-
1.
Correlation of ATP7B gene mutations with clinical phenotype and radiological features in Indian Wilson disease patients.
Chaudhuri, J, Biswas, S, Gangopadhyay, G, Biswas, T, Datta, J, Biswas, A, Pandit, A, Datta, AK, Mukherjee, A, Dutta, AK, et al
Acta neurologica Belgica. 2022;(1):181-190
Abstract
INTRODUCTION Wilson disease (WD) is characterized by a wide variety of clinical manifestations. Our study aimed to correlate genotype with clinical and radiological features in Indian WD patients. METHODS We conducted a descriptive observational study in a tertiary care neurology referral center of eastern India over a period of 2 years. Demographic data collection, clinical examination and relevant investigations were done for all WD patients meeting the inclusion criteria. Based on previous reports of mutation hotspots for WD in Eastern India, we performed PCR-Sanger sequencing of selected exons of ATP7B gene. To understand the role of each of these covariates on the occurrence of common mutation, we applied a logistic regression as well as random forest in a supervised learning framework. RESULTS Fifty-two WD patients were included in the study. c.813C > A (p.C271X) was the commonest identified mutation. The statistical methods applied to our data-set reveal the most important features for predicting common mutation or its absence. We also found that the state-of-the-art classification algorithms are good at predicting the absence of common mutation (with true positive rates being 0.7647 and 0.8823 for logistic classifier and random forest, respectively), but predicting the occurrence remains a harder modeling challenge. CONCLUSIONS WD patients in eastern India have significant genotypic and phenotypic diversity. Statistical methods for binary classification show some early promise of detecting common mutations and suggest important covariates, but further studies with larger samples and screening of remaining exons are warranted for understanding the full genetic landscape of Wilson disease.
-
2.
Familial Dilated Cardiomyopathy and Sudden Cardiac Arrest: New Association with a SCN5A Mutation.
Rico, Y, Ramis, MF, Massot, M, Torres-Juan, L, Pons, J, Fortuny, E, Ripoll-Vera, T, González, R, Peral, V, Rossello, X, et al
Genes. 2021;(12)
Abstract
Dilated cardiomyopathy (DCM) has significant morbidity and mortality. Familial transmission is reported in 20-35% of cases, highlighting the role of genetics in this disorder. We present an interesting family in which the index case is a 64-year-old woman who survived a sudden cardiac arrest. She presented left ventricular dilatation and dysfunction, which indicated the presence of DCM, as well as a history of DCM and sudden arrest in her family (mother and sister). Genetic testing identified a heterozygous mutation c.74A > G missense change that causes an amino acid, p.Glu25Gly, change in the N-terminal domain of the SCN5A protein. After performing an exhaustive family medical history, we found that this previously not described mutation segregated within the family. All relatives with the DCM phenotype were carriers, whereas none of the noncarriers showed signs of heart disease, so this mutation is the most likely cause of the disease. This is the first time that a variant in the N-terminal domain of SCN5A has been associated with DCM.
-
3.
The P274S Mutation of Lecithin-Cholesterol Acyltransferase (LCAT) and Its Clinical Manifestations in a Large Kindred.
