Digenic inheritance of STUB1 variants and TBP polyglutamine expansions explains the incomplete penetrance of SCA17 and SCA48.

PURPOSE: This study aimed to unravel the genetic factors underlying missing heritability in spinocerebellar ataxia type 17 (SCA17) caused by polyglutamine-encoding CAG/CAA repeat expansions in the TBP gene. Alleles with >49 CAG/CAA repeats are fully penetrant. Most patients, however, carry intermediate TBP41-49 alleles that show incomplete penetrance. METHODS: Using next-generation sequencing approaches, we investigated 40 SCA17/TBP41-54 index patients, their affected (n = 55) and unaffected (n = 51) relatives, and a cohort of patients with ataxia (n = 292). RESULTS: All except 1 (30/31) of the index cases with TBP41-46 alleles carried a heterozygous pathogenic variant in the STUB1 gene associated with spinocerebellar ataxias SCAR16 (autosomal recessive) and SCA48 (autosomal dominant). No STUB1 variant was found in patients carrying TBP47-54 alleles. TBP41-46 expansions and STUB1 variants cosegregate in all affected family members, whereas the presence of either TBP41-46 expansions or STUB1 variants individually was never associated with the disease. CONCLUSION: Our data reveal an unexpected genetic interaction between STUB1 and TBP in the pathogenesis of SCA17 and raise questions on the existence of SCA48 as a monogenic disease with crucial implications for diagnosis and counseling. They provide a convincing explanation for the incomplete penetrance of intermediate TBP alleles and demonstrate a dual inheritance pattern for SCA17, which is a monogenic dominant disorder for TBP≥47 alleles and a digenic TBP/STUB1 disease (SCA17-DI) for intermediate expansions.

Missing the pathological expansion in Huntington disease: de novo c.51C>G variant on the expanded allele causing intrafamilial allele dropout.

Huntington disease (HD) is an autosomal dominant disease characterized by motor, behavioral, and cognitive symptoms, caused by the pathological expansion of more than 35 CAG/CAA repeats in the HTT gene. We describe the phenotype of a patient compatible with HD. Several family members were reported as affected, and a paternal cousin and his daughter carried 39 and 42 CAG/CAA. HD genetic testing in proband showed homozygosity for a 14 CAG/CAA allele. Considering the phenotype and family history, HTT gene sequence was performed, revealing heterozygosity for the c.51C>G variant that changes the last nucleotide before the CAG tract, causing misannealing of forward primer (HD344) and dropout of the expanded allele. Polymerase chain reaction (PCR) analysis performed with an alternative forward primer demonstrated a 41 CAG/CAA allele. The c.51C>G variant was not detected in the affected cousin, thus suggesting a de novo occurrence. The lack of biological samples from the proband father and grandmother prevented further investigations to establish in which family member the variant occurred. These data indicate that patients presenting HD phenotype, and homozygous for a normal HTT CAG/CAA allele should be thoroughly evaluated for the presence of a genetic variant, even de novo, within the repeat region that may hamper genetic diagnosis.

Frequency and distribution of polyQ disease intermediate-length repeat alleles in healthy Italian population.

BACKGROUND: Huntington disease (HD) and spinocerebellar ataxia type 1-2-17 (SCA1-2-17) are adult-onset autosomal dominant diseases, caused by triplet repeat expansions in the HTT, ATXN1, ATXN2, and TBP genes. Alleles with a repeat number just below the pathological threshold are associated with reduced penetrance and meiotic instability and are defined as intermediate alleles (IAs). OBJECTIVES: We aimed to determine the frequencies of IAs in healthy Italian subjects and to compare the proportion of the IAs with the prevalence of the respective diseases. METHODS: We analyzed the triplet repeat size in HTT, ATXN1, ATXN2, and TBP genes in the DNA samples from 729 consecutive adult healthy Italian subjects. RESULTS: IAs associated with reduced penetrance were found in ATXN2 gene (1 subject, 0.1%) and TBP gene (0.82%). IAs at risk for meiotic instability were found in HTT (5.3%) and ATXN2 genes (2.7%). In ATXN1, we found a low percentage of IAs (0.4%). Alleles lacking the common CAT interruption within the CAG sequence were also rare (0.3%). CONCLUSIONS: The high frequencies of IAs in HTT and ATXN2 genes suggest a correlation with the prevalence of the diseases in our population and support the hypothesis that IAs could represent a reservoir of new pathological expansions. On the opposite, ATXN1-IA were very rare in respect to the prevalence of SCA1 in our country, and TBP- IA were more frequent than expected, suggesting that other mechanisms could influence the occurrence of novel pathological expansions.

