No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Testing for acanthocytosis
Abstract
The presence of acanthocytosis in peripheral blood smears remains the hallmark of the clinical diagnosis of most neuroacanthocytosis syndromes, such as chorea-acanthocytosis (ChAc) and McLeod syndrome. Genetic analyses and/or specific laboratory tests are available only for a minority of these disorders. Testing for acanthocytosis is hampered by the lack of data on normal amounts of acanthocytes assessed by a standardized method. We report a prospective reader-blinded study designed to establish control values for abnormally shaped erythrocytes in healthy volunteers and patients with movement disorders (MDs) using light microscopic assessment of erythrocyte morphology in standard EDTA and isotonically diluted blood samples. We investigated a total of 100 patients fulfilling clinical criteria of specific MDs, 31 patients with MDs not matching any clinical criteria, and 37 healthy controls. In patients with diagnosed MDs and healthy controls, acanthocytes in dry blood smears were significantly more frequent following isotonic dilution compared with standard EDTA blood. In unfixed wet blood preparations of both EDTA blood and isotonically diluted blood, acanthocyte levels were significantly higher than in standard dry blood smear preparations. There were no statistical differences of acanthocyte levels in all test conditions between diagnosed MDs and healthy volunteers. There was no significant correlation of acanthocyte levels in all blood samples and preparations with age, sex or diagnosis. Thus, normal values were defined as the 99th percentile of combined results of the two groups of volunteers. Diluted blood combined with wet blood preparation showed high specificity (0.98) and the highest sensitivity of all test procedures (all genetically confirmed ChAc patients were detected). The reported method is cheap, readily available, and provides high specificity and sensitivity in respect to clinically relevant acanthocytosis. The use of isotonically diluted blood samples combined with unfixed wet blood preparation with a normal range of <6.3% of total erythrocytes is recommended to search for significant acanthocytosis in movement disorders.
... The courses of the diseases are heterogeneous, usually slowly progressive, and often result in severe disability, while treatment options remain purely symptomatic so far [9]. Diagnosis is confirmed by genetic testing (VPS13A gene in ChAc, XK gene in MLS) and chorein expression detection by Western blot (ChAc) or immunohematological assessment (MLS) [5], although the initial detection often relies on blood smears [10]. Acanthocytes are deformed erythrocytes whose irregular membrane presents disordered, asymmetric spikes. ...
... For these rare diseases, diagnosis is challenging, and misdiagnoses are frequent, which additionally increases the patients' burden of disease. One of the reasons for delayed diagnosis is related to the difficult detection of acanthocytes in classical blood smears and routine laboratory testing: Sensitive detection requires special isotonically diluted blood samples [10], the number of acanthocytes varies among the patients, and their similarity to echinocytes often makes them hard to identify [6]. Therefore, it would be desirable to have an easier and more reliable initial diagnostic biomarker. ...
... Blood smears were prepared as described by Storch et al. (2005) [10]. Whole EDTA blood was suspended in a 1:1 ratio in a 0.9% sodium chloride solution containing 5 IU/mL heparin and incubated for 1 h at room temperature. ...
(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.
... Methods for wet and fixed smears were performed according to previously established protocols. 9 In brief, an aliquot (,5 mL) of whole blood, collected in EDTA tubes, was used to prepare a fixed smear on a glass slide and stained using the Rapidiff Stain (Diagnostic Media Products, South Africa). In parallel, unfixed wet smears were prepared within an hour of the blood draw. ...
... An acanthocytosis rate of greater than 1.2% in the dry smear or greater than 3.7% in the wet smear was designated a priori as the threshold for clinical significance based on previously established standards. 9 As a third approach to detecting abnormal hematological features in HDL2, red cell membranes were prepared from blood samples drawn in ACD tubes as described by Coetzer and Palek. 10 The protein concentration was determined using the Coomassie Plus Protein Assay Reagent (Pierce Biotechnology Incorporated, USA). ...
... 5 Echinocytes are difficult to differentiate from acanthocytes on light microscopy and are usually from smear processing errors whereas acanthocytes are of pathological relevance. The method we employed for the detection of acanthocytes by Storch et al. 9 was not published until 2005. This method is now considered to be the gold standard in testing for acanthocytes in neuroacanthocyte syndromes and reduces echinocytic stress. ...
