PIGQ-Related Glycophosphatidylinositol Deficiency Associated with Nonprogressive Congenital Ataxia.

The glycophosphatidylinositol (GPI) anchor pathway plays an essential role in posttranslational modification of proteins to facilitate proper membrane anchoring and trafficking to lipid rafts, which is critical for many cell functions, including embryogenesis and neurogenesis. GPI biosynthesis is a multi-step process requiring the activity of over 25 distinct genes, most of them belonging to the phosphatidylinositol glycan (PIG) family and associated with rare neurodevelopmental disorders. PIGQ encodes the phosphatidylinositol glycan class Q protein and is part of the GPI-N-acetylglucosaminyltransferase complex that initiates GPI biosynthesis from phosphatidylinositol (PI) and N-acetylglucosamine (GlcNAc) on the cytoplasmic side of the endoplasmic reticulum (ER). Pathogenic variants in the PIGQ gene have been previously reported in 10 patients with congenital hypotonia, early-infantile epileptic encephalopathy, and premature death occurring in more than half cases. We detected a novel homozygous variant in PIGQ (NM_004204.5: c.1631dupA; p.Tyr544fs*79) by WES trio-analysis of a male patient with a neurodevelopmental disorder characterized by nonprogressive congenital ataxia, intellectual disability, generalized epilepsy, and cerebellar atrophy. Flow cytometry confirmed deficiency of several GPI-anchored proteins on leukocytes (CD14, FLAER). Clinical features of this case broaden the phenotypic spectrum of PIGQ-related GPI deficiency, outlining the importance of glycophosphatidylinositol (GPI) anchor pathway in the pathogenesis of cerebellar ataxia.

Natural history of a cohort of ABCD1 variant female carriers.

BACKGROUND AND PURPOSE: The therapeutic scenario of X-linked adrenoleukodystrophy (X-ALD) is rapidly changing. Whereas the disease is well characterized in men, the condition remains to be fully clarified in women carrying ATP binding cassette subfamily D member 1 (ABCD1) variants. Specifically, data on clinical progression are needed, in order to recommend any appropriate management. The objective of this study was to outline the natural history of a cohort of untreated ABCD1 heterozygous female carriers. METHODS: Longitudinal data from a single-center population of 60 carriers were retrospectively reviewed. Demographics, anthropometrics, serum very long chain fatty acid (VLCFA) levels, clinical parameters and the Adult ALD Clinical Score (AACS) were collected from every recorded visit in a 7-year period and analyzed to define the phenotype modifications, to determine factors associated with clinical features, and to estimate the annual progression rate and the subsequent sample size for interventional trials. RESULTS: Thirty-two patients were eligible for the study, and 59.4% were symptomatic at baseline. Clinical severity worsens with age which increases risk of symptom onset, the cut-off of 41 years being crucial for phenoconversion. VLCFA levels were not predictive and did not change over time. Symptomatic carriers were followed up for 3.45 ± 2.1 years. The AACS increased at an annual rate of 0.24 points. The estimated sample size for 30% reduction in annual progression at 80% power was 272. CONCLUSIONS: This study provides data on the natural disease progression of untreated ABCD1 heterozygous female carriers, demonstrating the relevance of aging. The estimated annual increase of the AACS will be useful for future interventional studies.

Comparison of self-expanding and balloon-expandable transcatheter aortic valves morphology and association with paravalvular regurgitation: Evaluation using multidetector computed tomography.

OBJECTIVES: Compare final morphology of self-expanding and balloon-expandable prosthesis and association with paravalvular regurgitation (PVR). BACKGROUND: PVR after transcatheter aortic valve replacement (TAVR) remains a frequent complication. A better understanding of the prosthesis geometry may be important to improve selection of the best device for each case and possibly reduce the rates of PVR. METHODS: Retrospective study including patients consecutively submitted to transcatheter aortic valve replacement: August/2007-October/2016. Three months after the procedure a multidetector computed tomography (MDCT) was performed to assess prosthesis geometry: dimensions, eccentricity, and expansion. RESULTS: A total of 147 individuals were included (mean age of 78.8 ± 6.7 and 50.3% males), 57% treated with a self-expanding prosthesis. On the postprocedure MDCT, the self-expanding group had higher eccentricity index (15.0 vs. 7.1%, p < .001) and lower expansion (68.3 vs. 82.8%, p < .001). In that group, the volume of calcium of landing zone had a significant correlation with eccentricity index and under-expansion. Patients with ≥mild PVR presented higher eccentricity (12.6 vs. 7.9%, p < .001) and lower expansion (68 vs. 75%, p = .012). Eccentricity index and landing zone calcium volume were independent predictors of PVR. CONCLUSIONS: Self-expanding prosthesis have greater eccentricity and under-expansion. Calcium burden exerts more influence in the final morphology of that type of valve. Calcification and eccentricity are associated with the development of PVR. These factors should be considered in the selection of the most appropriate type of prosthesis for each scenario.

