scholarly journals Friedreich's Ataxia Frequency in a Large Cohort of Genetically Undetermined Ataxia Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Alexander F. Brown ◽  
Michael H. Parkinson ◽  
Hector Garcia-Moreno ◽  
Ese Mudanohwo ◽  
Robyn Labrum ◽  
...  
Keyword(s):  
Late Onset ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Diagnostic Process ◽  
Spinocerebellar Ataxias ◽  
Screening Process ◽  
Group A ◽  
Improve Patient Management ◽  
Group B ◽  
Testing Group

Background: Patients with suspected genetic ataxia are often tested for Friedreich's ataxia (FRDA) and/or a variety of spinocerebellar ataxias (SCAs). FRDA can present with atypical, late-onset forms and so may be missed in the diagnostic process. We aimed to determine FRDA-positive subjects among two cohorts of patients referred to a specialist ataxia centre either for FRDA or SCA testing to determine the proportion of FRDA cases missed in the diagnostic screening process.Methods: 2000 SCA-negative ataxia patients, not previously referred for FRDA testing (group A), were tested for FRDA expansions and mutations. This group was compared with 1768 ataxia patients who had been previously referred for FRDA testing (group B) and were therefore more likely to have a typical presentation. The phenotypes of positive cases were assessed through review of the clinical case notes.Results: Three patients (0.2%) in group A had the FRDA expansion on both alleles, compared with 207 patients (11.7%) in group B. The heterozygous carrier rate across both cohorts was of 41 out of 3,768 cases (1.1%). The size of the expansions in the three FRDA-positive cases in group A was small, and their presentation atypical with late-onset.Conclusions: This study demonstrates that FRDA is very rare among patients who were referred purely for SCA testing without the clinical suspicion of FRDA. Such cases should be referred to specialist ataxia centres for more extensive testing to improve patient management and outcomes.

scholarly journals Dissociation in the Effects of Induced Neonatal Hypoxia-Ischemia on Rapid Auditory Processing and Spatial Working Memory in Male Rats

2015 ◽  
Vol 37 (4-5) ◽  
pp. 440-452 ◽  
Author(s):  
Amanda L. Smith ◽  
Michelle Alexander ◽  
James J. Chrobak ◽  
Ted S. Rosenkrantz ◽  
R. Holly Fitch
Keyword(s):  
Working Memory ◽  
Auditory Processing ◽  
Spatial Working Memory ◽  
Task Group ◽  
Hypoxia Ischemia ◽  
Group A ◽  
Group B ◽  
Anatomic Measures ◽  
Testing Group

Infants born prematurely are at risk for cardiovascular events causing hypoxia-ischemia (HI; reduced blood and oxygen to the brain). HI in turn can cause neuropathology, though patterns of damage are sometimes diffuse and often highly variable (with clinical heterogeneity further magnified by rapid development). As a result, though HI injury is associated with long-term behavioral and cognitive impairments in general, pathology indices for specific infants can provide only limited insight into individual prognosis. The current paper addresses this important clinical issue using a rat model that simulates unilateral HI in a late preterm infant coupled with long-term behavioral evaluation in two processing domains - auditory discrimination and spatial learning/memory. We examined the following: (1) whether deficits on one task would predict deficits on the other (suggesting that subjects with more severe injury perform worse across all cognitive domains) or (2) whether domain-specific outcomes among HI-injured subjects would be uncorrelated (suggesting differential damage to orthogonal neural systems). All animals (sham and HI) received initial auditory testing and were assigned to additional auditory testing (group A) or spatial maze testing (group B). This allowed within-task (group A) and between-task (group B) correlation. Anatomic measures of cortical, hippocampal and ventricular volume (indexing HI damage) were also obtained and correlated against behavioral measures. Results showed that auditory discrimination in the juvenile period was not correlated with spatial working memory in adulthood (group B) in either sham or HI rats. Conversely, early auditory processing performance for group A HI animals significantly predicted auditory deficits in adulthood (p = 0.05; no correlation in shams). Anatomic data also revealed significant relationships between the volumes of different brain areas within both HI and shams, but anatomic measures did not correlate with any behavioral measure in the HI group (though we saw a hippocampal/spatial correlation in shams, in the expected direction). Overall, current data provide an impetus to enhance tools for characterizing individual HI-related pathology in neonates, which could provide more accurate individual prognoses within specific cognitive/behavioral domains and thus improved patient-specific early interventions.