... Methods for wet and fixed smears were performed according to previously established protocols. 9 In brief, an aliquot (,5 mL) of whole blood, collected in EDTA tubes, was used to prepare a fixed smear on a glass slide and stained using the Rapidiff Stain (Diagnostic Media Products, South Africa). In parallel, unfixed wet smears were prepared within an hour of the blood draw. ...
... An acanthocytosis rate of greater than 1.2% in the dry smear or greater than 3.7% in the wet smear was designated a priori as the threshold for clinical significance based on previously established standards. 9 As a third approach to detecting abnormal hematological features in HDL2, red cell membranes were prepared from blood samples drawn in ACD tubes as described by Coetzer and Palek. 10 The protein concentration was determined using the Coomassie Plus Protein Assay Reagent (Pierce Biotechnology Incorporated, USA). ...
... 5 Echinocytes are difficult to differentiate from acanthocytes on light microscopy and are usually from smear processing errors whereas acanthocytes are of pathological relevance. The method we employed for the detection of acanthocytes by Storch et al. 9 was not published until 2005. This method is now considered to be the gold standard in testing for acanthocytes in neuroacanthocyte syndromes and reduces echinocytic stress. ...
Background
Huntington’s Disease-like 2 (HDL2) is classified as a neuroacanthocytosis; however, this remains unverified. We aim to determine if acanthocytes are present in HDL2 and whether acanthocytes can differentiate HDL2 from Huntington’s disease (HD).
Methods
We prospectively compared 13 HD and 12 HDL2 cases against 21 unaffected controls in Johannesburg. Blood smears were prepared using international standards and reviewed by at least two blinded reviewers. An acanthocytosis rate of greater than 1.2% in the dry smear or greater than 3.7% in the wet smear was designated a priori as the threshold for clinical significance based on previously established standards. Flow cytometry was performed on all but four of the cases. Red cell membrane protein analysis was performed on all participants.
Results
There were 12 HDL2, 13 HD, and 21 controls enrolled. None of the HD or HDL2 participants had defined acanthocytosis or other morphological abnormalities. None of the HD or HDL2 cases had evidence of an abnormal band 3.
Discussion
Acanthocytosis was not identified in either HDL2 or HD in our patient population. Our results, based on the first prospective study of acanthocytes in HDL2 or HD, suggest that screening for acanthocytes will not help establish the diagnosis of HD or HDL2, nor differentiate between the two disorders and raises the question if HDL2 should be placed within the neuroacanthocytosis syndromes.
... The percentage of acanthocytes in both VPS13A disease and XK disease is variable (5-50%) under the course of disease, > 6.3% acanthocytes in peripheral blood is considered abnormal. To reduce the risk for false positive and negative cases, acanthocytosis is assessed with a specific protocol (Storch et al., 2005). The red blood cells membrane properties are determined by membrane structure, which in turn, identifies membrane deformability, mechanical stability and permeability. ...
... In all cases, the presence of acanthocytes was assessed according to the protocol for wet blood smears proposed by Storch et al. (2005). Erythrocytes were also studied using new generation osmotic gradient ektacytometry (LoRRca R Maxis; RR Mechatronics). ...
Background and objectives
The diseases historically known as neuroacanthocytosis (NA) conditions include VPS13A disease (formerly chorea-acanthocytosis) and XK disease (formerly McLeod syndrome). Here we report a patient with a hyperkinetic syndrome associated with variants in VPS13A with a concomitant homozygous nucleotide expansion in Replication factor C, subunit 1 (RFC1) and evaluate the role of ektacytometry for the assessment of acanthocytes.
Methods
Investigations included clinical assessments, neuroimaging studies, laboratory analyses, blood smears, ektacytometry, psychometric evaluation, and genetic analyses. Using ektacytometry, an osmoscan curve is obtained yielding a diffraction pattern as a measure of average erythrocyte deformability from circular at rest to elliptical at a high shear stress. The pattern allows the derivation of several parameters (mainly EI-max, O-min and O-Hyper points). Samples from two other patients with genetically proven VPS13A disorder and XK disease and varying numbers of acanthocytes as well as from a fourth with acanthocytosis due to liver failure were also analyzed.