Case-control study of hepatitis B and hepatitis C in older adults: Do healthcare exposures contribute to burden of new infections?

UNLABELLED: Reports of hepatitis B virus (HBV) and hepatitis C virus (HCV) transmission associated with unsafe medical practices have been increasing in the United States. However, the contribution of healthcare exposures to the burden of new infections is poorly understood outside of recognized outbreaks. We conducted a case-control study at three health departments that perform enhanced viral hepatitis surveillance in New York and Oregon. Reported cases of symptomatic acute hepatitis B and hepatitis C occurring in persons≥55 years of age from 2006 to 2008 were enrolled. Controls were identified using telephone directories and matched to individual cases by age group (55-59, 60-69, and ≥70 years) and residential postal code. Data collection covered exposures within 6 months before symptom onset (cases) or date of interview (controls). Forty-eight (37 hepatitis B and 11 hepatitis C) case and 159 control patients were enrolled. Case patients were more likely than controls to report one or more behavioral risk exposures, including sexual or household contact with an HBV or HCV patient, >1 sex partner, illicit drug use, or incarceration (21% of cases versus 4% of controls exposed; matched odds ratio [mOR]=7.1; 95% confidence interval [CI]: 2.1, 24.1). Case patients were more likely than controls to report hemodialysis (8% of cases; mOR=13.0; 95% CI: 1.5, 115), injections in a healthcare setting (58%; mOR=2.7; 95% CI: 1.3, 5.3), and surgery (33%; mOR=2.3; 95% CI: 1.1, 4.7). In a multivariate model, behavioral risks (adjusted OR [aOR]=5.4; 95% CI: 1.5, 19.0; 17% attributable risk), injections (aOR=2.7; 95% CI: 1.3, 5.8; 37% attributable risk), and hemodialysis (aOR=11.5; 95% CI: 1.2, 107; 8% attributable risk) were associated with case status. CONCLUSION: Healthcare exposures may represent an important source of new HBV and HCV infections among older adults.

Multi-phase post-mortem CT angiography: development of a standardized protocol.

The objective of this work was to develop an easily applicable technique and a standardized protocol for high-quality post-mortem angiography. This protocol should (1) increase the radiological interpretation by decreasing artifacts due to the perfusion and by reaching a complete filling of the vascular system and (2) ease and standardize the execution of the examination. To this aim, 45 human corpses were investigated by post-mortem computed tomography (CT) angiography using different perfusion protocols, a modified heart-lung machine and a new contrast agent mixture, specifically developed for post-mortem investigations. The quality of the CT angiographies was evaluated radiologically by observing the filling of the vascular system and assessing the interpretability of the resulting images and by comparing radiological diagnoses to conventional autopsy conclusions. Post-mortem angiography yielded satisfactory results provided that the volumes of the injected contrast agent mixture were high enough to completely fill the vascular system. In order to avoid artifacts due to the post-mortem perfusion, a minimum of three angiographic phases and one native scan had to be performed. These findings were taken into account to develop a protocol for quality post-mortem CT angiography that minimizes the risk of radiological misinterpretation. The proposed protocol is easy applicable in a standardized way and yields high-quality radiologically interpretable visualization of the vascular system in post-mortem investigations.

Paediatric cardiac CT examinations: impact of the iterative reconstruction method ASIR on image quality--preliminary findings.