Perturbation of precision grip in Friedreich's ataxia and late-onset cerebellar ataxia

1994 ◽  
Vol 9 (6) ◽  
pp. 650-654 ◽  
Author(s):  
Joachim Hermsdöourfer ◽  
Karl Wessel ◽  
Norbert Mai ◽  
Christian Marquardt
Keyword(s):  
Cerebellar Ataxia ◽  
Late Onset ◽  
Precision Grip ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia

scholarly journals Contribution of Population Pharmacokinetics to Dose Optimization of Ganciclovir-Valganciclovir in Solid-Organ Transplant Patients

2016 ◽  
Vol 60 (4) ◽  
pp. 1992-2002 ◽  
Author(s):  
A. Padullés ◽  
H. Colom ◽  
O. Bestard ◽  
E. Melilli ◽  
N. Sabé ◽  
...  
Keyword(s):  
Prediction Model ◽  
Population Pharmacokinetics ◽  
Late Onset ◽  
Organ Transplant ◽  
Solid Organ Transplant ◽  
Bayesian Prediction ◽  
Solid Organ ◽  
Infection Group ◽  
Group A ◽  
Group B

ABSTRACTTreatment of solid-organ transplant (SOT) patients with ganciclovir (GCV)-valganciclovir (VGCV) according to the manufacturer's recommendations may result in over- or underexposure. Bayesian prediction based on a population pharmacokinetics model may optimize GCV-VGCV dosing, achieving the area under the curve (AUC) therapeutic target. We conducted a two-arm, randomized, open-label, 40% superiority trial in adult SOT patients receiving GCV-VGCV as prophylaxis or treatment of cytomegalovirus infection. Group A was treated according to the manufacturer's recommendations. For group B, the dosing was adjusted based on target exposures using a Bayesian prediction model (NONMEM). Fifty-three patients were recruited (27 in group A and 26 in group B). About 88.6% of patients in group B and 22.2% in group A reached target AUC, achieving the 40% superiority margin (P< 0.001; 95% confidence interval [CI] difference, 47 to 86%). The time to reach target AUC was significantly longer in group A than in group B (55.9 ± 8.2 versus 15.8 ± 2.3 days,P< 0.001). A shorter time to viral clearance was observed in group B than in group A (12.5 versus 17.6 days;P= 0.125). The incidences of relapse (group A, 66.67%, and group B, 9.01%) and late-onset infection (group A, 36.7%, and group B, 7.7%) were higher in group A. Neutropenia and anemia were related to GCV overexposure. GCV-VCGV dose adjustment based on a population pharmacokinetics Bayesian prediction model optimizes GCV-VGCV exposure. (This study has been registered at ClinicalTrials.gov under registration no. NCT01446445.)

scholarly journals Exaggerated Premature Adrenarche in Boys: Comparative Study of a Therapeutic Intervention With the Aromatase Inhibitor Anastrozole Versus Morning Low Dose Hydrocortisone

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A666-A667
Author(s):  
Dimitrios T Papadimitriou ◽  
Eleni Dermitzaki ◽  
Kleanthis Kleanthous ◽  
Anastasios Papadimitriou ◽  
George Mastorakos
Keyword(s):  
Aromatase Inhibitors ◽  
Low Dose ◽  
Adult Height ◽  
Late Onset ◽  
Blood Lipid ◽  
Bone Age ◽  
Treated Group ◽  
Premature Adrenarche ◽  
Group A ◽  
Group B