Case presentation
The patient has impulsivity, chorea and disabling feeding dystonia refractory to treatment and 15% acanthocytes in peripheral blood. Genetic workup revealed compound heterozygous variants c.1732_1733del; p.(V578Ffs*9) and c.8282C > A, p.(S2761*) in VPS13A with absence of chorein in the blood, the latter variant is novel. In addition, he harbors a homozygous nucleotide expansion in the RFC1 gene, reported in cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). However, the patient does not display ataxia yet. Ektacytometry revealed significantly reduced erythrocyte deformability in this patient and in another man with VPS13A disease. In contrast, the patient with XK disease had 2% acanthocytes and mild abnormalities on ektacytometry. In the three cases, ektacytometry yielded a specific pattern, different from acanthocytosis due to liver failure.
Conclusion
Pathogenicity of the VPS13A variants is confirmed by absence of chorein, long-term follow up is required to evaluate any synergistic impact of for the underlying CANVAS mutation. New generation ektacytometry provides an objective measurement of erythrocytes’ rheological properties and may serve as a complement to blood smears. Finally, ektacytometry’s ability to detect deformability of erythrocytes in NA seems to depend on the degree of acanthocytosis.
... Hence, RBCs are clearly affected in NAS (Storch et al., 2005;Siegl et al., 2013;Cluitmans et al., 2015;Peikert et al., 2022b). It is not clear whether the acanthocytes are a byproduct of the disease, directly resulting from the genetic defect, or a secondary effect. ...
... The acanthocyte count is the oldest method that is purely based on the RBC shape, classifying a certain percentage of acanthocytes. This method, regardless of whether based on conventional dry blood smears or on optimized wet smears (Storch et al., 2005), proved to be challenging in practice. In patients, the number of acanthocytes can vary over time, including total absence (Malandrini et al., 1993;Sorrentino et al., 1999;Bayreuther et al., 2010). ...
Introduction
The unique red blood cell (RBC) properties that characterize the rare neuroacanthocytosis syndromes (NAS) have prompted the exploration of osmotic gradient ektacytometry (Osmoscan) as a diagnostic tool for these disorders. In this exploratory study, we assessed if Osmoscans can discriminate NAS from other neurodegenerative diseases.
Methods
A comprehensive assessment was conducted using Osmoscan on a diverse group of patients, including healthy controls (n = 9), neuroacanthocytosis syndrome patients (n = 6, 2 VPS13A and 4 XK disease), Parkinson’s disease patients (n = 6), Huntington’s disease patients (n = 5), and amyotrophic lateral sclerosis patients (n = 4). Concurrently, we collected and analyzed RBC indices and patients’ characteristics.
Results
Statistically significant changes were observed in NAS patients compared to healthy controls and other conditions, specifically in osmolality at minimal elongation index (Omin), maximal elongation index (EImax), the osmolality at half maximal elongation index in the hyperosmotic part of the curve (Ohyper), and the width of the curve close to the osmolality at maximal elongation index (Omax-width).
Discussion
This study represents an initial exploration of RBC properties from NAS patients using osmotic gradient ektacytometry. While specific parameters exhibited differences, only Ohyper and Omax-width yielded 100% specificity for other neurodegenerative diseases. Moreover, unique correlations between Osmoscan parameters and RBC indices in NAS versus controls were identified, such as osmolality at maximal elongation index (Omax) vs. mean cellular hemoglobin content (MCH) and minimal elongation index (EImin) vs. red blood cell distribution width (RDW). Given the limited sample size, further studies are essential to establish diagnostic guidelines based on these findings.
... Most recently, this was the case in 13 HD patients in whom Storch et al.'s standard technique was applied (Anderson et al., 2017). The systematic prospective readerblinded analysis of acanthocytosis in movement disorders by Storch et al. is still the de facto standard (albeit without EM confirmation; Storch et al., 2005). Their protocol recommends using isotonically diluted blood samples as unfixed wet preparation and analysis with phase contrast microscopy. ...
... To sum up, we strongly doubt that the authors' conclusion is warranted, and suspect that it only serves to contribute to confusion in the literature. It would have required appropriate controls, i.e., use of alternative methods such as the wet blood smear technique (Storch et al., 2005), the use of artificial networks for discrimination of acanthocytes from other abnormally shaped erythrocytes , or proxy ESR measurements . This discussion highlights the phenotypic complexity of the neurodegenerative/neurogenetic disorders characterized by chorea. ...