Fountoulakis, N, Lioudaki, E, Lygerou, D, Dermitzaki, EK, Papakitsou, I, Kounali, V, Holleboom, AG, Stratigis, S, Belogianni, C, Syngelaki, P, et al
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2019;(4):510-522
Abstract
RATIONALE & OBJECTIVE Lecithin-cholesterol acyltransferase (LCAT) catalyzes the maturation of high-density lipoprotein. Homozygosity for loss-of-function mutations causes familial LCAT deficiency (FLD), characterized by corneal opacities, anemia, and renal involvement. This study sought to characterize kidney biopsy findings and clinical outcomes in a family with FLD. STUDY DESIGN Prospective observational study. SETTING & PARTICIPANTS 2 (related) index patients with clinically apparent FLD were initially identified. 110 of 122 family members who consented to genetic analysis were also studied. PREDICTORS Demographic and laboratory parameters (including lipid profiles and LCAT activity) and full sequence analysis of the LCAT gene. Kidney histologic examination was performed with samples from 6 participants. OUTCOMES Cardiovascular and renal events during a median follow-up of 12 years. Estimation of annual rate of decline in glomerular filtration rate. ANALYTICAL APPROACH Analysis of variance, linear regression analysis, and Fine-Gray competing-risk survival analysis. RESULTS 9 homozygous, 57 heterozygous, and 44 unaffected family members were identified. In all affected individuals, full sequence analysis of the LCAT gene revealed a mutation (c.820C>T) predicted to cause a proline to serine substitution at amino acid 274 (P274S). Homozygosity caused a complete loss of LCAT activity. Kidney biopsy findings demonstrated lipid deposition causing glomerular basement membrane thickening, mesangial expansion, and "foam-cell" infiltration of kidney tissue. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with worse kidney outcomes. Estimated glomerular filtration rate deteriorated among homozygous family members at an average annual rate of 3.56 mL/min/1.73 m2. The incidence of cardiovascular and renal complications was higher among homozygous family members compared with heterozygous and unaffected members. Mild thrombocytopenia was a common finding among homozygous participants. LIMITATIONS The presence of cardiovascular disease was mainly based on medical history. CONCLUSIONS The P274S LCAT mutation was found to cause FLD with renal involvement. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with a worse renal prognosis.
-
4.
Clinical, pathophysiological and genetic features of motor symptoms in autosomal dominant Alzheimer's disease.
Vöglein, J, Paumier, K, Jucker, M, Preische, O, McDade, E, Hassenstab, J, Benzinger, TL, Noble, JM, Berman, SB, Graff-Radford, NR, et al
Brain : a journal of neurology. 2019;(5):1429-1440
-
-
Free full text
-
Abstract
Owing to an early and marked deposition of amyloid-β in the basal ganglia, autosomal dominant Alzheimer's disease could distinctly involve motor symptoms. Therefore, we aimed to assess the prevalence and characteristics of motor signs in autosomal dominant Alzheimer's disease. Baseline Unified Parkinson Disease Rating Scale part three scores (UPDRS-III) from 433 participants of the Dominantly Inherited Alzheimer's Network observational study were analysed. Motor symptoms were scrutinized with respect to associations with mutation carrier status, mutation site within PSEN1, basal ganglia amyloid-β as measured by Pittsburgh compound B PET, estimated years to symptom onset and Clinical Dementia Rating Scale-Sum of Boxes. Motor findings in mutation carriers were compared to patients with sporadic Alzheimer's disease using data of the National Alzheimer's Coordination Center. Mutation carriers showed motor findings at a higher frequency (28.4% versus 12.8%; P < 0.001) and severity (mean UPDRS-III scores 2.0 versus 0.4; P < 0.001) compared to non-carriers. Eleven of the 27 UPDRS-III items were statistically more frequently affected in mutation carriers after adjustment for multiple comparisons. Ten of these 11 items were subscale components of bradykinesia. In cognitively asymptomatic mutation carriers, dysdiadochokinesia was more frequent compared to non-carriers (right hand: 3.8% versus 0%; adjusted P = 0.023; left: 4.4% versus 0.6%; adjusted P = 0.031). In this cohort, the positive predictive value for mutation carrier status in cognitively asymptomatic participants (50% a priori risk) of dysdiadochokinesia was 100% for the right and 87.5% for the left side. Mutation carriers with motor findings more frequently were basal ganglia amyloid-β positive (84% versus 63.3%; P = 0.006) and showed more basal ganglia amyloid-β deposition (Pittsburgh compound B-standardized uptake value ratio 2.472 versus 1.928; P = 0.002) than those without. Frequency and severity of motor findings were greater in post-codon 200 PSEN1 mutations (36%; mean UPDRS-III score 3.03) compared to mutations pre-codon 200 PSEN1 (19.3%, P = 0.022; 0.91, P = 0.013). In mutation carriers, motor symptom severity was significantly positively correlated with basal ganglia amyloid-β deposition, Clinical Dementia Rating scores and estimated years to symptom onset. Mutation carriers with a Clinical Dementia Rating global score of 2 exhibited more pronounced motor symptoms than sporadic Alzheimer's disease patients with the same Clinical Dementia Rating global score (mean UPDRS-III scores 20.71 versus 5.96; P < 0.001). With a prevalence of approximately 30% and increasing severity with progression of dementia, motor symptoms are proven as a clinically relevant finding in autosomal dominant Alzheimer's disease, in particular in advanced dementia stages, that correlates with deposition of amyloid-β in the basal ganglia. In a very small per cent of cognitively asymptomatic members of families with autosomal dominant Alzheimer's disease, dysdiadochokinesia may increase the chance of an individual's status as mutation carrier.
