Expanded mutational spectrum of the GLI3 gene substantiates genotype-phenotype correlations.

Greig cephalopolysyndactyly syndrome (GCPS) and isolated preaxial polydactyly type IV (PPD-IV) are rare autosomal dominant disorders, both caused by mutations in the GLI3 gene. GCPS is mainly characterised by craniofacial abnormalities (macrocephaly/prominent forehead, hypertelorism) and limb malformations, such as PPD-IV, syndactyly and postaxial polydactyly type A or B (PAPA/B). Mutations in the GLI3 gene can also lead to Pallister-Hall syndrome (PHS) and isolated PAPA/B. In this study, we investigated 16 unrelated probands with the clinical diagnosis of GCPS/PPD-IV and found GLI3 mutations in 12 (75%) of them (nine familial and three sporadic cases). We also performed a detailed clinical evaluation of all 12 GLI3-positive families, with a total of 27 patients. The hallmark triad of GCPS (preaxial polydactyly, macrocephaly/prominent forehead, hypertelorism) was present in 14 cases (52%), whereas at least one typical dysmorphic feature was manifested in 17 patients (63%). Upon sequencing of the GLI3 gene, we demonstrated eight novel and two previously reported heterozygous point mutations. We also performed multiplex ligation-dependent probe amplification (MLPA) to screen for intragenic copy number changes and identified heterozygous deletions in the two remaining cases (16.7%). Our findings fully support previous genotype-phenotype correlations, showing that exonic deletions, missense mutations, as well as truncating variants localised out of the middle third of the GLI3 gene result in GCPS/PPD-IV and not PHS. Additionally, our study shows that intragenic GLI3 deletions may account for a significant proportion of GCPS/PPD-IV causative mutations. Therefore, we propose that MLPA or quantitative polymerase chain reaction (qPCR) should be implemented into routine molecular diagnostic of the GLI3 gene.

CCL3 correlates with the number of mood disturbances and personality changes in patients with Alzheimer's disease.

Although Alzheimer's disease (AD) is a primary degenerative disorder, a microglial-mediated inflammatory response, provoked by amyloid beta (Abeta), contributes to the neurodegeneration and subsequently to the cell loss. Since such an inflammatory contribution to neurodegeneration may influence disease progression, a basic question arises concerning the mechanisms of possible clinical signs dependent on inflammatory reactions. In the present study we investigated the levels of CCL3 in the peripheral blood of AD patients and correlated findings with the results of clinical tests such as the Mini-Mental State Examination (MMSE) and the Global Deterioration Scale (GDS), as well as with disturbances of behaviour, mood and personality, thereby extending the spectrum of clinical symptoms to ones not assessed by the MMSE or the GDS. CCL3 levels were lower in patients with AD but correlated positively with such noncognitive symptoms as mood disturbances and personality changes.We found that CCL3 did not correlate with the severity of dementia as assessed by the MMSE or with the degree of disease deterioration as assessed by the GDS. The results from our study on CCL3 levels in AD may, in part, explain the mechanisms of some concomitant, noncognitive clinical features of the disease.

[Assessment of the cognitive, functioning and emotional impairments in patients with Alzheimer's disease in relation to lifestyle behaviours in the stage of life prior to the diagnosis of disease]. / Ocena stopnia zaburzen procesów poznawczych, sprawnosci funkcjonowania oraz stanu emocjonalnego wsród pacjentów z choroba Alzheimera w odniesieniu do ich stylu zycia w okresie poprzedzajacym rozpoznanie choroby.

AIMS: The purpose of the study is to estimate whether the cognitive, functioning and emotional impairments in patients with Alzheimer's disease are related to lifestyle behaviours in the stage of life prior to the diagnosis of the disease. METHODS: Altogether, 65 patients with Alzheimer's disease, 55 women and 10 men, participants of the day center, run by the Wielkopolska Association of Alzheimer's Disease and residents of the Senior Nursing Home in Koprzywnica, were examined. Cognitive, functioning and emotional impairments of patients as well as lifestyle behaviours in the stage of life prior to the diagnosis of AD were estimated using AD-specific questionnaire, which were completed by caregivers. Qantitative and qualitative analyses were run using appropriate statistical procedures available in the Statistica 7.1 programme [StatSoft. Inc.2005 Statistica for Windows]. RESULTS: The findings revealed that patients with AD aged 70 years and older were likely to be more frequently impaired with daily life functioning than their younger counterparts. Patients with a higher attainment of education were more frequently impaired with cognitive than emotional problems and depression. Of all the variables in question, calendar age, educational attainment and intellectual activity in the stage of life prior to the diagnosis of disease were most significant in explaining the variation in the current impairments. Persons who were younger and intellectually active prior to the disease, were likely to be suffering less from the burden of AD than the older and less intellectually active counterparts. CONCLUSIONS: The association between educational attainment and intellectual activity in the stage of life prior to the occurrence of AD, and the burden of AD, found in the study, indicates that a lifelong intellectual activity may help to reduce disabilities and improve the patients' quality of life.