Abstract Background: In boys, idiopathic premature adrenarche (IPA) is defined as the appearance of pubic or axillary hair/odor before the age of 9 yrs, not due to pathology of the adrenal glands. Exaggerated Adrenarche (EXAD), occurring in 10-15% of children with IPA, is characterized by an elevated &gt;10 DHEA/Δ4 ratio (theoretically indicating reduced 3-β-HSD activity) and accelerated bone age (BA) maturation, continuously increasing the projecting distance from the target height (TH) curve, beyond the one observed in the pattern of Constitutional Advancement of Growth (CAG), eventually leading to short stature (SS). It is traditionally successfully treated with a morning (6-8 am) low dose of hydrocortisone (8 mg/m2) in order to reduce the androgens produced and delay BA progression, similarly to the standard treatment of non-classical (late-onset) CAH. Third generation aromatase inhibitors (AI) have been shown to delay BA by inhibiting the peripheral aromatization of androgens and are being widely used off-label to treat short SS in boys. Aims: To evaluate the effectiveness of the AI anastrozole in delaying BA in boys with EXAD. Methods: 39 boys with advanced BA and a predicted adult height (PAH) &lt;170cm and &gt; -1SDS from TH) were included. Group-A (n=28) received anastrozole 1mg x 1 p.o. and group-B (n=11) low dose (8 mg/m2) hydrocortisone at 6-8 am for at least 3 yrs. All measurements were made on the same height meter by the same examiner. The two groups did not differ in terms of age at intervention onset: 8.6 in group A vs 8.74 yrs in group B, TH: 175.7 vs 175.7 cm, PAH: 168.4 vs 167.8 cm and BA advancement: +2.3 yrs in group A vs +2.4 yrs in group B. A 6-month follow-up included clinical examination, BA assessment, and laboratory tests (general blood, lipid chart, LH, FSH, TESTO, E2, E1, and complete calcium metabolism). Lumbar spine DEXA scan and X-Ray was performed on an annual basis. Results: Both groups had a statistically significant gain in PAH after 3yrs of treatment: Group A +10.3 cm (1.53 SD), p&lt;0.001, and group B +7.1 cm (1.06 SD), p=0.007. Thus, group A exceeded their TH by +3cm (0.45 SDS) and group B reached -0.8cm (-0.11 SDS) from their TH, p=0.03. The reduction of BA advancement was statistically significant in both groups (p&lt;0.05), with superiority of the anastrozole-treated group: at 3yrs in group A BA advancement was +0.48 yrs, and at group B +1.24 yrs (p&lt;0.001). No clinical adverse events or abnormal tests were noted in any of the groups. Bone density and vertebral morphology was not affected within or between groups. Conclusions: Aromatase Inhibitors may have a place in managing exaggerated adrenarche in boys, showing superiority to traditional low-dose hydrocortisone in improving predicted adult height and delaying bone age maturation, but notably by overcoming quality of life and compliance issues associated with hydrocortisone therapy (mandatory 6-8 am).

Molecular Immunoprofiling the T Cell Repertoire after Rituximab Administration Reveals Frequent Oligoclonality Albeit with Different Patterns Depending on the Clinical Context

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5792-5792
Author(s):  
Apostolia Papalexandri ◽  
Michail Iskas ◽  
Evangelia Stalika ◽  
Maria Karypidou ◽  
Barbara Tachynopoulou ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Late Onset ◽  
Sequence Data ◽  
Lymphocytic Leukemia ◽  
Cytotoxic T Cell ◽  
Cell Populations ◽  
Gene Repertoire ◽  
Group A ◽  
Group B

Abstract In patients with B lymphoid malignancies, depletion of B cells by Rituximab, an anti-CD20 humanized monoclonal antibody, can induce changes in the subset composition, activation and function of T cells. The spectrum of resultant immune-mediated sequelae encompasses organ-specific manifestations (e.g. pneumonitis, gastritis) as well as Rituximab-associated late onset neutropenia (R-LON). Although the pathogenesis of these clinical syndromes is not fully elucidated, evidence suggests that at least a fraction of cases may develop in a setting of expanded cytotoxic T cell populations with a large granular lymphocyte (LGL) phenotype (CD3+CD8+CD57+). Similar cytotoxic T cell expansions can be observed after Rituximab administration in other clinical settings e.g. allogeneic transplantation (allo-HCT), where selective restriction of the T-cell receptor (TR) gene repertoire is probably driven by multifactorial mechanisms. Here, we sought to obtain more insight into this phenomenon by molecular immunoprofiling of the TR gene repertoire in two groups of patients who received Rituximab: (i) Group A: patients (n=10) with chronic lymphocytic leukemia (CLL) treated with fludarabine-cyclophosphamide-rituximab (FCR); and, Group B: patients (n=14) who underwent allo-HCT for hematologic malignancies and received Rituximab either as pre-emptive treatment for EBV reactivation or against refractory cGvHD. Each patient included in the study received a mean of 6 cycles of Rituximab (range, 1-14). TR repertoire analysis was performed 11-88 (median, 36) and 5-24 months (median, 5) after the first Rituximab administration in Group A and Group B, respectively. TR beta gene rearrangements were PCR amplified on genomic DNA isolated from bone marrow samples using the BIOMED2 protocol and subjected to classic subcloning/Sanger sequencing. Sequence data were analyzed using the IMGT/V-QUEST tool. A total of 579 productive TRBV-TRBD-TRBJ rearrangements were analysed, 291 for Group A, 288 for Group B (6-91/case, median=20). Among the 46 TRBV functional genes identified, 3 accounted for >25% of cases in both groups: (i) TRBV27 (13% in both Groups A and B); ii) TRBV19-1 (13% in group A, 7% in group B); and, (iii) TRBV6-1 (7% and 6%, respectively). Clusters of identical (>=2) rearrangements corresponding to clonotypes were identified in all patients. Oligoclonality with immunodominant clonotypes (>12% of the repertoire) accounting for over 30% of the analyzed sequences was more frequent in Group A (7/10 cases) versus Group B (5/10 cases); however, larger clonotype expansions were seen in group B. Longitudinal analysis was performed in 3 patients with oligoclonality, 1 from group A and 2 from Group B: in the Group A patient, immunodominant clonotypes disappeared, while both patients in Group B retained the oligoclonal repertoire. Lymphocyte subpopulation analysis by flow cytometry was performed in 6 patients of each group. T-LGL proliferations (defined as CD4/CD8 abnormal ratio and CD3+CD8+CD57+ >30%) were found more often in Group B (3/6 cases in Group A versus 6/6 in Group B). They were related to oligoclonal TR gene repertoire in Group A (3/3) but not in Group B patients (3/6 cases). However, true expansions could be considered only in group B patients, since CD8+ lymphocytes >1.0*109/l were seen in all 6 Group B versus only 1/6 group A cases. Self-limiting R-LON was observed in 8 patients (4 in each group), but no association of oligoclonality to R-LON could be found. In conclusion, we report frequent development of oligoclonal T cell populations after Rituximab treatment in two different clinical contexts. The Groups analyzed differed with respect to the extent of oligoclonality, suggesting that the precise clinical setting determines the amplitude of TR repertoire skewing after Ritximab. Sustained oligoclonal cytotoxic expansions were recognised more often among allo-HCT patients, presenting with a highly restricted TR gene repertoire and likely reflecting strong antigenic stimulation by viruses and/or cGVHD aggravated by T cell imbalances induced by Rituximab. Disclosures Stamatopoulos: Gilead: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria, Other: Travel expenses; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding.