BNP and NT-proBNP elevation after running--a systematic review.

OBJECTIVE: A systematic review was carried out to study the pattern of BNP and NT-proBNP release after running. METHODS: Data were collected by searching the PubMed, ISI Web of Knowledge and Scopus databases. RESULTS: Fifty-three reports were identified as meeting the pre-specified criteria. Twenty-seven reports, representing 1,034 participants, presented data comparing post-running BNP or NT-proBNP levels with a pre-specified cut-off. Values exceeding the upper reference limit were seen in 22.9% and 35.9% of runners, respectively. CONCLUSION: Studies have shown post-running values exceeding the upper reference limit in up to a third of runners.

Validation of low-cost system for gait assessment in children with ataxia.

BACKGROUND: Ataxic syndromes include several rare, inherited and acquired conditions. One of the main issues is the absence of specific, and sensitive automatic evaluation tools and digital outcome measures to obtain a continuous monitoring of subjects' motor ability. OBJECTIVES: This study aims to test the usability of the Kinect system for assessing ataxia severity, exploring the potentiality of clustering algorithms and validating this system with a standard motion capture system. METHODS: Gait evaluation was performed by standardized gait analysis and by Kinect v2 during the same day in a cohort of young patient (mean age of 13.8±7.2). We analyzed the gait spatio-temporal parameters and we looked at the differences between the two systems through correlation and agreement tests. As well, we tested for possible correlations with the SARA scale as well. Finally, standard classification algorithm and principal components analysis were used to discern disease severity and groups. RESULTS: We found biases and linear relationships between all the parameters. Significant correlations emerged between the SARA and the Speed, the Stride Length and the Step Length. PCA results, highlighting that a machine learning approach combined with Kinect-based evaluation shows great potential to automatically assess disease severity and diagnosis. CONCLUSIONS: The spatio-temporal parameters measured by Kinect cannot be used interchangeably with those parameters acquired with standard motion capture system in clinical practice but can still provide fundamental information. Specifically, these results might bring to the development of a novel system to perform easy and quick evaluation of gait in young patients with ataxia, useful for patients stratification in terms of clinical severity and diagnosis.

Spatio-temporal parameters of ataxia gait dataset obtained with the Kinect.

Ataxic syndromes include several rare, inherited and acquired conditions. One of the main issues is the absence of specific, and sensitive automatic evaluation tools and digital outcome measures to obtain a continuous monitoring of subjects' motor ability. Gait evaluation was performed by Kinect v2 in a cohort of young participant affected by ataxia syndrome. The dataset is composed of the spatio-temporal parameters calculated by the skeleton acquired by the Kinect sensor, by the diagnosis of each participant, and by the total score of the clinical scale SARA. These parameters have been previously validated and corrected as requested by the Bland-Altman test.

EMG-based Indicators of Muscular Co-Activation during Gait in Children with Duchenne Muscular Dystrophy.

Muscular weakness is one of the main signs associated with the onset and progression of Duchenne Muscular Dystrophy. During motor functions, this disease also determines deviations in muscular activity, especially in terms of coordination and activation between muscles acting on the same joints. In this study, surface EMG activity of the lower limb muscles of 10 children with Duchenne Muscular Dystrophy at different times from disease onset were recorded along with kinematics during unconstrained gait. Muscular co-activation of muscle pairs was then evaluated by extracting different co-activation indicators, and linking them with kinematic markers of motor function. The combination of disease progression and pharmacological treatment resulted in a significant decrease in terms of co-activation indexes for two pairs of agonist-antagonist muscles, and for one of these two pairs the decrease in co-activation was correlated with a decrease in the motor function of gait.

