Pathophysiology of feline hyperadrenocorticism clinical. Case presentation

Hyperadrenocorticism is a rare endocrine disease in the cat; it is characterized by elevated blood cortisol level that generates numerous clinical signs including hyperglycemia, polyuria, polydipsia, polyphagia and skin diseases. The average age of onset is around 10 years. This disease usually occurs link with other endocrine disorders such as diabetes mellitus.The disease can be produced by functional alteration of the pituitary gland or the adrenal. A case report, with differential diagnosis and review of the literature, is presented.

Interleukin 18 promoter polymorphisms are not strongly associated with type 1 diabetes in a UK population

Interleukin 18 (IL18) is a proinflammatory cytokine whose levels are increased in the subclinical stage of insulin-dependent (type I) diabetes mellitus. Previous case-control studies have reported associations between IL18 -607C>A and -137G>C promoter polymorphisms and type I diabetes. We performed case-control and family-based association studies employing Pyrosequencing to assess if these IL18 polymorphisms are also associated with the development of type I diabetes in the Northern Ireland population. The chi2 analysis of genotype and allele frequencies for the IL18 polymorphisms in cases (n=433) vs controls (n=426) revealed no significant differences (P>0.05). Assessment of allele transmission distortion from informative parents to affected offspring also failed to confirm previously reported associations. Stratification of these analyses for age-at-onset and HLA-DR type did not reveal any significance associations. In conclusion, our data do not support the strong positive associations of IL18 promoter polymorphisms with type I diabetes reported in previous smaller studies.

Incidence of Type 1 Diabetes in Sweden Among Individuals Aged 0–34 Years, 1983–2007:An analysis of time trends

OBJECTIVE: To clarify whether the increase in childhood type 1 diabetes is mirrored by a decrease in older age-groups, resulting in younger age at diagnosis.
RESEARCH DESIGN AND METHODS: We used data from two prospective research registers, the Swedish Childhood Diabetes Register, which included case subjects aged 0-14.9 years at diagnosis, and the Diabetes in Sweden Study, which included case subjects aged 15-34.9 years at diagnosis, covering birth cohorts between 1948 and 2007. The total database included 20,249 individuals with diabetes diagnosed between 1983 and 2007. Incidence rates over time were analyzed using Poisson regression models.
RESULTS: The overall yearly incidence rose to a peak of 42.3 per 100,000 person-years in male subjects aged 10-14 years and to a peak of 37.1 per 100,000 person-years in female subjects aged 5-9 years and decreased thereafter. There was a significant increase by calendar year in both sexes in the three age-groups <15 years; however, there were significant decreases in the older age-groups (25- to 29-years and 30- to 34-years age-groups). Poisson regression analyses showed that a cohort effect seemed to dominate over a time-period effect.
CONCLUSIONS: Twenty-five years of prospective nationwide incidence registration demonstrates a clear shift to younger age at onset rather than a uniform increase in incidence rates across all age-groups. The dominance of cohort effects over period effects suggests that exposures affecting young children may be responsible for the increasing incidence in the younger age-groups.

Association analysis of proopiomelanocortin (POMC) haplotypes in type 1 diabetes in a UK population

Aim

To assess the association of POMC haplotype-tagged single nucleotide polymorphisms (htSNPs) with the development of type 1 diabetes (T1D) in a Caucasian population.

Methods

All exons, intron 1, and approximately 6-kb upstream and 3-kb downstream of the POMC gene were bidirectionally resequenced to identify DNA polymorphisms in 30 individuals. Allele frequencies were determined (60 chromosomes) and efficient htSNPs were selected using the htSNP2 programme. Genotyping was performed in 390 cases, 339 controls and 245 T1D parent-offspring trios, using Taqman, Sequenom and direct-sequencing technologies.

Results

Thirteen polymorphisms (two novel) with a minor allele frequency greater than 1% were identified. Six POMC htSNPs (rs3754863 G>A, ss161151662 A>G, rs3754860 C>T, rs1009388 G>C, rs3769671 A>C, rs1042571 G>A) were identified. Allele and haplotype frequencies were similar between case and control groups (P>0.60 by permutation test), and assessment of allele transmission distortion from informative parents to affected offspring also failed to find any association. Stratification of these analyses for age-at-onset and HLA-DR risk group (DR3/DR4) revealed no significant associations. A haplotype block of 9.86-kb from rs3754863 to rs1042571 was identified, encompassing the POMC gene. Comparison of haplotype frequencies identified the GGCGAG haplotype as protective against T1D in 12.9% of cases vs. 18.3% of controls: ?2=8.18, Pc=0.03 by permutation test.

Conclusion

The POMC SNP haplotype GGCGAG may have a protective effect against T1D in the UK population. However, this finding needs to be replicated, and the cellular and molecular processes influenced by this POMC haplotype determined to fully appreciate its impact.