BACKGROUND: Radiation dose exposure is of particular concern in children due to the possible harmful effects of ionizing radiation. The adaptive statistical iterative reconstruction (ASIR) method is a promising new technique that reduces image noise and produces better overall image quality compared with routine-dose contrast-enhanced methods. OBJECTIVE: To assess the benefits of ASIR on the diagnostic image quality in paediatric cardiac CT examinations. MATERIALS AND METHODS: Four paediatric radiologists based at two major hospitals evaluated ten low-dose paediatric cardiac examinations (80 kVp, CTDI(vol) 4.8-7.9 mGy, DLP 37.1-178.9 mGy·cm). The average age of the cohort studied was 2.6 years (range 1 day to 7 years). Acquisitions were performed on a 64-MDCT scanner. All images were reconstructed at various ASIR percentages (0-100%). For each examination, radiologists scored 19 anatomical structures using the relative visual grading analysis method. To estimate the potential for dose reduction, acquisitions were also performed on a Catphan phantom and a paediatric phantom. RESULTS: The best image quality for all clinical images was obtained with 20% and 40% ASIR (p < 0.001) whereas with ASIR above 50%, image quality significantly decreased (p < 0.001). With 100% ASIR, a strong noise-free appearance of the structures reduced image conspicuity. A potential for dose reduction of about 36% is predicted for a 2- to 3-year-old child when using 40% ASIR rather than the standard filtered back-projection method. CONCLUSION: Reconstruction including 20% to 40% ASIR slightly improved the conspicuity of various paediatric cardiac structures in newborns and children with respect to conventional reconstruction (filtered back-projection) alone.

Aortic remodelling in Fabry disease.

AIMS: To evaluate thoracic aortic dilation in patients with Fabry disease (FD). METHODS AND RESULTS: A cohort of 106 patients with FD (52 males; 54 females) from three European centres were studied. The diameter of the thoracic aorta was assessed at three levels (sinus of Valsalva, ascending aorta, and descending aorta) using echocardiograms and cardiovascular magnetic resonance imaging. Aortic dilation at the sinus of Valsalva was found in 32.7% of males and 5.6% of females; aneurysms were present in 9.6% of males and 1.9% of females. No aortic dilation was observed in the descending aorta. There was no correlation between aortic diameter at the sinus of Valsalva and cardiovascular risk factors. CONCLUSION: Fabry disease should be considered as a cardiovascular disease that affects the heart and arterial vasculature, including the thoracic aorta. Thus, patients with FD should be closely monitored for the presence, and possible progression and complications of aortic dilation. CLINICAL TRIAL REGISTRATION: Protocol 101/01. Ethics committee, Faculty of Medicine, Lausanne.

Ascending aorta measurements as assessed by ECG-gated multi-detector computed tomography: a pilot study to establish normative values for transcatheter therapies.

The aim of this study was to provide an insight into normative values of the ascending aorta in regards to novel endovascular procedures using ECG-gated multi-detector CT angiography. Seventy-seven adult patients without ascending aortic abnormalities were evaluated. Measurements at relevant levels of the aortic root and ascending aorta were obtained. Diameter variations of the ascending aorta during cardiac cycle were also considered. Mean diameters (mm) were as follows: LV outflow tract 20.3 +/- 3.4, coronary sinus 34.2 +/- 4.1, sino-tubular junction 29.7 +/- 3.4 and mid ascending aorta 32.7 +/- 3.8 with coefficients of variation (CV) ranging from 12 to 17%. Mean distances (mm) were: from the plane passing through the proximal insertions of the aortic valve cusps to the right brachio-cephalic artery (BCA) 92.6 +/- 11.8, from the plane passing through the proximal insertions of the aortic valve cusps to the proximal coronary ostium 12.1 +/- 3.7, and between both coronary ostia 7.2 +/- 3.1, minimal arc of the ascending aorta from left coronary ostium to right BCA 52.9 +/- 9.5, and the fibrous continuity between the aortic valve and the anterior leaflet of the mitral valve 14.6 +/- 3.3, CV 13-43%. Mean aortic valve area was 582.0 +/- 131.9 mm(2). The variation of the antero-posterior and transverse diameters of the ascending aorta during the cardiac cycle were 8.4% and 7.3%, respectively. Results showed large inter-individual variations in diameters and distances but with limited intra-individual variations during the cardiac cycle. A personalized approach for planning endovascular devices must be considered.