-
5.
An observational study of functional abilities in infants, children, and adults with type 1 SMA.
Pane, M, Palermo, C, Messina, S, Sansone, VA, Bruno, C, Catteruccia, M, Sframeli, M, Albamonte, E, Pedemonte, M, D'Amico, A, et al
Neurology. 2018;(8):e696-e703
-
-
Free full text
-
Abstract
OBJECTIVE To report cross-sectional clinical findings in a large cohort of patients affected by type 1 spinal muscular atrophy. METHODS We included 122 patients, of age ranging between 3 months and 22 years, 1 month. More than 70% (85/122) were older than 2 years and 25% (31/122) older than 10 years. Patients were classified according to the severity of phenotype and to the number of SMN2 copies. RESULTS Patients with the more common and the most severe phenotype older than 2 years were, with few exceptions, on noninvasive ventilation and, with increasing age, more often had tracheostomy or >16-hour ventilation and a gastrostomy inserted. In contrast, 25 of the 28 patients with the mildest phenotype older than 2 years had no need for tracheostomy or other ventilatory or nutritional support. In patients older than 2 years, the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores were generally lower compared to those found in younger patients and showed distinct levels of functional abilities according to the severity of the phenotype. Similar findings were also observed on the Hammersmith Infant Neurological Examination. CONCLUSIONS Our findings confirm that, after the age of 2 years, patients with type 1 spinal muscular atrophy generally survive only if they have gastrostomy and tracheostomy or noninvasive ventilation >16 hours and have low scores on the functional scales. More variability, however, can be expected in those with the mildest phenotype, who achieve head control. These data provide important baseline information at the time treatments are becoming available.
-
6.
HCMV UL97 phosphotransferase gene mutations may be associated with antiviral resistance in immunocompromised patients in Belém, PA, Northern Brazil.
Silva, DFLD, Cardoso, JF, Silva, SPD, Arruda, LMF, Medeiros, RLF, Moraes, MM, Sousa, RCM
Revista da Sociedade Brasileira de Medicina Tropical. 2018;(2):141-145
Abstract
INTRODUCTION Human cytomegalovirus is one of the causes of opportunist infections in immunocompromised patients, and is triggered by factors such as state of viral latency, weakened immune responses, and development of antiviral resistance to ganciclovir, the only drug offered by the public health system in Brazil to treat the infection. The goal of this study was to identify mutations that may be associated with antiviral resistance in immunocompromised patients. METHODS Molecular analysis was performed in 82 blood samples and subjected to genomic DNA extraction by a silica-based method. Three sequences of the HCMV UL97 gene, which encodes a phosphotransferase protein required for activation of ganciclovir, were amplified by polymerase chain reaction. Pyrosequencing methods were applied to one external 2096-bp segment DNA and two internal sequences between nucleotides 1087 to 1828 to detect mutations in this gene. RESULTS Approximately 10% of sequences contained mutations between nucleotides 377 and 594, in conserved regions of the UL97 gene, leading to amino acid changes. Eleven coding mutations were identified, including changes leading to amino acid substitutions, E596K and S604F, which were observed in 100% of samples and are described for the first time in Brazil. In addition, one mutation (A594V) that is associated with ganciclovir resistance was detected in a kidney transplant patient. CONCLUSIONS Further studies to detect mutations associated with HCMV resistance to antiviral drugs are required to demonstrate the need to increase the variety and availability of drugs used to treat viral infections in the public health care system in Brazil.
-
7.
JAK2V617F and calreticulin mutations in recurrent venous thromboembolism: results from the EDITH prospective cohort.