A clinical diagnostic algorithm for early onset cerebellar ataxia.

Early onset cerebellar Ataxia (EOAc) comprises a large group of rare heterogeneous disorders. Determination of the underlying etiology can be difficult given the broad differential diagnosis and the complexity of the genotype-phenotype relationships. This may change the diagnostic work-up into a time-consuming, costly and not always rewarding task. In this overview, the Childhood Ataxia and Cerebellar Group of the European Pediatric Neurology Society (CACG-EPNS) presents a diagnostic algorithm for EOAc patients. In seven consecutive steps, the algorithm leads the clinician through the diagnostic process, including EOA identification, application of the Inventory of Non-Ataxic Signs (INAS), consideration of the family history, neuro-imaging, laboratory investigations, genetic testing by array CGH and Next Generation Sequencing (NGS). In children with EOAc, this algorithm is intended to contribute to the diagnostic process and to allow uniform data entry in EOAc databases.

[Influence of the male genomic imprinting on the reproduction]. / Influencia de la impronta genómica masculina en la reproducción.

OBJECTIVE: Genomic imprinting is the epigenetic change that occurred differentially in the specific genes in spermatozoa and oocyte according to their paternal or maternal origin, thus allowing a monoallelic expression. This review is a critical analysis of the published information relating to the role of the male imprinting on the successful reproduction. METHODS: We performed a literature search on some of the components that regulate the male genomic imprinting and the possible role on reproductive events such as spermatogenesis, and placental and embryo development. RESULTS: The literature analysis allowed us to appreciate structural, genetic and epigenetic changes occurring during the formation of the male gamete that could have an impact on embryo development, mainly in the formation of extraembryonic tissues as the placenta. CONCLUSION: Alterations in the molecular mechanisms involved in the sperm DNA methylation during the spermatogenesis, could induce alterations in the normal pattern of expression required in the fetal-placental components development.

Acute coronary syndrome and depression.

INTRODUCTION: Clinical depression is associated with poor compliance in risk reduction recommendations and has been suggested as an independent risk factor for increased postmyocardial infarction morbidity and mortality. AIM: To determine the prevalence of depressive symptoms, their main determinants and their influence on clinical evolution in acute coronary syndromes (ACS) patients. METHODS: We studied depressive symptoms, sociodemographic variables, cardiovascular status and therapeutic procedures in 240 consecutive patients admitted for ACS. Depressive symptoms were assessed using the Beck Depression Inventory (BDI) after clinical stabilization, in patients with more than 4 years' education. RESULTS: The majority of the patients were male (203); their average age was 59.4 +/- 13 yrs; 31.8% were admitted for unstable angina, 33.1% for acute myocardial infarction with ST elevation and 31.8% without ST elevation. Depressive symptoms (BDI > or =10) were present in 100 patients (41.6%). Depressed patients were older (61.1 vs. 58.2 years, p = 0.06) and had a history of previous cardiovascular events /47.5 vs. (34.8% p = 0.05). The proportion of female was higher in the group of patients with BDI > or =10 (24% vs. 9.3%, p = 0.02). Traditional cardiovascular risk factors were not associated with depressive symptoms. There were no statistically significant differences between the depressed and non-depressed patients in admission diagnosis, in-hospital clinical evolution and treatment. There were 35 patients (14.6%) with moderate/severe depression (BDI > or =19), 12 of whom were women (OR = 3.8, p = 0.001); no relation was established between age and previous cardiac events. These scores were less frequent in patients with a higher level of education (OR = 0.28, p = 0.09) and married (OR = 0.31 vs. not married, p = 0.03). Clinical follow-up of 158 patients was achieved (16 +/- 4 months), in patients with BDI > or =19, the presence of cardiovascular symptoms (angina, congestive heart failure) was higher (46% vs. 23%, OR = 2.8, p = 0.03), even after adjustment for age (OR = 2.5; p = 0.06). However, there was no association between the presence of depressive symptoms and readmission and/or fatal events. CONCLUSION: Depression is a common finding after hospital admission for ACS, particularly in women, and is mainly associated with prehospital factors. In our group of patients, the presence of depressive symptoms was closely related to clinical status during follow-up.

Acute coronary syndrome and predictors of quality of life.

