 2008;17:1527-1539.
Gourfinkel-An I, Duyckaerts C, Camuzat A, et al. Clinical and neuropathologic study of a French family with a mutation in the neuroserpin gene. Neuology. 2007;69:79-83.
Davis RL, Shrimpton AE, Carrell RW, et al. Association between conformational mutations in neuroserpin and onset and severity of dementia. Lancet. 2002;359:2242-2247.
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