[Cardiomyopathy and cardiac magnetic resonance]. / Rôle de l'IRM cardiaque dans le dépistage des cardiomyopathies de l'adulte.

Cardiovascular magnetic resonance (CMR) is a rapidly emerging non-invasive imaging technique free of X-Ray and offers higher spatial resolution than alternative forms of cardiac imaging for the assessment of left ventricular (LV) anatomy, function, and viability due to the unique capability of myocardial tissue characterization after gadolinium-chelates contrast administration. This imaging technique has clinical utility over a broad spectrum of heart diseases: ranging from ischaemic to non ischaemic aetiologies. Cardiomyopathies (CMP) are a heterogeneous group of diseases of the myocardium associated with architectural abnormalities and mechanical dysfunction. CMR can help excluding coronary artery disease and can provide positive diagnostic features for several CMP resulted in better diagnosis and management, Leading to improvements in mortality.

Detection of ingested cocaine-filled packets--diagnostic value of unenhanced CT.

PURPOSE: Emergency departments are facing nowadays an increasing number of illegal drug-related health problems, associated with medicolegal and/or social consequences. Body stuffers are street cocaine dealers, who either store wrapped packets of drugs in their rectum or hastily swallow them, prompted by fear of police's arrest. These packets can be life threatening in case of leakage. We evaluate the diagnostic value of unenhanced multidetector CT (MDCT) for detection of cocaine-filled packets (CFP) ingested by body stuffers in a phantom model. MATERIALS AND METHODS: Our phantom simulated normal bowel contents in which a varying number of true and false CFP were randomly mixed. Both only differ in radiological density. During 18 different reading sessions, four radiologists independently evaluated the presence and number of true and false CFP. Interobserver agreement, sensitivity, specificity, positive and negative predictive value were calculated. RESULTS: Interobserver agreement for detection of any packets, for visualization of true, and false CFP was good (kappa=0.63, 0.74 and 0.58, respectively). Sensitivity, specificity, positive and negative predictive value for detection of any packets was 95.6%, 100%, 100% and 62.5%, respectively; for visualization of the true CFP 86.5%, 100%, 100% and 77.6%, respectively; and for the false packets 98.1%, 65%, 88.6% and 87.5%, respectively. CONCLUSION: Unenhanced MDCT without bowel preparation is a fast, reliable and easily reproducible imaging modality for the immediate detection of ingested CFP, thus facilitating medicolegal management of body stuffers.

[Forensic imaging]. / L'magerie forensique.

In recent years, modern techniques of medical imaging such as MDCT (multidetector-computed tomography) and MRI (magnetic resonance imaging) have pioneered post mortem (pm) investigations, especially in forensic medicine. Particularly pm angiography permits investigating the vascular system in a way which is not possible by performing only conventional autopsy. Beside these radiological methods, other modem visualizing techniques like the three dimensional (3D) surface scan have been implemented in order perform reconstructions of complex cases. By the use of pm imaging techniques, more objective and accurate documentations can be realized that permit an increase of quality in forensic investigations.

Multiple system atrophy and CAG repeat length: A genetic screening of polyglutamine disease genes in Italian patients.

