Encephalopathy, Familial, With Neuroserpin Inclusion Bodies

A number sign (#) is used with this entry because of evidence that familial encephalopathy with neuroserpin inclusion bodies (FENIB) is caused by heterozygous mutation in the SERPINI1 gene (602445) on chromosome 3q26.

Clinical Features

Davis et al. (1999) described familial encephalopathy with neuroserpin inclusion bodies (FENIB), an autosomal dominant form of dementia, characterized histologically by unique neuronal inclusion bodies, and biochemically by polymers of the neuron-specific serpin, neuroserpin. The authors reported 2 unrelated Caucasian families living within the United States, both of whom were affected with presenile dementia. In the larger family, affected individuals presented clinically around the fifth decade of life with cognitive decline, including deficits in attention and concentration, response regulation difficulties, and impaired visuospatial skills. Memory was also impaired, but to a lesser degree than is typically seen in patients with Alzheimer disease (AD; 104300). After several years of disease progression, most affected individuals were unable to work and eventually required nursing-home care. The second, much smaller family showed an earlier clinical onset, during the second or third decade of life. Affected individuals presented with both epilepsy and progressive cognitive decline ending in institutionalization.

Takao et al. (2000) reported 2 brothers with progressive myoclonic epilepsy and dementia. The proband developed seizures at age 24, which progressed to status epilepticus over several years. He also developed slow speech, diplopia, nystagmus, dysarthria, and myoclonus in the extremities. He had rapid development of dementia at age 28, was institutionalized at age 32, and died at age 43 from aspiration pneumonia. Detailed neuropathologic examination showed neuronal loss, gliosis, and widespread eosinophilic intraneuronal PI12-immunoreactive inclusion bodies in the cerebral cortex, substantia nigra, and other areas of the central nervous system. Their deceased mother was reportedly similarly affected. Molecular analysis identified a heterozygous mutation in the PI12 gene (602445.0002) in both brothers.

Bradshaw et al. (2001) found that cognitive changes in mildly to moderately affected subjects were characterized by deficits in processes dependent on frontal and frontal-subcortical areas. The continued progressive deterioration of cerebral functions with relative sparing of recall memory suggested a unique dementia associated with this disorder.

Davis et al. (2002) reported additional patients with the disorder. A 23-year-old man had an 8-year history of progressive myoclonic epilepsy, dementia, tremor, and dysarthria. The second patient was a 13-year-old girl with progressive myoclonus epilepsy with intractable seizures, myoclonus, and dementia. She died at age 19 years during status epilepticus. Her father was said to be mentally deficient, and a paternal uncle had died from epilepsy at 18 years of age.

Coutelier et al. (2008) reported an 11-year-old girl with a variant form of FENIB. She had normal neuropsychologic development until 8 years of age, when she rapidly developed aggressive behavior, intellectual decline, psychic seizures, and subtle seizures with eyelid myoclonia. EEG showed electrical activity suggestive of epilepsy with continuous spike-and-waves during slow-wave sleep. She was given a general diagnosis of epilepticus of slow-wave sleep, a childhood epileptic encephalopathy. As her epilepsy was refractory to all medications, she underwent a neurosurgical procedure including subpial transections in left temporal and parietal lobes, because the left temporal hemisphere was dominant. At age 11 years, she had the psychomotor status of an 18-month-old child. Histologic examination of temporal and parietal left lobe biopsies revealed the presence of Collins bodies that stained positively with an anti-neuroserpin antibody. There was no family history of a similar disorder.

Pathogenesis

The principal neuropathologic finding in the 2 families studied by Davis et al. (1999) was the presence of eosinophilic neuronal inclusions distributed throughout the deeper layers of the cerebral cortex and in many subcortical nuclei, especially the substantia nigra. These inclusions, which Davis et al. (1999) called Collins bodies, are round, 5 to 50 micron in diameter, and strongly periodic acid-Schiff (PAS) positive but diastase resistant. They are distinctly different from Lewy, Pick, and Lafora bodies. Inclusions were shown to be composed of a single major protein, neuroserpin, or PI12. Electron microscopy revealed that the inclusions are formed by entangled fibrils which immunogold-label for neuroserpin. Sonication of these fibrils showed that they have the typical appearance of other serpin loop-sheet polymers. The accumulation of protein is similar to that seen in alpha-1-antitrypsin deficiency leading to cirrhosis (see 613490). Davis et al. (1999) concluded that FENIB belongs to the general pattern of neurodegeneration caused by aberrant protein processing and tissue deposition, so-called 'conformational diseases' (Belorgey et al., 2002).

Molecular Genetics

In affected members of 2 unrelated families with FENIB, Davis et al. (1999) identified 2 different heterozygous mutations in the PI12 gene (S49P; 602445.0001 and S52R; 602445.0002, respectively).

Davis et al. (2002) identified 2 different heterozygous mutations in the PI12 gene (602445.0003 and 602445.0004, respectively) in 2 unrelated patients with a severe form of the disorder characterized by progressive myoclonic epilepsy. They observed that the amount of neuronal inclusions in brain tissue correlated with the severity of disease and age of onset, as well as with the predicted conformational instability on the crystallographic structure of the protein resulting from specific mutations.

Molinari et al. (2003) reviewed the molecular pathogenesis of neuroserpin mutations in FENIB.

Animal Model

Takano et al. (2006) found that transgenic rats (Tgmeg) with overexpression of megsin (603357), a serine protease inhibitor, developed a phenotype similar to that of FENIB. Homozygous Tgmeg rats developed PAS-positive, diastase-resistant intracellular droplets in the kidneys and pancreas that was accompanied by marked upregulation of endoplasmic reticulum (ER) stress chaperones. Homozygous Tgmeg rats displayed early and progressive organ damage, but heterozygotes failed to show abnormalities in either renal or endocrine function. Although heterozygotes had a similar life span compared to nontransgenic littermates, they developed PAS-positive intracellular inclusion in neurons of the cerebral cortex, hippocampus, and substantia nigra, associated with slowly progressive neurodegeneration, upregulation of ER-stress proteins, and neuronal death. Takano et al. (2006) proposed that ER stress may have a pathogenic role in the development of serpinopathy, ultimately leading to neurodegeneration.