... Diagnosis is complicated, often delayed, and needs to be confirmed by genetic testing (VPS13A gene in ChAc, XK gene in MLS) and chorein in western blot (ChAc) or immunohaematological assessments (MLS) (Peikert et al., 2022). Acanthocyte detection relies on a wet unfixed blood smear, which is not a generally available diagnostic method (Storch et al., 2005). The erythrocyte sedimentation rate (ESR) is slower in NAS patients compared to healthy control subjects and was hence recently proposed as an additional diagnostic marker . ...
... Their RBCs have different properties compared to healthy controls as already indicated in the disease group name. However, up to now, the classification of acanthocytes is difficult and prone to mistakes (Storch et al., 2005;Darras et al., 2021) leaving reliable diagnosis a challenge. Our first general approach based on the Erysense device already gives promising results comparing 4 healthy controls with 3 ChAc and 4 MLS patients. ...
In many medical disciplines, red blood cells are discovered to be biomarkers since they “experience” various conditions in basically all organs of the body. Classical examples are diabetes and hypercholesterolemia. However, recently the red blood cell distribution width (RDW), is often referred to, as an unspecific parameter/marker (e.g., for cardiac events or in oncological studies). The measurement of RDW requires venous blood samples to perform the complete blood cell count (CBC). Here, we introduce Erysense, a lab-on-a-chip-based point-of-care device, to evaluate red blood cell flow properties. The capillary chip technology in combination with algorithms based on artificial neural networks allows the detection of very subtle changes in the red blood cell morphology. This flow-based method closely resembles in vivo conditions and blood sample volumes in the sub-microliter range are sufficient. We provide clinical examples for potential applications of Erysense as a diagnostic tool [here: neuroacanthocytosis syndromes (NAS)] and as cellular quality control for red blood cells [here: hemodiafiltration (HDF) and erythrocyte concentrate (EC) storage]. Due to the wide range of the applicable flow velocities (0.1–10 mm/s) different mechanical properties of the red blood cells can be addressed with Erysense providing the opportunity for differential diagnosis/judgments. Due to these versatile properties, we anticipate the value of Erysense for further diagnostic, prognostic, and theragnostic applications including but not limited to diabetes, iron deficiency, COVID-19, rheumatism, various red blood cell disorders and anemia, as well as inflammation-based diseases including sepsis.
... Considering diagnosis, ChAc is often diagnosed late and is also prone to misdiagnosis due to, e.g., (i) the difficulty to identify acanthocytes in the blood smears [8] and (ii) the fact that approximately 10% of the patients do not show acanthocytes at all [9]. The prevalence of approximately 1:1,000,000 is not in favor of increasing awareness of the disease. ...
... For shape classification of RBCs, we performed confocal imaging and 3D rendering [10], with results shown in Figure 3A, that presents acanthocytes (left column) in comparison to echinocytes (right column). The discrimination between acanthocytes and echinocytes can be challenging and is, therefore, error-prone and likely to be biased [8,10]. Thus, we used an artificial neural network (ANN) to classify cells in an unbiased, automated manner [16]. ...
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.
... A related, common misconception concerns the role of acanthocytosis for diagnosis: the conviction still appears prevalent that neither ChAc nor McLeod syndrome are likely unless acanthocytes were seen on peripheral blood smear at least once out of three attempts. Acanthocytosis is notoriously difficult to identify [10,11]. In the only systematic blinded study of peripheral acanthocytosis [10], Storch and colleagues incubated samples of peripheral blood with heparinized normal saline (1:1) for 30-120 minutes at room temperature on a shaker, and examined wet, unfixed smears using phase-contrast microscopy. ...
... Acanthocytosis is notoriously difficult to identify [10,11]. In the only systematic blinded study of peripheral acanthocytosis [10], Storch and colleagues incubated samples of peripheral blood with heparinized normal saline (1:1) for 30-120 minutes at room temperature on a shaker, and examined wet, unfixed smears using phase-contrast microscopy. While this method has become the most widely-accepted for determination of acanthocytes, the authors note that this method does not distinguish between acanthocytes and echinocytes, and they did not validate the presence of acanthocytes using the most definitive methodology, which is examination of glutaraldehyde-fixed erythrocytes using electron microscopy. ...