[Familial Westphal variant of Huntington's disease. Case report]. / Rodzinna postac odmiany Westphala choroby Huntingtona. Opis przypadku.

Huntington's disease (HD) is commonly recognized, and the most common autosomal dominant neurodegenerative disease of the central nervous system. The major clinical symptoms in adults include mood changes, choreic movements and progressive cognitive decline. Juvenile HD known as Westphal variant presents with significantly different signs characterized mainly by rigidity, myoclonus, and therefore causes diagnostic difficulties. In this paper, we present the patient with Westphal variant of HD in the third generation of women.

Greater frequency of subcortical lesions in severely demented patients with early onset Alzheimer's disease.

BACKGROUND: Recent data have shown that in the early stages of Alzheimer's disease (AD), vascular brain lesions might promote the progression of cognitive decline or might even precede neuronal damage. METHODS: Ischemic brain lesions, recognized on computed tomography or magnetic resonance imaging, were analyzed retrospectively in 72 patients with early and late onset sporadic AD. RESULTS: All types of ischemic lesions occurred more frequently in the AD patients than in the controls. Analysis of subgroups of early and late onset AD patients diagnosed by magnetic resonance imaging showed a more frequent occurrence of subcortical lesions in severely demented patients with early onset AD. CONCLUSIONS: The non-stroke subcortical ischemic lesions occurring more frequently in our AD patients might be recognized as the concomitant vascular pathology that characterizes severely demented patients with early onset sporadic AD.

[Alzheimer's disease and HSV-1 infection]. / Choroba Alzheimera a infekcja wirusowa HSV-1.

Alzheimer's disease is a complex neurodegenerative disorder. Several risk factors have been reported and compiled from genetic and epidemiological studies. Many theories on the cause of Alzheimer's disease have been proposed over the past. Amyloid hypothesis is still the most important one and guides a lot of scientific research on AD. But there is general consent that amyloid deposits are the products of degenerating neurons, not a cause of degeneration. Recently, epidemiological data for the correlation between HSV-1 infection and AD have been collected. It was revealed that HSV-1 is present in a latent form in the brains of a high proportion of elderly people and is a risk factor for AD in carriers of APOEepsilon4. On the other hand, there is negative evidence for HSV-1 as a risk factor of APOEepsilon4 positive AD cases. Finally, some investigations raise a possibility that viruses other than HSV-1 may influence Alzheimer's disease. In the present paper the possible role of HSV-1 infection in pathology of AD is discussed.

Constitutive patterns of RANTES, MCP-1 and MIP-1 alpha expression at the mRNA and protein level during postnatal development of the rat brain.

The importance of chemokines seems to extend far beyond their well-known role as mediators of an inflammatory response. The most interesting hypothesis is that these molecules may influence the migration of progenitor cells during development. Primary sensory neurones have been shown to migrate towards RANTES in vitro. Recent evidence has revealed that MCP-1, MIP-1alpha and MIP-1beta are potent chemoattractants for glial cell populations. The exact role of the constitutive appearance of chemokines in the CNS during postnatal development is still largely unknown. The intention was to show whether constitutive temporal and spatial profiles of RANTES, MCP-1 and MIP-1alpha expression vary during the postnatal development of the rat brain. RT-PCR was used to assess the levels of mRNA production at different developmental stages. Semi-quantitative analysis of the immunofluorescence signal from glial cells harbouring chemokines was used to determine the spatial-temporal patterns of protein expression. It has been shown here that all chemokines are constitutive factors within the brain microenvironments where the postnatal migration phenomenon occurs. The chemokines were characterised by variable temporal patterns of mRNA production and distinct spatial-temporal patterns of protein appearance. This may support the differences between RANTES, MCP-1 and MIP-1alpha functional significance in vivo in terms of influence on the migration of distinct cell populations.