Encephalopathy familiar with neuroserpin inclusion bodies (Familial encephalopathy With neuroserpin inclusion bodies -FENIB-) - Gen SERPINI1.

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a disorder that leads to encephalopathy and characterized by dementia and seizures. Initially, affected individuals may have difficulty sustaining attention and concentration. They can express thoughts, speech or repetitive movements. As the disease progresses, changes in personality, and reasoning, understanding and memory deteriorate occur. Affected individuals lose the ability to perform activities of daily living, and most will eventually require comprehensive care.

Signs and symptoms of FENIB vary depending on their severity and age of onset. In severe cases, the disease leads to seizures and myoclonic episodes in addition to dementia. These signs may occur from adolescence. Less severe cases are characterized by a progressive decline in intellectual functioning from forty or fifty years old.

This process is due to mutations in the gene SERPINI1, located on the long arm of chromosome 3 (3q26.1). This gene encodes a protein called neuroserpin, which is a kind of serine protease inhibitor (serpin). Serpins help control various kinds of chemical reactions by inhibiting the activity of certain proteins. Neuroserpin inhibits the activity of an enzyme called tissue plasminogen activator (tPA), which plays a role in cell migration, blood clotting and inflammation. As its name suggests, the neuroserpin is involved in the development and function of the nervous system. This protein helps control the growth of neurons, particularly axons required for transmission of nerve impulses. Neuroserpin also plays a role in the development of synapses, as it helps regulate synaptic plasticity, suggesting that it may be important for learning and memory.

They have identified at least four mutations in the gene leading to SERPINI1 family encephalopathy with neuroserpin inclusion bodies (FENIB). Each of these mutations change a single amino acid in the protein coding, leading to an unstable version of neuroserpin. Inside neurons, neuroserpin defective proteins be connected together to form accumulations called inclusion bodies or bodies Collins. These clusters disrupt the normal functioning of cells and ultimately lead to cell death. The gradual loss of neurons in certain parts of the brain leads to progressive dementia in people with FENIB. Furthermore, mutations in the gene SERPINI1 also reduce or eliminate the ability to inhibit tPA neuroserpin to neurons. It is likely to uncontrolled activity of tPA can also contribute to the signs and symptoms of this disease.

Some mutations in the gene leads to SERPINI1 more serious than other forms FENIB. The disease severity and age of onset correlates with the number of bodies within neurons Collins. A mutation, known as neuroserpin Syracuse, is associated with a moderate form of the disease that causes progressive loss of intellectual functioning in the early forty or fifty years old. This genetic change replaces the amino acid serine to proline amino acid at position 49 in the protein neuroserpin (Ser49Pro or S49P). Other mutations in the gene SERPINI1 lead to a more severe form of FENIB characterized by seizures and episodes of myoclonus in addition to dementia. These signs may appear in adolescence. One of these mutations, called Portland neuroserpin, replaces the amino acid serine by the amino acid arginine at position 52 in the protein neuroserpin (Ser52Arg or S52R). Another mutation replaces the amino acid glycine by one of the other two amino acids, glutamic acid , or arginine at position protein 392 (Gly392Glu and Gly392Arg, respectively.) Children with one of these gene changes have a very intense form of the disease It includes myoclonic epilepsy and developmental delay.

This disease is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the disease. In many cases, an affected person has a parent with the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with familial encephalopathy with neuroserpin inclusion bodies (FENIB), by complete PCR amplification of the gene exons SERPINI1, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).