The term "neuroacanthocytosis" (NA) is used for a spectrum of neurological disorders in which there are thorny red blood cells. While NA historically referred to disorders of lipoprotein absorption, we have promoted it as an overarching term for a group of basal ganglia disorders, with specific reference to two diseases that we defined as "core" NA syndromes. "Neuroacanthocytosis" has also been used to refer to a specific, now genetically-defined disease, otherwise known as "chorea-acanthocytosis". These various usages have resulted in diagnostic confusion, and in a number of cases have quite likely prevented the pursuance of precise, molecular, diagnosis. Disease nomenclature is an ever-evolving field, especially in the current era of expanding genetics, and naming proposals are often far from ideal. We, however, suggest that the term "neuroacanthocytosis" should no longer be generally used and if so, only with appropriate understanding of its limitations. Further, we propose that chorea-acanthocytosis be renamed as "VPS13A disease" in accordance with its genetic etiology.
... Based on the available medical history, clinical features, neurological findings and laboratory biomedical findings, a diagnosis of ChAc was proposed. Peripheral blood smears with standard settings (Storch et al., 2005) were then performed, revealing that 35% of red blood cells were acanthocytes. Electron microcopy scans showed the shape of acanthocytes more clearly. ...
... Additionally, the diagnosis of NA syndromes cannot be ruled out merely by absence of acanthocyte (Bayreuther et al., 2010) as there are also cases where no acanthocytes may be detected (Bayreuther et al., 2010;Sorrentino et al., 1999;Walker, 2015). The efficiency of acanthocyte detection depends to a large extent on several specific endogenous factors and blood sample processing methods, thus conducting a study in a standard manner (Storch et al., 2005) and repeating a test several times in highly suspicious cases may improve the positive rate of detection. Scanning electron microscopy is the most reliable morphological diagnostic method for acanthocytes, but it is not yet popular. ...
Neuroacanthocytosis is a rare progressive neurodegenerative disease, including chorea-acanthocytosis, McLeod syndrome, Huntington’s disease-like 2, and pantothenate kinase-associated neurodegeneration, where chorea-acanthocytosis occupies the main entity of this disease group. Here, a classic case of chorea-acanthocytosis is reported that exhibited gradually deteriorating abnormal movements of limbs and face, swallowing difficulty, and lip and cheek biting for the past two years. Peripheral blood smears revealed that 35% of the red blood cells were acanthocytes and electron microcopy scans clearly showed the morphology of acanthocytes. VPS13A gene sequencing found a heterozygous novel VPS13A gene mutation (c.80dupT). Brain magnetic resonance imaging scans showed moderate anterior horn dilation of lateral ventricles and bilateral atrophy of the head of caudate nucleus. Several suggestive features are summarized to provide diagnostic clues for chorea-acanthocytosis and facilitate future diagnosis and treatment.
... However, the finding is neither specific nor sensitive enough for clinical diagnosis [13,14]. Moreover, the in vitro diagnosis of acanthocytes is technically demanding and prone of false positive testing [62]. Therefore, Storch et al. suggested a modified technique to assess peripheral blood smears for acanthocytes. ...
... Therefore, Storch et al. suggested a modified technique to assess peripheral blood smears for acanthocytes. According to Storch et al., quantification of acanthocytes needs to be done using wet smear of diluted blood sample and by applying dark filed microscopy [62]. Due to technical demanding procedure and the low disease specificity of acanthocytes, this test has lost its diagnostic power. ...
... An unfixed wet blood smear achieves the highest sensitivities for quantifying acanthocyte levels in suspected neuroacanthocytosis, although the presence of >1.2% acanthocytes using our method remains highly specific. 4 In addition, we were unable to perform genetic evaluation of the patient's family members. ...
... This method is cost-effective, easily accessible, and provides high specificity and sensitivity for detecting clinically significant acanthocytosis. It is recommended to use isotonically diluted blood samples with an unfixed wet blood preparation to effectively identify significant acanthocytosis in movement disorders [8]. Protein assays or genetic testing stands out as a more sensitive laboratory parameter in detecting ChAc [4]. ...
