The apolipoprotein E epsilon4 allele causes a faster decline of cognitive performances in Down's syndrome subjects.

The apolipoprotein E gene (APOE), located on human chromosome 19, has three common alleles (epsilon2, epsilon3, epsilon4) which encode for the three main isoforms indicated as E2, E3 and E4 respectively. Several findings indicate epsilon4 allele as an important risk factor in both sporadic and familial late-onset Alzheimer's disease (AD). Pathological changes similar to AD are seen in almost all patients with Down's syndrome (DS) aged over 35 (senile plaques, neurofibrillary tangles and neuronal loss); a proportion of these may subsequently develop dementia. Aim of this study is to evaluate the possible pathological role of epsilon4 allele as risk factor for developing AD in a DS population. ApoE epsilon4 allele frequency is not significantly different in DS cases and controls. We found a statistically significant inverse correlation between full scale IQ values and age of patients in the subgroup of DS subjects selected for the presence of at least one epsilon4 allele, while no correlation was observed in DS subjects with other ApoE genotypes. A longitudinal analysis of cognitive performances (available in 38 patients) showed a faster rate of decline in intellectual ability in those subjects carrying at least one epsilon4 allele. Our data support the hypothesis that ApoE epsilon4 allele has a contributory role in accelerating the mental deterioration of AD-type in DS patients.

Cytochrome c oxidase subunit I microdeletion in a patient with motor neuron disease.

An out-of-frame mutation of the mitochondrial DNA-encoded subunit I of cytochrome c oxidase (COX) was discovered during investigation of a severe isolated muscle COX deficiency in a patient with motor neuron-like degeneration. The mutation is a heteroplasmic 5-bp microdeletion located in the 5' end of the COI gene, leading to premature termination of the corresponding translation product. Western blot analysis, immunohistochemistry, and single-fiber polymerase chain reaction demonstrated a tight correlation between COX defect, COX I expression, and percentage of mutation. COX subunits II, III, and IV were decreased as well, suggesting a defective assembly of COX holoenzyme. The mutation was associated with a clinical phenotype unusual for a mitochondrial disorder, that is, an isolated motor neuron disease (MND) with some atypical findings, including early onset, preferential involvement of the upper motor neuron, and increased cerebrospinal fluid protein content. MND may arise from impaired scavenging and overproduction of free oxygen radicals, a by-product of oxidative phosphorylation (OXPHOS). Our observation suggests that OXPHOS impairment could play a role in the pathogenesis of some MND cases.