Multiple system atrophy (MSA) is an adult onset, progressive, neurodegenerative disorder of unknown etiology characterized by autonomic dysfunction, parkinsonism (MSA-P) and cerebellar ataxia (MSA-C). The phenotypic spectrum may present overlapping features with other neurodegenerative diseases, particularly the autosomal dominant inherited polyglutamine disorders. To investigate the possible contribution of CAG expansions in the MSA phenotype, we analyzed the triplet repeat length in the autosomal dominant causative genes for spinocerebellar ataxia (SCA) type 1, 2, 3, 6, 7, 17, dentatorubral-pallidoluysian atrophy (DRPLA) and Huntington disease (HD) in a cohort of 246 Italian MSA patients. As comparison, 223 controls were also analyzed. The alleles were classified on the basis of CAG repeat length as "normal", "intermediate" or "expanded" according to literature. The MSA patients (101 men/145 women) had a mean age at onset of 58 years and a mean age at genetic testing of 63 years. MSA-C patients had significantly younger age at onset and at examination in comparison to MSA-P (p < 0.0001). We identified a SCA1 intermediate allele in a MSA-C subject (36 CAG), a SCA2 intermediate allele in a MSA-P patient (31 CAG), and a pathologically expanded SCA2 allele (36 CAG) in a patient initially misdiagnosed as MSA-C. No intermediate or expanded SCA alleles were detected in controls. The distribution of CAG repeat length was similar among groups except for SCA1 gene that showed a higher percentage of longer normal alleles in MSA-C as compared to MSA-P and controls (p < 0.0001). This study supports the utility of polyQ genetic testing in the differential diagnosis of MSA, and may suggest a possible role of SCA1 repeat length as risk factor for MSA-C. SCA1 and SCA2 genetic screening is recommended in MSA Italian patients.

Cortical thickness, stance control, and arithmetic skill: An exploratory study in premanifest Huntington disease.

BACKGROUND: Huntington disease (HD) is an inherited neurodegenerative disorder most commonly manifesting in adulthood. Identification of biomarkers tracking neurodegeneration before the onset of motor symptoms is important for future interventional studies. Our study aimed to contribute in the phenotypic characterization of the premanifest HD phase. METHODS: 28 premanifest subjects (preHD), 25 age-matched controls, and 12 manifest HD patients were enrolled for the study. The participants underwent a multimodal protocol including cognitive evaluations, arithmetic ability test, posturography, composite cerebellar functional test (CCFS), and brain 3T-MRI. PreHD were divided at the group median for predicted years to expected onset into "far-from-onset" (>15 years, PreHD-far), and "close-to-onset" (≤15 years, preHD-close). Basal ganglia volumes and cortical thickness were computed using FreeSurfer. RESULTS: PreHD-close showed significantly lower scores than controls in Symbol Digit Modalities Test (p = 0.017), Arithmetic subtraction task (p = 0.04), and MMSE (p < 0.006). At posturography, preHD-close showed increased sway velocity (<0.04) and distance (p < 0.02) compared to controls. PreHD-close had reduced striatum and globus pallidus volumes and left occipital cortical thinning compared to controls. Compared to PreHD far-from-onset, PreHD-close showed bilateral cortical thinning in occipital and parahippocampal regions, inversely correlating with burden score and prognostic index for HD. CCFS only differed between controls and manifest HD. PreHD far-from-onset did not show significant differences in comparison with controls. CONCLUSIONS: We confirmed that quantitative brain MRI represents a valid biomarker of neurodegeneration in preHD. Posturography and Arithmentic tests seem promising tools for detecting early changes in premanifest HD, but need to be further confirmed in large cohorts.

Reduced-intensity conditioning containing low-dose alemtuzumab before allogeneic peripheral blood stem cell transplantation: graft-versus-host disease is decreased but T-cell reconstitution is delayed.