Neuroacanthocytosis (NA) syndromes are a group of rare genetic disorders characterized by the presence of abnormally shaped red blood cells (acanthocytes) and the progressive degeneration of the basal ganglia, leading to various neurological and systemic symptoms. The “rubber man” gait, characterized by distinctive flexions of the neck (manifesting as head drops) and the trunk, is seen in advanced chorea-acanthocytosis. A 35-year-old male patient presented with progressive abnormal movements affecting his limbs and face, along with dysphagia resulting from involuntary protrusion of the tongue and biting of the cheeks and lips over the past three years. He used to place the food on the back of his tongue and throw his head back to begin swallowing. He also kept a towel in his mouth to absorb saliva and prevent cheek and lip biting. The neurologic examination revealed generalized chorea, severe orolingual dystonia (eating dystonia), and sudden loss of tone while walking, resulting in flexion of the trunk followed by extension. We believe that these features could serve as definitive clinical indicators for chorea-acanthocytosis, providing valuable diagnostic insights, especially when accompanied by self-mutilatory mouth movements or feeding-related tongue dystonia.
... In a particular group of diseases known as the neuroacanthocytosis syndrome [18], patients carry a dedicated phenotype red blood cell shape, the acanthocytes (Table 1, #1). They were proposed as a diagnostic marker [19], although the relation of this peculiar red blood cell morphology to the mutations causing neuroacanthocytosis is still elusive. ...
This Editorial ‘Advances in Red Blood Cell Research’ is the preface for the special issue with the same title which files 14 contributions listed in Table 1 [...]
... There appear to be rare cases, likely due to missense mutations, in which VPS13A is present on Western blot but dysfunctional. When acanthocytosis is present in a significant percentage of red blood cells on peripheral blood smear (ideally performed as per Storch et al., 2005), this is supportive of the diagnosis, however, this is not a consistent finding and can be absent (Malandrini et al., 1993;Sorrentino et al., 1999;Bayreuther et al., 2010;Peikert et al., 2022b). The relationship between this observation and neurodegeneration remains unclear, and there is not a clear correlation between disease severity or progression and this laboratory finding. ...
The two very rare neurodegenerative diseases historically known as the “neuroacanthocytosis syndromes” are due to mutations of either VPS13A or XK. These are phenotypically similar disorders that affect primarily the basal ganglia and hence result in involuntary abnormal movements as well as neuropsychiatric and cognitive alterations. There are other shared features such as abnormalities of red cell membranes which result in acanthocytes, whose relationship to neurodegeneration is not yet known. Recent insights into the functions of these two proteins suggest dysfunction of lipid processing and trafficking at the subcellular level and may provide a mechanism for neuronal dysfunction and death, and potentially a target for therapeutic interventions.
... Higher levels of acanthocytes have previously been observed in healthy volunteers and people with movement disorders when isotonic dilution or wet preparations have been used. 26 These methods may not have been used in our patient, in whom no acanthocytes were seen on peripheral blood films. At autopsy, acanthocytes were only observed in the vessels of the choroid plexus of the lateral ventricle. ...
We present a comprehensive characterization of clinical, neuropathological, and multisystem features of a man with genetically confirmed McLeod neuroacanthocytosis syndrome, including video and autopsy findings. A 61-year-old man presented with a movement disorder and behavioral change. Examination showed dystonic choreiform movements in all four limbs, reduced deep-tendon reflexes, and wide-based gait. He had oromandibular dyskinesia causing severe dysphagia. Elevated serum creatinine kinase (CK) was first noted in his thirties, but investigations, including muscle biopsy at that time, were inconclusive. Brain magnetic resonance imaging showed white matter volume loss, atrophic basal ganglia, and chronic small vessel ischemia. Despite raised CK, electromyography did not show myopathic changes. Exome gene panel testing was negative, but targeted genetic analysis revealed a hemizygous pathogenic variant in the XK gene c.895C > T p.(Gln299Ter), consistent with a diagnosis of McLeod syndrome. The patient died of sepsis, and autopsy showed astrocytic gliosis and atrophy of the basal ganglia, diffuse iron deposition in the putamen, and mild Alzheimer's pathology. Muscle pathology was indicative of mild chronic neurogenic atrophy without overt myopathic features. He had non-specific cardiomyopathy and splenomegaly. McLeod syndrome is an ultra-rare neurodegenerative disorder caused by X-linked recessive mutations in the XK gene. Diagnosis has management implications since patients are at risk of severe transfusion reactions and cardiac complications. When a clinical diagnosis is suspected, candidate genes should be interrogated rather than solely relying on exome panels.