Ianotto, JC, Chauveau, A, Mottier, D, Ugo, V, Berthou, C, Lippert, E, Delluc, A
Annals of hematology. 2017;(3):383-386
Abstract
Cancer incidence in patients with recurrent unprovoked venous thromboembolism (VTE) is much higher than after a first event, but the incidence of myeloproliferative neoplasms (MPN) in this situation is still unknown. We tested for JAK2V617F and calreticulin mutants, 372 DNA samples of patients treated for (VTR). Among these patients, 10 (2.7%) were carrying JAK2V617F mutation and none of them any of the calreticulin (CALR) mutations. Among the 19 patients who had VTE recurrence under vitamin K antagonists, 4 patients (21.0%) were positive for JAK2V617F. Despite the identification of JAK2V617F mutation, only three patients were diagnosed for MPN despite a median follow-up of 4 years. We showed that the screening for JAK2V617F not CALR mutations should be helpful in this indication especially if recurrence happened under VKA therapy.
-
8.
Skin reaction and regeneration after single sodium lauryl sulfate exposure stratified by filaggrin genotype and atopic dermatitis phenotype.
Bandier, J, Carlsen, BC, Rasmussen, MA, Petersen, LJ, Johansen, JD
The British journal of dermatology. 2015;(6):1519-1529
Abstract
BACKGROUND Filaggrin is key for the integrity of the stratum corneum. Mutations in the filaggrin gene (FLGnull) play a prominent role in atopic dermatitis (AD) pathogenesis. People with AD have increased susceptibility to irritants. However, little is known about the effect of filaggrin genotype and AD phenotype on irritant response and skin regeneration. OBJECTIVES To investigate the role of FLGnull and AD groups for skin reaction and recovery after sodium lauryl sulfate (SLS) irritation. METHODS This is a case-control study comprising 67 subjects, including healthy controls and patients with and without FLGnull and AD. Reactivity to different doses of SLS at 24, 48, 72 and 145 h after SLS application was measured by transepidermal water loss (TEWL) and laser Doppler flowmetry (LDF). Reactivity was assessed univariately and by pattern analysis. RESULTS All patient groups showed a higher degree of skin-barrier disruption and inflammation than did controls in response to SLS. Assessing reactivity by the delta value of the area under the curve for both TEWL and LDF showed significant differences between healthy controls and those with the AD phenotype, irrespective of filaggrin mutation. The poorest regeneration was among those with the AD phenotype. The two AD phenotype groups were separated by multivariate technique, due to earlier inflammatory reactivity among subjects with FLGnullplus AD compared with the AD phenotype alone. CONCLUSIONS Both skin reaction and regeneration were significantly different between the patient population and the healthy controls. Additionally, response severity and regeneration depended more on AD phenotype than on filaggrin genotype, whereas the response was more rapid among the FLGnullplus AD individuals.
-
9.
Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation.
Alonso, R, Andres, E, Mata, N, Fuentes-Jiménez, F, Badimón, L, López-Miranda, J, Padró, T, Muñiz, O, Díaz-Díaz, JL, Mauri, M, et al
Journal of the American College of Cardiology. 2014;(19):1982-9
Abstract
OBJECTIVES The aim of this study was to determine the relationship between lipoprotein(a) [Lp(a)] and cardiovascular disease (CVD) in a large cohort of patients with heterozygous familial hypercholesterolemia (FH). BACKGROUND Lp(a) is considered a cardiovascular risk factor. Nevertheless, the role of Lp(a) as a predictor of CVD in patients with FH has been a controversial issue. METHODS A cross-sectional analysis of 1,960 patients with FH and 957 non-FH relatives recruited for SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study), a long-term observational cohort study of a molecularly well-defined FH study group, was performed. Lp(a) concentrations were measured in plasma using an immunoturbidimetric method. RESULTS Patients with FH, especially those with CVD, had higher Lp(a) plasma levels compared with their unaffected relatives (p < 0.001). A significant difference in Lp(a) levels was observed when the most frequent null and defective mutations in LDLR mutations were analyzed (p < 0.0016). On multivariate analysis, Lp(a) was an independent predictor of cardiovascular disease. Patients carrying null mutations and Lp(a) levels >50 mg/dl showed the highest cardiovascular risk compared with patients carrying the same mutations and Lp(a) levels <50 mg/dl. CONCLUSIONS Lp(a) is an independent predictor of CVD in men and women with FH. The risk of CVD is higher in those patients with an Lp(a) level >50 mg/dl and carrying a receptor-negative mutation in the LDLR gene compared with other less severe mutations.