Late Onset Neutropenia Develops Selectively in Only a Subset of Patients with T Large Granular Lymphocyte Proliferation After Rituximab Treatment for Lymphoma,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3675-3675
Author(s):  
Apostolia Papalexandri ◽  
Michalis Iskas ◽  
Evangelia Stalika ◽  
Leonidas Marinos ◽  
Barbara Tachynopoulou ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Late Onset ◽  
Autologous Transplantation ◽  
Lymphocyte Subset ◽  
Large Granular Lymphocyte ◽  
Cytotoxic T Cell ◽  
Group A ◽  
Group B

Abstract Abstract 3675 Emerging evidence suggests that B cells can actively modulate T cell immune responses by presenting antigen, providing co-stimulation and secreting cytokines. This has prompted investigation whether B cell depletion by monoclonal antibodies, including Rituximab, can alter the subset composition, activation or function of T cells. Rituximab-associated late onset neutropenia (R-LON) is increasingly recognized as a long-term adverse event of Rituximab. Although the etiology of R-LON is not fully elucidated, the syndrome seems to be multifactorial and likely caused by immune-mediated mechanisms. We have previously shown that at least a proportion of R-LON may develop in a setting of expanded cytotoxic T cell populations in peripheral blood (PB) with a large granular lymphocyte (LGL) phenotype (CD3+CD8+CD57+). Here, we extend our observations regarding PB lymphocyte subset composition in a cohort of 107 Rituximab-treated patients with available results from PB flow cytometry analysis performed at roughly similar intervals after the initial Rituximab administration. The present cohort included 107 patients, aged 16–83 (median 60), who received Rituximab for the treatment of chronic lymphocytic leukemia (CLL) (29), diffuse large B cell lymhoma (DLBCL) (20), marginal zone lymphomas (15), follicular lymhoma (FL) (15), mantle cell lymphoma (MCL) (8) and auto-immune cytopenias (20). Overall, we found: (i) increased (>1.0×109/l) CD8+ cells in 45/107 (42%) cases; (ii) CD4+/CD8+ cell ratios <0.7 in 56/107 (52%) cases; and, (iii) T-LGLs >20% in 66/107 (63%) cases. Within this cohort, 33 cases (group A) developed R-LON, whereas the remainder (group B, n=74) did not develop this syndrome over a comparable observation period. Importantly, no patient with autoimmune cytopenia developed R-LON. R-LON was significantly more frequent in patients with lymphoma subtypes treated with intensive chemotherapy (CLL, DLBCL, MCL), as well as patients who underwent autologous transplantation (p\q0.001 for all comparisons). No significant differences were noted between groups A or B regarding PB lymphocyte subset composition. We next evaluated the findings from the histopathological study of bone marrow biopsy samples, available in 17 Group A and 19 Group B cases, all with a diagnosis of lymphoma. The morphological and immunohistochemical examination revealed a series of features common in both groups, summarized as follows: (i) mild-to-moderate small lymphocytic infiltration by CD20-CD79a-CD3+CD45RO+CD43+ (CD3>CD45RO) cells, predominantly nodular and/or interstitial (non intrasinusoidal); (ii) pronounced hyperplasia of the erythroid and megakaryocytic series with prominent dyserythropoiesis and dysmegakaryopoiesis, respectively, including abnormal paratrabecular localization, suggestive of myelodysplasia (MDS); and (iii) remarkable shift-to-the-left of the granulocytic series, often with abnormal localization of immature progenitors (ALIP), always with \q2% CD34+ cells. A proportion of cases showed hyperplasia of the granulocytic series. However, a major difference between the two Groups concerned hypoplasia of the granulocytic series, which was noted almost exclusively in group A. We conclude that lymphoma patients treated with Rituximab often develop cytotoxic T cell expansions than can have a variable impact on hematopoiesis, with R-LON perhaps representing the end of a spectrum of T-LGL-mediated autoimmune myelopathy/myelodyplasia. The selective development of R-LON in only a proportion of cases with expanded cytotoxic T cells associated with prominent hypoplasia of the granulocytic series and MDS-like changes of the hematopoietic marrow post Rituximab raises several questions regarding the underlying (genetically determined?) immunopathogenetic mechanisms. Disclosures: No relevant conflicts of interest to declare.