Progression of retinal pigment epithelial atrophy in stargardt disease

• PURPOSE: To evaluate retinal pigment epithelial (RPE) atrophy in patients with Stargardt disease using autofluorescence imaging (AF). • DESIGN: Retrospective observational case series. • METHODS: Demographics, best-corrected visual acuity (BCVA), AF images, and electrophysiology responses (group 1, macular dysfunction; group 2, macula + cone dysfunction; group 3, macula + cone-rod dysfunction) were evaluated at presentation and follow-up in a group of 12 patients (24 eyes) with Stargardt disease. The existence, development, and rate of enlargement of areas of RPE atrophy over time were evaluated using AF imaging. A linear regression model was used to investigate the effects of AF and electrophysiology on rate of atrophy enlargement and BCVA, adjusting for age of onset and duration of disease. • RESULTS: Eight male and 4 female patients (median age 42 years; range 24-69 years) were followed for a median of 41.5 months (range 13-66 months). All 12 patients had reduced AF compatible with RPE atrophy at presentation and in all patients the atrophy enlarged during follow-up. The mean rate of atrophy enlargement for all patients was 1.58 mm /y (SD 1.25 mm /y; range 0.13-5.27 mm /y). Only the pattern of functional loss present as detected by electrophysiology was statistically significantly associated with the rate of atrophy enlargement when correcting for other variables (P <.001), with patients in group 3 (macula + cone-rod dysfunction) having the fastest rate of atrophy enlargement (1.97 mm /y, SD 0.70 mm /y) (group 1 [macula] 1.09 mm /y, SD 0.53 mm /y; group 2 [macula + cone] 1.89 mm /y, SD 2.27 mm /y). • CONCLUSION: Variable rates of atrophy enlargement were observed in patients with Stargardt disease. The pattern of functional loss detected on electrophysiology was strongly associated with the rate of atrophy enlargement over time, thus serving as the best prognostic indicator for patients with this inherited retinal disease. © 2012 Elsevier Inc. All rights reserved.

Phenotypic subtypes of Stargardt macular:Dystrophy-fundus flavimaculatus

Objective: To determine if phenotypic subtypes exist in Stargardt macular dystrophy-fundus flavimaculatus (SMD-FFM). Methods: A cross-sectional study of 63 patients with autosomal recessive SMD-FFM was undertaken. The age of onset, duration of symptoms, visual acuity, and clinical features on fundus examination, color fundus photographs, and fundus autofluorescence images were recorded. Electrophysiological tests, including pattern, focal, and full-field electroretinogram (ERG), electro-oculogram, and color-contrast sensitivity measurement, were also performed. Results: Based on electrophysiological attributes (ERG), patients with SMD-FFM could be classified into 3 groups. In group 1, there was severe pattern ERG abnormality with normal scotopic and full-field ERGs. In group 2, there was additional loss of photopic function, and in group 3, there was loss of both photopic and scotopic function. Differences in scotopic or photopic function among groups were not explained on the basis of differences in age of onset or duration of disease. Conclusions: Patients with SMD-FFM can be classified into 3 groups based on the absence or presence of generalized loss of either photopic or photopic and scotopic function. It appears that these 3 groups may represent distinct phenotypic subtypes in SMD-FFM.

Intrafamilial variation of phenotype in Stargardt macular dystrophy- fundus flavimaculatus

Purpose. To evaluate the intrafamilial phenotypic variation in Stargardt macular dystrophy-Fundus flavimaculatus (SMD-FFM). Methods. Thirty-one siblings from 15 families with SMD-FFM were examined. Age of onset, visual acuity, and clinical features on fundus examination and fundus autofluorescence images, including presence or absence of central and peripheral atrophy and distribution of flecks, were recorded. In addition, electrophysiological studies were undertaken. Results. Large differences between siblings in age of onset (median, 12 years; range, 5-23 years) were observed in six of the 15 families studied, whereas in 9 families differences in age of onset between siblings were small (median, 1 year; range, 0-3 years). Visual acuity varied two or more lines among siblings in nine families. In 10 families (67%) siblings were found to have different clinical appearance on fundus examination and fundus autofluorescence images, whereas in 5 families (33%), affected siblings had similar clinical features. Electrodiagnostic tests were performed on affected members of 12 families and disclosed similar qualitative findings among siblings. In nine families there was loss of central function only; in two, global loss of cone function; and in one, global loss of cone and rod function. Conclusions. In this series, although differences in age of onset, visual acuity, and fundus appearance were observed between siblings, electrophysiological studies demonstrated intrafamilial homogeneity in retinal function. The findings are difficult to reconcile with expression studies showing ABCR transcripts in rod photoreceptors but not in cones.

