Literatura académica sobre el tema "Acanthocyte"

(1) Background: Chorea-acanthocytosis and McLeod syndrome are the core diseases among the group of rare neurodegenerative disorders called neuroacanthocytosis syndromes (NASs). NAS patients have a variable number of irregularly spiky erythrocytes, so-called acanthocytes. Their detection is a crucial but error-prone parameter in the diagnosis of NASs, often leading to misdiagnoses. (2) Methods: We measured the standard Westergren erythrocyte sedimentation rate (ESR) of various blood samples from NAS patients and healthy controls. Furthermore, we manipulated the ESR by swapping the erythrocytes and plasma of different individuals, as well as replacing plasma with dextran. These measurements were complemented by clinical laboratory data and single-cell adhesion force measurements. Additionally, we followed theoretical modeling approaches. (3) Results: We show that the acanthocyte sedimentation rate (ASR) with a two-hour read-out is significantly prolonged in chorea-acanthocytosis and McLeod syndrome without overlap compared to the ESR of the controls. Mechanistically, through modern colloidal physics, we show that acanthocyte aggregation and plasma fibrinogen levels slow down the sedimentation. Moreover, the inverse of ASR correlates with the number of acanthocytes (R2=0.61, p=0.004). (4) Conclusions: The ASR/ESR is a clear, robust and easily obtainable diagnostic marker. Independently of NASs, we also regard this study as a hallmark of the physical view of erythrocyte sedimentation by describing anticoagulated blood in stasis as a percolating gel, allowing the application of colloidal physics theory.

Dysplastic hematopoiesis associated with erythrocyte macrocytosis is a morphologic hallmark of myelodysplasia. We report the cases of six patients with myelodysplasia in which acanthocytosis was the predominant red blood cell (RBC) abnormality. In each case acanthocytes represented 5% to 10% of circulating RBC forms and was the primary reason for referral in two cases. None of the patients had comorbid conditions known to be associated with acanthocyte formation. Myelodysplasia should be considered in the differential diagnosis of acanthocytosis, particularly in the anemic, elderly individual. Acanthocytosis may be a harbinger of an unrecognized, hematologic stem-cell disorder.

Key Points Gain-of-function Lyn mice develop hemolytic anemia with acanthocyte red blood cells and display compensatory extramedullary erythropoiesis. Hyperactive Lyn notably alters Epo receptor signaling, particularly an Akt-FoxO3 pathway, enhancing viability and delaying differentiation.

Background: Chorea-acanthocytosis (ChAc) is a rare hereditary neurodegenerative disease with deformed red blood cells (RBCs), so-called acanthocytes, as a typical marker of the disease. Erythrocyte sedimentation rate (ESR) was recently proposed as a diagnostic biomarker. To date, there is no treatment option for affected patients, but promising therapy candidates, such as dasatinib, a Lyn-kinase inhibitor, have been identified. Methods: RBCs of two ChAc patients during and after dasatinib treatment were characterized by the ESR, clinical hematology parameters and the 3D shape classification in stasis based on an artificial neural network. Furthermore, mathematical modeling was performed to understand the contribution of cell morphology and cell rigidity to the ESR. Microfluidic measurements were used to compare the RBC rigidity between ChAc patients and healthy controls. Results: The mechano-morphological characterization of RBCs from two ChAc patients in an off-label treatment with dasatinib revealed differences in the ESR and the acanthocyte count during and after the treatment period, which could not directly be related to each other. Clinical hematology parameters were in the normal range. Mathematical modeling indicated that RBC rigidity is more important for delayed ESR than cell shape. Microfluidic experiments confirmed a higher rigidity in the normocytes of ChAc patients compared to healthy controls. Conclusions: The results increase our understanding of the role of acanthocytes and their associated properties in the ESR, but the data are too sparse to answer the question of whether the ESR is a suitable biomarker for treatment success, whereas a correlation between hematological and neuronal phenotype is still subject to verification.

Huntington's disease and neuroacanthocytosis may present similar clinical and MRI features. It is important to differentiate these findings since treatment and prognosis vary vastly between them. The aim of this article is to familiarize radiologists with the differentiating features of Huntington's disease and various diseases comprising neuroacanthocytosis. A 40-year-old Indian man with extrapyramidal symptoms was referred for MRI. The clinical diagnosis was Huntington's disease, but there were a few atypical clinical features such as a history of biting the tongue, tics, marked hyporeflexia and lower limb muscle wasting. MR showed atrophy of the caudate nucleus and putamen with iron deposition in the basal ganglia, which can be seen in Huntington's disease and in neuroacanthocytosis. An increased blood acanthocyte level was subsequently confirmed. Further work-up revealed increased serum creatine phosphokinase levels, normal serum lipoprotein levels and depressed K cell antigen activity on serological studies, confirming the diagnosis of McLeod syndrome. McLeod syndrome is one of the distinct phenotypes of neuroacanthocytosis. Neuroacanthocytosis is a group of disorders with increased serum acanthocyte counts and neurological involvement. Various causes of neuroacanthocytosis are discussed. It is important to consider the possibility of neuroacanthocytosis when features typical of Huntington's disease are encountered on imaging.