Abstract 19687: Morphological and Clinical Characteristics of Late and Young Age Onset Apical Hypertrophic Cardiomyopathy: Insight from a 13-Year Registry of Hypertrophic Cardomyopathy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Hyemoon Chung ◽  
Geu-Ru Hong ◽  
Jungwoo Son ◽  
In-Jeong Cho ◽  
Chi Young Shim ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Early Onset ◽  
Clinical Characteristics ◽  
Late Onset ◽  
Disease Onset ◽  
Apical Hypertrophic Cardiomyopathy ◽  
Group A ◽  
Group B ◽  
Onset Group ◽  
Lv Diastolic Function

Background: Apical hypertrophic cardiomyopathy (ApHCM) might have different morphological and clinical features according to the age of disease onset, probably result from the distinct mechanism of pathogenesis. The aim of this study was to evaluated the morphological and clinical differences according to the age of disease onset in patients with ApHCM. Methods: This was a retrospective, observational study of 56 ApHCM patients (31 males, mean 65±9 years). Among 426 patients with diagnosed ApHCM from 2000 until 2013, we selected 56 patients who met the inclusion criteria: [[Unable to Display Character: &#9332;]] patiens who diagnosed with ApHCM before 60 years old and current age >60 years old, (group A, early onset, n=16); and [[Unable to Display Character: &#9333;]] who diagnosed with ApHCM after 60 years old who had no evidence of apical hypertrophy confirmed by previous echocardiography (group B, late onset, n=40). Morphological LV feature was assessed by transthoracic echocardiography, which were divided into pure and mixed type. Furthermore, hemodynamic parameters and clinical events were also evaluated. Results: There were no differences in the presence of hypertension, LV systolic function and left atrial volume index between group A and B. However, early onset group A had more increased maximal wall thickness of LV apex (17.08±2.02 vs 15.43±1.68mm, p=0.005), and more incidence of pure type (100% (16/16) vs 56.8% (21/40), p=0.001) compare than late onset group B. Group B had older age (65±5 vs 72±4 years, p=0.001), increased LV end-diastolic dimension (51.25±2.32 vs 48.58±3.37mm, p=0.006), increased E/E’ (11.24±2.94 vs 14.60±6.37, p=0.049) with decreased E’ (5.61±1.34 vs 4.66±1.38cm/s, p=0.024) respectively.There were no significant differences in the risk of cardiovascular complication such as atrial fibrillation and stoke between group A and B. Conclusions: There was obvious different clinical characteristics according to the age of disease onset. Early onset ApHCM has typical morphological feature and relatively preserved LV diastolic function, compared with late onset ApHCM. Our result supports that late onset ApHCM was related to decreased LV diastolic function and increased LV wall thickness, which reflects the potential myocardial remodeling with aging.

scholarly journals The Neuropathology of Late-Onset Friedreich’s Ataxia

2010 ◽  
Vol 10 (1) ◽  
pp. 96-103 ◽  
Author(s):  
Arnulf H. Koeppen ◽  
Jennifer A. Morral ◽  
Rodney D. McComb ◽  
Paul J. Feustel
Keyword(s):  
Late Onset ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia
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