INTRODUCTION: Coronary disease in its various forms of presentation is associated with a reduction in the patients' own perception of their quality of life (QoL). QoL is an important measure of effectiveness of treatment; however, the predictors of QoL after admission for acute coronary syndrome (ACS) are not completely clear. AIM: To identify the clinical, demographic and psychosocial characteristics of patients admitted for ACS that were predictive of QoL in clinical follow-up. METHODS: Physical and mental QoL were prospectively evaluated in 278 patients admitted for ACS, using Short Form-36 v2 physical (PCS) and mental (MCS) component summary scales. Based on the median PCS (55) and MCS (56) scores, the population was divided into two groups. Depressive symptoms were assessed using the Beck Depression Inventory. RESULTS: The patients with a better QoL perception were male, young, smokers and had more than 12 years' education. A greater proportion of patients with PCS and MCS below the median score presented prior cardiovascular events and depressive symptoms. A worse physical QoL perception was more common in unmarried, hypertensive and diabetic patients. There was no association between clinical evolution or in-hospital complications and baseline QoL scores. Baseline PCS and MCS were 55 +/- 24 and 55 +/- 27 and at 16 months, 63 +/- 25 and 66 +/- 29. Clinical follow-up was achieved in 181 patients. A worse mental QoL perception at follow-up was related to female gender, baseline MCS < 56 and depressive symptoms. A PCS below median score at follow-up was more frequent in women and in patients with prior cardiovascular events, hypertension, diabetes, dyslipidemia and a lower level of education. Patients with better physical QoL at follow-up were smokers, presented higher baseline PCS and MCS, and had fewer depressive symptoms. Percutaneous myocardial revascularization was associated with a better physical QoL. In a logistic regression model the independent predictors of PCS were: gender, baseline PCS, level of education and prior cardiovascular events. Gender and depressive symptoms were independent predictors of MCS. CONCLUSIONS: In the study population, baseline clinical and psychosocial characteristics were the most important predictors of QoL after ACS. Depression was associated with worse mental QoL. In-hospital evolution and treatment did not appear to strongly affect patients' follow-up perceptions of QoL.

Transcatheter device occlusion of atrial septal defects and patent foramen ovale under intracardiac echocardiographic guidance.

BACKGROUND: Transcatheter device occlusion of atrial septal defects is becoming an effective alternative to surgery. In order to avoid the discomfort of transesophageal echocardiography and the need for general anesthesia we started using intracardiac ultrasound (ICUS) to guide device implantation in adult patients. OBJECTIVE: To assess the efficacy and safety of transcatheter closure of atrial septal defect (ASD) and patent foramen ovale (PFO) assisted by ICUS. METHODS: Between April 2001 and November 2002, 27 patients with ASD and four patients with PFO were selected for transcatheter device occlusion. Patient selection was based on previous transesophageal echocardiogram and clinical data. All patients were treated without anesthesia or sedation. The percutaneous occlusion technique was assisted by ICUS and fluoroscopy. Morphological aspects of the defect and measurement of its largest diameter were used to select device diameter. RESULTS: Thirty-one patients were treated (27 with ASD, four with PFO); 21 (68%) were female, mean age was 40.1+/-13.5 years, and mean ASD diameter was 20.1+/-6.4 mm. We implanted ASD Amplatzer occluding devices in all ASD patients, the size being selected by adding 4 to 6 mm to the maximum ASD diameter. The patients with PFO had an Amplatzer PFO occluder. Mean total procedure time was 50.1+/-18.9 minutes and mean fluoroscopy time was 11.7+/-5.9 minutes. All devices were successfully deployed. We had neither complications nor mortality. Follow-up evaluation was performed by transthoracic echocardiography at 24 hours, one, six and 12 months after occlusion. During a mean follow-up period of 8.5+/-7.1 months, all patients were free of symptoms and on transthoracic echocardiographic evaluation at 24 hours all but three patients had complete occlusion (three ASD patients had insignificant residual shunt), with 100% occlusion rate at six months. CONCLUSIONS: Transcatheter occlusion of atrial septal defects can be effectively and safely performed using ICUS to guide device implantation in selected adult patients.

Value of fractional flow reserve in the management of patients with moderate coronary stenosis.

