Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2.

Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11 Volga German families, 101 who are likely to have the same N141I mutation in presenilin 2 (54 genotyped confirmed). We have also assessed the detailed neuropathologic findings in 18 autopsies from these families and reviewed the world's literature on other presenilin 2 mutations; presenting a novel mutation that is predicted to lead to a premature truncation codon. Seven presenilin 2 mutations reported in the literature have strong evidence for pathogenicity whereas others may be benign polymorphisms. One hundred and one affected persons, with sufficient historical information from the Volga German pedigrees (N141I mutation), had a mean onset age of 53.7 years+/-7.8 (range 39-75) and mean age at death of 64.2 years+/-9.8 (range 43-88). These figures overlap with and generally fall between the results from the subjects in our centre who have late onset familial Alzheimer's disease or mutations in presenilin 1. Seizures were noted in 20 (30%) of 64 subjects with detailed medical records. Two mutation carriers lived beyond age 80 without developing dementia, representing uncommon examples of decreased penetrance. Two persons had severe amyloid angiopathy and haemorrhagic stroke. Eighteen cases had detailed histopathology available and analysed at our institution. Braak stage was five or six, amyloid angiopathy and neuritic plaques were common and more than 75% had Lewy bodies in the amygdala. TAR DNA-binding protein-43 inclusions were uncommon. In addition, a 58-year-old female with a 2 year course of cognitive decline and no family history of dementia has abnormal fludeoxyglucose-positron emission tomography imaging and a novel 2 base pair deletion in presenilin 2 at nucleotide 342/343, predicted to produce a frame-shift and premature termination. We conclude that mutations in presenilin 2 are rare with only seven being well documented in the literature. The best studied N141I mutation produces an Alzheimer's disease phenotype with a wide range of onset ages overlapping both early and late onset Alzheimer's disease, often associated with seizures, high penetrance and typical Alzheimer's disease neuropathology. A novel premature termination mutation supports loss of function or haploinsufficiency as pathogenic mechanisms in presenilin 2 associated Alzheimer's disease.

Reversible cytotoxic edema in a cirrhotic patient following TIPS.

The authors report the magnetic resonance imaging (MRI) findings in a 52-year-old man with cirrhosis from chronic hepatitis C who developed episodic acute hepatic encephalopathy Type C following placement of transjugular intrahepatic portosystemic shunt (TIPS). Brain MRI revealed hyperintense T2 signal and restricted diffusion distributed through the cerebral cortex. The patient's mentation improved with treatment of his hyperammonemia. Brain MRI performed 5 months later revealed diffuse cerebral atrophy and new areas of hyperintense T2 signal in the cerebral white matter. The cortical signal abnormalities and low apparent diffusion coefficient values on the initial MRI resolved with exception of a mild amount of hyperintense FLAIR signal in the cingulate cortex. Acute hepatic encephalopathy following portosystemic shunting -- either from placement of TIPS or from development of spontaneous shunts -- is a widely recognized complication of portal hypertension and cirrhosis. We report MRI findings of reversible cytotoxic edema in a patient with acute hepatic encephalopathy following placement of TIPS.