A presenilin 1 mutation (L420R) in a family with early onset Alzheimer disease,seizures and cotton wool plaques,but not spastic paraparesis

Over 100 mutations in the presenilin‐1 gene (PSEN1) have been shown to result in familial early onset Alzheimer disease (EOAD), but only a relatively few give rise to plaques with an appearance like cotton wool (CWP) and/or spastic paraparesis (SP). A family with EOAD, seizures and CWP was investigated by neuropathological study and DNA sequencing of the PSEN1 gene. Aβ was identified in leptomeningeal vessels and in cerebral plaques. A single point mutation, p.L420R (g.1508T > G) that gives rise to a missense mutation in the eighth transmembrane (TM8) domain of PS1 was identified in two affected members of the family. p.L420R (g.1508T > G) is the mutation responsible for EOAD, seizures and CWP without SP in this family.     

Complete maternal uniparental isodisomy of chromosome 4 in a subject with major depressive disorder detected by high density SNP genotyping arrays.

Uniparental isodisomy (iUPD) is a rare genetic condition caused by non-disjunction during meiosis that ultimately leads to a duplication of either the maternal or paternal chromosome in the affected individual. Two types of disorders can result, those due to imprinted genes and those due to homozygosity of recessive disease-causing mutations. Here, we describe the third known case of complete chromosome 4 iUPD of maternal origin. This condition became apparent during whole genome linkage studies of psychiatric disorders in the Portuguese population. The proband is an adult female with normal fertility and no major medical complaints, but a history of major depressive disorder and multiple suicide attempts. The proband's siblings and parents had normal chromosome 4 genotypes and no history of mood disturbance. A brief review of other studies lends support for the possibility that genes on chromosome 4 might confer risk for mood disorders. We conclude that chromosome 4 maternal uniparental disomy (UPD) is a rare disorder that may present with a major depressive phenotype. The lack of a common disease phenotype between this and two other cases of chromosome 4 iUPD [Lindenbaum et al. [1991] Am J Med Genet 49(Suppl 285):1582; Spena et al. [2004] Eur J Hum Genet 12:891-898) would suggest that there is no vital maternal gene imprinting on chromosome 4. However, since there is no reported case of paternal chromosome 4 UPD, paternal gene imprinting on chromosome 4 cannot be excluded.     

Can supplements help meet the micronutrient needs of the developing world?

Supplementation has many potential advantages over fortification and dietary approaches for improving micronutrient intake. Pregnant and lactating women and infants are most likely to benefit from supplementation. Recent experience with vitamin A supplementation in young children has proved to be remarkably successful. Demonstrated efficacy of vitamin A supplements for improved child survival in many settings and a technical consensus on how to implement interventions were major factors in achieving this success. Bilateral and UN agencies worked together so that in 1999 80 % of children under 5 years of age in the least-developed countries received a vitamin A capsule in the last 6 months. At least one million child lives saved were associated with the increase in coverage in the last 2 years of the 1990s. Experience with Fe-folate supplements has not been as successful. Whilst a technical consensus has been reached on how to implement programmes to control Fe deficiency, the lack of convincing evidence of efficacy of Fe-folate supplements in terms of maternal and child survival outcomes has undoubtedly contributed to the limited pursuit of effective action. A new multiple micronutrient supplement for use amongst women of reproductive age in developing countries has been formulated. UNICEF is employing the supplement in programmes aimed at helping to prevent low birth weight. The new supplement is likely to be more efficacious than Fe-folate supplements for both maternal and child survival and development outcomes. Successful completion of rigorous efficacy trials will be critical for creating the political support needed to achieve universal coverage.     

Influence of patient age on normalized effective doses calculated for CT examinations

Monte Carlo simulations of CT examinations have been performed to estimate effective doses, normalized to axial air kerma, for six mathematical phantoms representing ages from newborn to adult, and for three CT scanner models covering a range of designs. Organ doses were calculated for CT exposures of contiguous, 1 cm wide, transverse slices in each phantom and summed to give normalized effective doses for scans of four regions of the trunk and head. In all cases an inverse trend is observed between normalized effective dose and phantom age, with the dose to the newborn from head and neck scans being 2.2-2.5 times higher than that to the adult, depending on scanner model. Corresponding increases for scans of the trunk region are more variable between scanners and range from a factor of 1.3 to 2.4. If typical clinical exposure conditions for adults are also utilized for children, then, for example, the effective dose to the newborn from a chest scan could be above 15 mSv. It is concluded that CT has the potential to deliver significantly greater radiation doses to children than to adults and in view of their greater susceptibility to radiation effects, special efforts should be made in clinical practice to reduce doses to children by the use of size-specific scan protocols.     