Serum Inflammatory Markers and Preeclampsia in Type 1 Diabetes:A prospective study

OBJECTIVE Inflammation and endothelial dysfunction have been associated with the immunobiology of preeclampsia (PE), a significant cause of adverse pregnancy outcomes. The prevalence of PE is elevated several fold in the presence of maternal type 1 diabetes mellitus (T1DM). Although cross-sectional studies of pregnancies among women without diabetes have shown altered inflammatory markers in the presence of PE, longitudinal studies of diabetic women are lacking. In maternal serum samples, we examined the temporal associations of markers of inflammation with the subsequent development of PE in women with T1DM. RESEARCH DESIGN AND METHODS We conducted longitudinal analyses of serum C-reactive protein (CRP), adhesion molecules, and cytokines during the first (mean ± SD, 12.2 ± 1.9 weeks), second (21.6 ± 1.5 weeks), and third (31.5 ± 1.7 weeks) trimesters of pregnancy (visits 1-3, respectively). All study visits took place before the onset of PE. Covariates were BMI, HbA1c, age of onset, duration of diabetes, and mean arterial pressure. RESULTS In women with T1DM who developed PE versus those who remained normotensive, CRP tended to be higher at visits 1 (P = 0.07) and 2 (P = 0.06) and was significantly higher at visit 3 (P <0.05); soluble E-selectin and interferon-?-inducible protein-10 (IP-10) were significantly higher at visit 3; interleukin-1 receptor antagonist (IL-1ra) and eotaxin were higher and lower, respectively, at visit 2 (all P <0.05). These conclusions persisted following adjustment for covariates. CONCLUSIONS In pregnant women with T1DM, elevated CRP, soluble E-selectin, IL-1ra, and IP-10 and lower eotaxin were associated with subsequent PE. The role of inflammatory factors as markers and potential mechanisms of the high prevalence of PE in T1DM merits further investigation.

Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria:an analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort

Microalbuminuria is a common diagnosis in the clinical care of patients with type 1 diabetes mellitus. Long-term outcomes after the development of microalbuminuria are variable.

Development of a genotyping microarray for Usher syndrome

Usher syndrome, a combination of retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction, displays a high degree of clinical and genetic heterogeneity. Three clinical subtypes can be distinguished, based on the age of onset and severity of the hearing impairment, and the presence or absence of vestibular abnormalities. Thus far, eight genes have been implicated in the syndrome, together comprising 347 protein-coding exons.

Irish study on high-density schizophrenia families:field methods and power to detect linkage

Large samples of multiplex pedigrees will probably be needed to detect susceptibility loci for schizophrenia by linkage analysis. Standardized ascertainment of such pedigrees from culturally and ethnically homogeneous populations may improve the probability of detection and replication of linkage. The Irish Study of High-Density Schizophrenia Families (ISHDSF) was formed from standardized ascertainment of multiplex schizophrenia families in 39 psychiatric facilities covering over 90% of the population in Ireland and Northern Ireland. We here describe a phenotypic sample and a subset thereof, the linkage sample. Individuals were included in the phenotypic sample if adequate diagnostic information, based on personal interview and/or hospital record, was available. Only individuals with available DNA were included in the linkage sample. Inclusion of a pedigree into the phenotypic sample required at least two first, second, or third degree relatives with non-affective psychosis (NAP), one whom had schizophrenia (S) or poor-outcome schizo-affective disorder (PO-SAD). Entry into the linkage sample required DNA samples on at least two individuals with NAP, of whom at least one had S or PO-SAD. Affection was defined by narrow, intermediate, and broad criteria. The phenotypic sample contained 277 pedigrees and 1,770 individuals and the linkage sample 265 pedigrees and 1,408 individuals. Using the intermediate definition of affection, the phenotypic sample contained 837 affected individuals and 526 affected sibling pairs. Parallel figures for the linkage sample were 700 and 420. Individuals with schizophrenia from these multiplex pedigrees resembled epidemiologically sampled cases with respect to age at onset, gender distribution, and most clinical symptoms, although they were more thought-disordered and had a poorer outcome. Power analyses based on the model of linkage heterogeneity indicated that the ISHDSF should be able to detect a major locus that influences susceptibility to schizophrenia in as few as 20% of families. Compared to first-degree relatives of epidemiologically sampled schizophrenic probands, first-degree relatives of schizophrenic members from the ISHDSF had a similar risk for schizotypal personality disorder, affective illness, alcoholism, and anxiety disorder. With sufficient resources, large-scale ascertainment of multiplex schizophrenia pedigrees is feasible, especially in countries with catchmented psychiatric care and stable populations. Although somewhat more severely ill, schizophrenic members of such pedigrees appear to clinically resemble typical schizophrenic patients. Our ascertainment process for multiplex schizophrenia families did not select for excess familial risk for affective illness or alcoholism. With its large sample ascertained in a standardized manner from a relatively homogeneous population, the ISHDSF provides considerable power to detect susceptibility loci for schizophrenia.