Chorea-acanthocytosis (ChAc) is a neurodegenerative disease caused by mutations in the VPS13A gene. It is characterized by several neurological symptoms and the appearance of acanthocytes. Elevated tyrosine kinase Lyn activity has been recently identified as one of the key pathophysiological mechanisms in this disease, and therefore represents a promising drug target. Methods: We evaluated an individual off-label treatment with the tyrosine kinase inhibitor dasatinib (100 mg/d, 25.8–50.4 weeks) of three ChAc patients. Alongside thorough safety monitoring, we assessed motor and non-motor scales (e.g., MDS-UPDRS, UHDRS, quality of life) as well as routine and experimental laboratory parameters (e.g., serum neurofilament, Lyn kinase activity, actin cytoskeleton in red blood cells). Results: Dasatinib appeared to be reasonably safe. The clinical parameters remained stable without significant improvement or deterioration. Regain of deep tendon reflexes was observed in one patient. Creatine kinase, serum neurofilament levels, and acanthocyte count did not reveal consistent effects. However, a reduction of initially elevated Lyn kinase activity and accumulated autophagy markers, as well as a partial restoration of the actin cytoskeleton, was found in red blood cells. Conclusions: We report on the first treatment approach with disease-modifying intention in ChAc. The experimental parameters indicate target engagement in red blood cells, while clinical effects on the central nervous system could not be proven within a rather short treatment time. Limited knowledge on the natural history of ChAc and the lack of appropriate biomarkers remain major barriers for “clinical trial readiness”. We suggest a panel of outcome parameters for future clinical trials in ChAc.