INTRODUCTION: A considerable number of patients present a single intermediate lesion (>40% and <70%) in one coronary artery on coronary angiography, with no clear evidence that the lesion is responsible for the patient's symptoms. Fractional flow reserve is a method of evaluating the functional importance of stenosis, a value of <0.75 indicating hemodynamically significant lesions. The aim of this study is to determine the safety of non-revascularization of an angiographically moderate and hemodynamically non-significant lesion. METHODS: Fractional flow reserve (FFR) was evaluated in 87 patients over a period of 34 months. Retrospective analysis and follow-up were conducted of patients referred for coronary angiography, without acute coronary syndrome, who presented an angiographically moderate lesion of a single epicardial coronary artery with an FFR of 0.75, and in whom intervention was deferred. RESULTS: We found 21 patients with a mean age of 66 years, 66.7% male. All patients presented vascular risk factors, 14 with prior cardiovascular events. Before coronary angiography 7 patients were asymptomatic, 7 had atypical symptoms and 7 presented CCS class 2 angina. Among these patients, 16 performed a non-invasive stress test, which was positive in 11 patients and inconclusive or doubtful in the others. Angiographically most of the lesions were located in the left anterior descending artery (12 patients). In the 19 +/- 12-month follow-up, 16 patients were asymptomatic and the others maintained the same symptoms. There was no change in the amount of antianginal drugs prescribed. No cardiac events occurred. CONCLUSION: FFR is a useful tool when clinical symptoms and non-invasive tests are inconclusive in the presence of moderate stenosis in a coronary artery. In our group of patients, the decision to defer intervention based on an FFR of 0.75 was found to be safe and associated with absence of clinical events.

[Myocardial revascularization surgery, depressive symptoms and labeling effect]. / Cirurgia de revascularização miocárdica, sintomas depressivos e efeito rotulação.

INTRODUCTION: The individual awareness of one's own disease, the so called labeling effect, may result in a reduction of one's sense of perceived health. In patients submitted to coronary artery bypass surgery it has been reported that the diagnosis of depression is associated with a higher rate of hospitalization and it's an independent risk factor for cardiac events. The aim of this study was to evaluate the modification of depressive symptoms induced by the information of medical indication for myocardial revascularization surgery. METHODS: We studied the presence of depressive symptoms, socio-demographic variables, cardiovascular status and therapeutic procedures in two groups of consecutive patients admitted for acute coronary syndrome. In the labeled group the BDI-1 was performed after clinical stabilization and the BDI-2 after the information of myocardial revascularization surgery need. In the control group the BDI-1 was answered after clinical stabilization and the BDI-2 48-72 hours later. The Mann-Whitney test was used to compare the difference of depressive symptoms between the groups. RESULTS: Distribution by age, marital status and education level was similar between the two groups. The cardiovascular risk profile was alike. The difference between BDI-1 and BDI-2 was significantly higher in the labeled group (4.6-/+4.2 vs 0.8-/+3.2; p=0.005). There were no significant differences between the final diagnosis (unstable angina in the labeled group 50% vs control group 45.5%; AMI without Q wave 30% vs 27.3%; AMI with Q wave 20% vs 27.3%) and in hospital clinical evolution. CONCLUSION: The individual awareness of the need to coronary bypass surgery was associated with a clinical and statistical significant increase of depressive symptoms. Hence, routine evaluation of depressive symptoms as a part of a preoperative protocol, may allow identification of the patients, who may benefit from therapeutic intervention.

Variations in the vulvar temperature of sows during proestrus and estrus as determined by infrared thermography and its relation to ovulation.

The prediction of ovulation time is one of the most important and yet difficult processes in pig production, and it has a considerable impact on the fertility of the herd and litter size. The objective of this study was to assess the vulvar skin temperature of sows during proestrus and estrus using infrared thermography and to establish a possible relationship between the variations in vulvar temperature and ovulation. The experimental group comprised 36 crossbred Large White × Landrace females, of which 6 were gilts and 30 were multiparous sows. Estrus was detected twice daily and the temperature was obtained every 6 hours from the vulvar area and from two control points in the gluteal area (Gluteal skin temperature [GST]). A third variable, vulvar-gluteal temperature (VGT) was obtained from the difference between the vulvar skin temperature and the GST values. The animals were divided into two subgroups: group A consisting of 11 animals with estrus detected at 6:00 AM, Day 4 postweaning, and group B comprising seven animals with estrus detected at 6:00 AM, Day 5 post-weaning. Both groups showed a similar trend in the VGT. The VGT increased during the proestrus, reaching a peak 24 hours before estrus in group A and 48 hours before estrus in group B. The VGT then decreased markedly reaching the lowest value in groups A and B, respectively, 12 and 6 hours after estrus. Although the time of ovulation was only estimated on the basis of a literature review, the matching between the temporal variations of the VGT values and the predicted time of the peak of estradiol secretion that ultimately leads to the ovulation processes suggests that the VGT values represent a potential predictive marker of the ovulatory events.