Resemblance of psychotic symptoms and syndromes in affected sibling pairs from the Irish Study of High-Density Schizophrenia Families:evidence for possible etiologic heterogeneity

The authors sought to determine whether the clinical manifestations of schizophrenia and other psychotic disorders are correlated in affected sibling pairs.

Novel Metabolite Biomarkers of Huntington's Disease As Detected by High-Resolution Mass Spectrometry

Huntington's disease (HD) is a fatal autosomal-dominant neurodegenerative disorder that affects approximately 3-10 people per 100 000 in the Western world. The median age of onset is 40 years, with death typically following 15-20 years later. In this study, we biochemically profiled post-mortem frontal lobe and striatum from HD sufferers (n = 14) and compared their profiles with controls (n = 14). LC-LTQ-Orbitrap-MS detected a total of 5579 and 5880 features for frontal lobe and striatum, respectively. An ROC curve combining two spectral features from frontal lobe had an AUC value of 0.916 (0.794 to 1.000) and following statistical cross-validation had an 83% predictive accuracy for HD. Similarly, two striatum biomarkers gave an ROC AUC of 0.935 (0.806 to 1.000) and after statistical cross-validation predicted HD with 91.8% accuracy. A range of metabolite disturbances were evident including but-2-enoic acid and uric acid, which were altered in both frontal lobe and striatum. A total of seven biochemical pathways (three in frontal lobe and four in striatum) were significantly altered as a result of HD. This study highlights the utility of high-resolution metabolomics for the study of HD. Further characterization of the brain metabolome could lead to the identification of new biomarkers and novel treatment strategies for HD.

Genetic profiling of ApoE in dementia

A demência é uma das principais causas de incapacidade entre os idosos, afetando mais de 36 milhões de pessoas em todo o mundo. É caracterizada pela deterioração progressiva das funções cognitivas, resultando em dificuldades no desempenho das atividades diárias do indivíduo. A idade de aparecimento dos sintomas, bem como a sua taxa de progressão, são variáveis entre a maior parte das demências, sendo estas geralmente caracterizadas por uma natureza progressiva, aumentando de gravidade ao longo do tempo. Entre os tipos mais frequentes de demência encontram-se a Doença de Alzheimer (DA), Demência Vascular, Demência de Corpos de Lewy e Demência Frontotemporal. O diagnóstico diferencial das demências é realizado tipicamente por testes neuro-psicológicos (para a exclusão de outras demências) e por exames imagiológicos. Contudo, muitos dos sintomas clínicos característicos podem sobrepor-se entre os diversos tipos de demência, o que pode constituir um problema devido a falta de especificidade e erros de diagnóstico. A compreensão dos fatores de risco ambientais e genéticos que podem modular o aparecimento e/ou progressão de doenças abre novas perspetivas relativamente à gestão destas neuropatologias. O gene da apolipoproteína E (ApoE) é reconhecido como o maior fator de risco na demência, desempenhando um papel central em particular no desenvolvimento da DA, sendo que os portadores do alelo ε4 são mais suscetíveis para a doença. Além disso, possíveis associações foram também propostas entre este gene e outras doenças neurológicas, sendo no entanto estes dados ainda controversos. Assim, o objetivo principal deste trabalho consistiu em determinar as frequências alélicas e genotípicas do gene ApoE num grupo de estudo piloto de pacientes com demência na região de Aveiro. Este grupo foi subdividido com base no diagnóstico neuroquímico, no qual foram avaliados os níveis de Aβ1-42, Tau-total e fosfo-Tau 181 no líquido cefalorraquidiano dos pacientes. Como resultado, observou-se que o alelo ε3 foi o mais frequente no grupo total, independentemente do tipo de patologia, e que o alelo ε2 foi o menos comum. O alelo ε4 foi de facto mais frequente em pacientes com DA do que em pacientes com outras neuropatologias, o que está de acordo com a relação proposta por outros autores. Adicionalmente, foi possível verificar que a frequência deste alelo nos pacientes com patologia amilóide é semelhante à observada no grupo DA, sugerindo um papel relevante para o ApoE no metabolismo e acumulação cerebral do Aβ. Consequentemente, estes indivíduos podem ter uma maior suscetibilidade para o desenvolvimento de DA no futuro. Deste modo, os nossos dados corroboram a ideia de que o alelo ε4 é um forte fator de risco para a DA e que deve ser considerado como um teste genético relevante que pode contribuir para o diagnóstico clínico da demência.

Copy number variation and Huntington’s disease

Tese de doutoramento, Ciências Biomédicas (Neurociências), Universidade de Lisboa, Faculdade de Medicina, 2014