Il termine neuroacantocitosi (NA) raggruppa diverse malattie genetiche rare che condividono manifestazioni neurologiche simili e la presenza di globuli rossi stellati nella circolazione periferica, gli acantociti. Le due principali malattie classificate come NA sono Corea acantocitosi (ChAc) e sindrome di McLeod (MLS). Poiché la presenza di acantociti è una caratteristica comune di questi disordini, lo studio dei meccanismi alla base della loro formazione può aiutare a comprendere la patogenesi delle NA. In questa tesi viene presentata una serie di studi sui meccanismi di signaling e sulle modificazioni strutturali di globuli rossi di pazienti di ChAc e MLS. Nel primo studio abbiamo analizzato con tecniche di proteomica la fosforilazione in tirosina di globuli rossi di pazienti affetti da ChAc . Nei globuli rossi di questi pazienti abbiamo riscontrato un aumento della fosforilazione in tirosina su diverse proteine di membrana e legate alla membrana tra cui banda 3, β-spectrina e adducina. In particolare, la fosforilazione sul residuo Tyr-904 della banda 3, target della chinasi Lyn, era molto elevata, mentre sul residuo Tyr-8 della stessa proteina, target della chinasi Syk, non abbiamo riscontrato un aumento della fosforilazione. Nei pazienti di ChAc, la fosforilazione della banda 3 da parte di Lyn è indipendente dal meccanismo canonico di fosforilazione sequenziale mediato da Syk. Le alterazioni dell’organizzazione delle proteine di membrana correlate con ChAc sembrano quindi essere il risultato di un aumento della fosforilazione in tirosina che porta a cambiamenti nel legame della banda 3 con i ponti multiproteici tra la membrana e il citoscheletro. Proponiamo quindi quest’alterazione nell’associazione tra membrana e citoscheletro mediata da fosforilazione in tirosina come un nuovo meccanismo che porta alla formazione di acantociti in ChAc. Nel secondo studio abbiamo combinato i nostri set di dati fosfo-proteomici su eritrociti di pazienti di ChAc e MLS con l’analisi topologica di network proteici per predirre quali sub-network della trasduzione del segnale possano essere coinvolti nella formazione degli acantociti. Abbiamo identificato tutte le interazioni che legano le due proteine mutate nelle due patologie in esame (rispettivamente coreina e XK) con le proteine differenzialmente fosforilate dei nostri dati sperimentali. Quindi, abbiamo analizzato nello specifico solo cluster di proteine coinvolte nella trasduzione del segnale che interagiscono molto strettamente tra loro e che possono essere coinvolte nella formazione di acantociti in entrambe le patologie. Abbiamo identificato un cluster di 14 chinasi che possono essere coinvolte in tale processo e meritano ulteriori approfondimenti. Come studio preliminare nel contesto di una collaborazione internazionale abbiamo analizzato globuli rossi da pazienti affetti da Neurodegenerazione con Accumulo di Ferro nel Cervello (NBIA) e di loro parenti di primo grado. Il nostro scopo era quello di determinare se fossero presenti acantociti nei pazienti e nei soggetti correlati ma privi di sintomi clinici e di studiare le caratteristi che strutturali dei loro eritrociti. Nell’ultimo studio abbiamo validato con l’applicazione a tecniche di analisi proteomica un nuovo copolimero basato su acrilamide e polivinil alcool modificato con gruppi olefinici. Questo nuovo idrogel è semplice da maneggiare anche a basse concentrazioni e la sua macroporosità lo rende particolarmente adatto alla separazione di proteine ad alto peso molecolare quale la coreina.
Neuroacanthocytosis (NA) is a group of rare genetic disorders that share similar neurological clinical manifestations and the presence of thorny red cells in the peripheral circulation, the acanthocytes. The two core NA diseases are Chorea-Acanthocytosis (ChAc) and McLeod Syndrome (MLS). Since acanthocytes are an hallmark of NA, studying the mechanisms underlying the generation of acanthocytes might shed light on the pathogenesis of NA syndromes. Here, we present a set of studies on the signaling mechanisms and structural changes in red cells from ChAc and MLS patients. In the first study, we evaluated tyrosine phosphorylation of red cells from ChAc patients by proteomics analysis. Increased Tyr-phosphorylation state of several membrane proteins including band 3, β-spectrin and adducin was found in ChAc RBCs. In particular, band 3 was highly phosphorylated on the Tyr-904 residue, a functional target of Lyn, but not on Tyr-8, a functional target of Syk. In ChAc RBCs band 3 Tyr-phosphorylation by Lyn was independent of the canonical Syk mediated pathway. The ChAc-associated alterations in RBC membrane-protein organization appear to be the result of increased Tyr-phosphorylation leading to altered linkage of band 3 to the junctional complexes involved in anchoring the membrane to the cytoskeleton. We propose this altered association between cytoskeleton and membrane proteins as a novel mechanism in the generation of acanthocytes in ChAc. In the second study, we combined phosphoproteomics datasets on ChAc and MLS with network topology analysis to predict signaling sub-networks involved in acanthocyte generation. We identified all the interactomic shortest paths linking the two proteins mutated in NA syndromes, respectively chorein and XK, to the differentially phosphorylated proteins in our proteomics data. Then, we refined the analysis considering only restricted clusters of highly interacting signaling proteins which can be involved in acanthocyte formation in both diseases. We identified a cluster of 14 kinases that might be related to red cell shape alterations and deserve further investigation. As preliminary study in the context of an international collaboration we analyzed red cells from Neurodegeneration with Brain Iron Accumulation (NBIA) patients and their first degree relatives. Our aim was to assess the presence of acanthocytes in these subjects and to study their structural characteristics. In the last study, we validated a new co-polymer based on acrylamide and polyvinyl alcohol bearing olefinic moieties in proteomic analysis of red cells. This new hydrogel is easy to handle and its macroporosity makes it suitable for the separation of high molecular weight proteins such as chorein.

Introduction: NBIA is a rare disease, with a prevalence of 1/1,000,000.It is characterized by abnormal iron accumulation. Clinical findings may include progressive extrapyramidal disorders, involvement of the pyramidal, peripheral, autonomic nervous systems, superior cortical, visual and cerebellar functions. The diagnosis is made through the association of clinical findings and complementary exams. Currently, the treatment is only symptomatic, with no specific therapy. Case report: 5-year-old female, reporting involuntary movements and difficulty walking a day ago. Presented agitation and delayed neuropsychomotor development, seen since 1 year of age. On examination, dysarthria, dystonia and parkinsonian stiffness were observed. MRI of the brain showed the radiological signal “tiger’s eye” and the ophthalmological evaluation showed retinal dystrophy. Positive acanthocyte screening. NBIA’s NGS panel confirmed the diagnosis. Triexfenid was started and there was an improvement in movement disorders. In outpatient follow-up, the symptoms worsened. Levodopa was associated with the return of walking without support and ability to pick up objects. Discussion: In this case, Triexafenid 2mg/day was initially prescribed, with a slight improvement in movement disorders. Levodopa was started with the aim of improving symptoms of parkinsonian stiffness. The excellent response to the association of the drug in low doses stands out, enabling ambulation and functionality for daily activities. Conclusion: NBIA is a rare disease, with rapid onset and progression. Studies show limited benefits of levodopa in the case of PKAN. We emphasize significant clinical improvement, with a return to walking after administration of the drug.