Cognitive deficits associated with a recently reported familial neurodegenerative disease: familial encephalopathy with neuroserpin inclusion bodies

BACKGROUND: We recently discovered an autosomal dominant disease causing a progressive dementia. The disease is caused by a point mutation in the gene coding for the serine protease inhibitor (ie, serpin) neuroserpin. The mutation results in an unstable neuroserpin protein that readily aggregates into intraneuronal inclusions that we identify as Collins bodies. The bodies are distributed throughout the cerebral hemispheres but are significantly more numerous in the cortex and the substantia nigra. We have named the disease familial encephalopathy with neuroserpin inclusion bodies (FENIB). OBJECTIVES: To describe the cognitive and neurophysiological changes exhibited by individuals with FENIB and to correlate the phenotypic expression of the disease with the neuropathological findings. DESIGN: Multiple case studies using neuropsychological assessment, electroencephalography (EEG), magnetic resonance imaging (MRI), and single-photon emission computed tomographic (SPECT) studies of family members were performed. Using these measures, we also compared family members in whom the mutation is present with family members in whom the mutation was absent to control for nonspecific familial factors. SUBJECTS: Nine individuals (5 women, aged 31-64 years; 4 men, aged 43-67 years) from 2 generations of family members related to the first reliably identified individual with symptoms of this disease. Symptoms, by self-report and reports of other family members, ranged from asymptomatic to severe dementia. Six of the 9 individuals carried the disease mutation. RESULTS: All subjects with the mutation demonstrated some cognitive changes, with the greatest demonstrated by subjects older than 40 years. The changes included restricted attention, concentration, and response regulation functions, reduced controlled oral fluency (word-list generation), and restricted visuospatial organization. In general, recall memory was not as affected as other cognitive domains. The most severely affected subject demonstrated global dementia with prominent frontal lobe features. Findings on SPECT showed anomalies limited to frontal areas in the less affected subjects and more global, patchy areas of hypoperfusion in the more severely affected subjects. The 3 oldest and most affected subjects demonstrated slowing on EEG findings. The MRI findings were noncontributory except in the 2 most severe cases, which showed global cortical atrophy. CONCLUSIONS: Cognitive changes in mildly to moderately affected subjects were characterized by deficits in frontal and frontal-subcortical area-dependent processes. Continued progressive deterioration of cerebral functions with relative sparing of recall memory suggests a unique dementia associated with this disease.     

Molecular delineation of deletions on 2q37.3 in three cases with an Albright hereditary osteodystrophy-like phenotype

A minority of the reported cases of terminal 2q37 deletion clinically resemble Albright hereditary osteodystrophy (AHO)/pseudopseudohypoparathyroidism and have only mild-to-moderate mental retardation. Our molecular and cytogenetic fluorescence in situ hybridization (FISH) findings on an additional three patients further reduce the size of the minimal critical region deleted in this syndrome to about 3 Mb. This region includes the G-protein-coupled receptor 35 (GPR35), glypican 1 (GPC1), and serine/threonine protein kinase 25 (STK25) genes on 2q37.3. We have further defined several polymorphic variants within the coding region and flanking regions of GPR35 gene, which could potentially be useful for rapid detection of GPR35 gene deletion. We postulate that the absence of GPR35 may, at least partly, account for the phenotypic resemblance to the AHO. We also believe that the deletion of GPR35 could be responsible for the entity brachydactyly mental retardation syndrome (OMIM #600430), which was coined based on the above minority of patients with terminal 2q37 deletion. We recommend that every patient with AHO phenotype should undergo 2q subtelomeric FISH screen and subsequently a molecular study on the GPR35 gene. GPC1 and/or STK25 haploinsufficiency may also contribute to the AHO-like phenotype.     

Treatment costs and priority setting in health care: A qualitative study

Background

The aim of this study is to investigate whether the public believes high cost patients should be a lower priority for public health care than low cost patients, other things being equal, in order to maximise health gains from the health budget. Semi-structured group discussions were used to help participants reflect critically upon their own views and gain exposure to alternative views, and in this way elicit underlying values rather than unreflective preferences. Participants were given two main tasks: first, to select from among three general principles for setting health care priorities the one that comes closest to their own views; second, to allocate a limited hospital budget between two groups of imaginary patients. Forty-one people, varying in age, occupation, income and education level, participated in a total of six group discussions with each group comprising between six and eight people.

Results

After discussion and deliberation, 30 participants rejected the most cost-effective principle for setting priorities, citing reasons such as 'moral values' and 'a personal belief that we shouldn't discriminate'. Only three participants chose to allocate the entire hospital budget to the low cost patients. Reasons for allocating some money to inefficient (high cost) patients included 'fairness' and the desire to give all patients a 'chance'.

Conclusion

Participants rejected a single-minded focus on efficiency – maximising health gains – when setting priorities in health care. There was a concern to avoid strategies that deny patients all hope of treatment, and a willingness to sacrifice health gains for a 'fair' public health system.