OBJECTIVE: In vivo administration of alemtuzumab (an anti-CD52 antibody) is effective to decrease the incidence of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT). However, posttransplant immune reconstitution is impaired, increasing the infection risk. We investigated the effect of in vivo administration of a low-dose alemtuzumab on GVHD prevention and kinetics of immune reconstitution. PATIENTS AND METHODS: Twenty-seven patients entered a pilot study employing reduced-intensity conditioning and low-dose alemtuzumab (15 or 7.5 mg/m2) before peripheral blood allo-SCT from human leukocyte antigen-identical or one antigen-mismatched sibling donors. All lymphoid subsets were longitudinally studied at 1-3, 6, 9, 12 months after transplantation. T-cell receptor (TCR) spectratyping and T-cell receptor excision circles (TRECs) were also analyzed at various time points after allo-SCT. RESULTS: All patients but one were engrafted. The probability of nonrelapse mortality at 100 days and 1 year were 7 and 11%, respectively; the overall survival at 2 years was 77%. The cumulative incidence of grade II-IV acute GVHD at day 100 was 11%. The overall incidence of chronic GVHD was 28%. The median time to achieve more than 200 CD4+/microL and 500 CD8+/microL were 6 and 9 months, respectively. Natural killer cells remained between the value of 300/microL and 500/microL throughout the period of follow-up whereas the median time to reach CD19+ blood concentrations of >200 cells/microL was 9 months. The normalization of TCR repertoire and increase of TREC counts began at 6 months after allo-SCT. CONCLUSION: We have shown that low-dose alemtuzumab is effective for GVHD prevention, but its use still impairs the immune reconstitution.

Long-term follow-up of indolent lymphoma patients treated with high-dose sequential chemotherapy and autografting: evidence that durable molecular and clinical remission frequently can be attained only in follicular subtypes.

PURPOSE: To evaluate the prognostic relevance of molecular monitoring of minimal residual disease in indolent lymphomas receiving high-dose sequential chemotherapy and autografting. PATIENTS, MATERIALS, AND METHODS: A polymerase chain reaction- (PCR-)based strategy was used to evaluate the presence of residual tumor cells in a panel of 70 indolent lymphoma patients: 40 with follicular (FCL), 14 with small lymphocytic (SLL), and 16 with mantle-cell (MCL) lymphomas. They were treated either with first-line (n = 61) or second-line (n = 9) therapy with an intensified high-dose chemotherapy program followed by peripheral-blood progenitor cells autografting. The Bcl-1, Bcl-2, and immunoglobulin gene rearrangements were used as lymphoma-specific markers. Overall, a molecular marker was obtained from the diagnostic tissue in 60 of 70 patients (86%). Results The collection of PCR-negative cells and the achievement of posttransplantation molecular remission (MR) were common in patients with FCL subtype (54% and 70%, respectively), whereas they were not frequent among SLL and MCL (25% and 12.5%, respectively) patients. With a median molecular follow-up of 75 months, an 88% incidence of relapse was observed among patients never attaining MR. In contrast, relapse incidence was only 8% among patients attaining a durable MR (P <.005). At present, 26 patients (20 with FCL and six with non-FCL) are long-term survivors in absence of clinical and molecular disease. CONCLUSION: Our results indicate that among indolent lymphomas, FCL and non-FCL subtypes show a significantly different behavior in terms of MR achievement, and MR after intensive chemotherapy and autografting is predictive for a prolonged disease-free survival, whereas persistent PCR positivity is associated with a high risk of relapse.

Characterization of chronic hepatitis B cases among foreign-born persons in six population-based surveillance sites, United States 2001-2010.

National surveys indicate prevalence of chronic hepatitis B among foreign-born persons in the USA is 5.6 times higher than US-born. Centers for Disease Control and Prevention funded chronic hepatitis B surveillance in Emerging Infections Program sites. A case was any chronic hepatitis B case reported to participating sites from 2001 to 2010. Sites collected standardized demographic data on all cases. We tested differences between foreign- and US-born cases by age, sex, and pregnancy using Chi square tests. We examined trends by birth country during 2005-2010. Of 36,008 cases, 21,355 (59.3%) reported birth in a country outside the USA, 2,323 (6.5%) were US-born. Compared with US-born, foreign-born persons were 9.2 times more frequent among chronic hepatitis B cases. Foreign-born were more frequently female, younger, ever pregnant, and born in China. Percentages of cases among foreign-born persons were constant during 2005-2010. Our findings support information from US surveillance for Hepatitis B screening and vaccination efforts.