Respiratory and cardiac function in congenital muscular dystrophies with alpha dystroglycan deficiency.

The aim of this retrospective study was to assess respiratory and cardiac function in a large cohort of patients with congenital muscular dystrophies (CMD) with reduced glycosylation of alphadystroglycan (α-DG). Thirteen of the 115 patients included in the study died between the age of 1 month and 20 years. The age at last follow up of the surviving 102 ranged between 1 year and 68 years (median: 9.3 years). Cardiac involvement was found in 7 of the 115 (6%), 5 with dilated cardiomyopathy, 1 cardiac conductions defects and 1 mitral regurgitation. Respiratory function was impaired in 14 (12%). Ten of the 14 required non invasive nocturnal respiratory support, while the other four required invasive ventilation. Cardiac or respiratory involvement was found in patients with mutations in FKRP, POMT1, POMT2. All of the patients in whom mutation in POMGnT1 were identified had normal cardiac and respiratory function.

Functional changes in Duchenne muscular dystrophy: a 12-month longitudinal cohort study.

OBJECTIVE: The aim of the study was to assess different outcome measures in a cohort of ambulant boys with Duchenne muscular dystrophy (DMD) over 12 months in order to establish the spectrum of possible changes in relation to age and steroid treatment. METHODS: The study is a longitudinal multicentric cohort study. A total of 106 ambulant patients with DMD were assessed using the 6-minute walk test (6MWT) and North Star Ambulatory Assessment (NSAA) at baseline and 12 months. Clinical data including age and steroid treatment were collected. RESULTS: During the 12 months of the study, we observed a mean decline of 25.8 meters in the 6MWT with a SD of 74.3 meters. On NSAA, the mean decline was 2.2 points with a SD of 3.7. Not all the boys with DMD in our cohort showed a decline over the 12 months, with young boys showing some improvement in their 6MWT and NSAA scores up to the age of 7. NSAA and the 6MWT had the highest correlation (r = 0.52, p < 0.001). CONCLUSIONS: This study provides longitudinal data of NSAA and 6MWT over a 12-month period. These data can be useful when designing a clinical trial.

Congenital muscular dystrophies with cognitive impairment. A population study.

BACKGROUND: Cognitive impairment has been reported in a significant proportion of patients with congenital muscular dystrophies (CMD), generally associated with brain changes. OBJECTIVES: The aim of this study was to establish 1) the overall prevalence of CMD and cognitive impairment in the Italian population; 2) the frequency of individual genetically defined forms; and 3) the presence of distinct phenotypes not associated with mutations in the known genes. METHODS: We included all patients with CMD and cognitive impairment followed in all the Italian tertiary neuromuscular centers. Clinical, brain MRI, and morphologic data were collected. Genetic screening of the known genes was performed according to clinical and muscle biopsy findings. RESULTS: Ninety-two of the 160 (58%) patients with CMD followed in our centers had cognitive impairment. alpha-Dystroglycan (alpha-DG) reduction on muscle biopsy was found in 73/92 (79%), with 42/73 carrying mutations in the known genes. Another 6/92 (7%) showed a laminin alpha2 deficiency on muscle biopsy and 5 of the 6 carried mutations in LAMA2. The remaining 13/92 (14%) patients had normal alpha-DG and laminin alpha2 expression on muscle. CONCLUSIONS: This is the first population study establishing the prevalence of CMD and cognitive impairment and providing a classification on the basis of clinical, MRI, and genetic findings. We also showed that cognitive impairment was not always associated with alpha-DG or laminin alpha2 reduction or with structural brain changes.