... • A standard routine procedure is to dilute blood 1:1 with 0.9% saline containing 10 U/mL heparin, and examine it using phase-contrast microscopy after 30 minutes' incubation in a shaker and wet blood smear preparation. In control samples, fewer than 6.3% of cells are speculated [Storch et al 2005]. ...
Clinical characteristics:
VPS13A disease, caused by VPS13A loss-of-function pathogenic variants, is characterized by a spectrum of movement disorders (chorea, dystonia, tics, sometimes parkinsonism); predominant orofacial choreic and dystonic movements and tics (with involuntary tongue protrusion on attempted swallowing, habitual tongue and lip biting resulting in self-mutilation, involuntary vocalizations); dysarthria and dysphagia; psychiatric, cognitive, and behavioral changes ("frontal lobe type"); seizures; and progressive neuromuscular involvement. Huntingtonism (triad of progressive movement disorder and cognitive and behavioral alterations) is a typical presentation. Phenotypic variability is considerable even within the same family, including for monozygotic twins. Mean age of onset is about 30 years. VPS13A disease runs a chronic progressive course and may lead to major disability within a few years. Some affected individuals are bedridden or wheelchair dependent by the third decade. Age at death ranges from 28 to 61 years; several instances of sudden unexplained death or death during epileptic seizures have been reported.
Diagnosis/testing:
The diagnosis of VPS13A disease is established in a proband with suggestive findings and biallelic pathogenic variants in VPS13A identified by molecular genetic testing.
Management:
Treatment of manifestations: There is no cure for VPS13A disease. Supportive treatment to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields of neurology, psychiatry, physiatry, physical therapy (PT), occupational therapy (OT), speech-language therapy, feeding, neuropsychology, and medical genetics. Pharmacotherapy for movement disorders may include dopamine antagonists/depleters such as atypical neuroleptics or tetrabenazine (or its derivatives) for limb and trunk dystonia and orofaciolingual dystonia (which may also benefit from botulinum toxin). Issues with mobility, activities of daily living, and need for assistive devices can be addressed by physiatry, PT, and OT. In persons with dysphagia, feeding assistance can include speech therapy and gastrostomy tube placement as needed to reduce weight loss and/or risk of aspiration. For dysarthria or mutism, therapy can include the use of technical means for augmentative and alternative communication, such as speech-generating devices. Seizure management can include use of phenytoin, clobazam, valproate, and levetiracetam. For psychiatric/behavioral issues, antidepressant or antipsychotic medications are used per conventional approaches. Surveillance: Regular monitoring of existing manifestations, the individual's response to pharmacotherapy and other supportive care, and the emergence of new manifestations is recommended per the multidisciplinary treating specialists. Agents/circumstances to avoid: Seizure-provoking circumstances (e.g., sleep deprivation, alcohol intake) and anticonvulsants that may worsen involuntary movements (e.g., carbamazepine, lamotrigine).
Genetic counseling:
VPS13A disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a VPS13A pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once the VPS13A pathogenic variants have been identified in an affected family member, carrier testing for at�risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
... Vor allem die Anfertigung von nassen Präparationen in isotoner Kochsalzlösung war dem Verfahren mit trockenen Ausstrichen überlegen. Dabei wurde in der Arbeit nicht zwischen Echinozyten und Akanthozyten unterschieden und festgestellt, dass sich bei den Patienten durch die Mischung mit isotoner Flüssigkeit ausgelöster echinozytischer Stress stärker auf Patienten als auf Kontroll-Erythrozyten auswirkt(Storch et al. 2005). Ich habe Blutausstriche nach Dilution mit 0,9% Kochsalzlösung angefertigt und nach dem Trocknen gefärbt. ...
... Acanthocyte detection in peripheral blood smear has been shown to be helpful for diagnosis of ChAc, while it is very insensitive (positive rates as low as 5%-50%) and acanthocytes may only appear late in the disease course [25] and may occasionally be detected in other diseases, such as mitochondrial diseases and metabolic disorders [26]. The detection efficiency of acanthocytes is largely dependent on several specific endogenous factors and blood sample treatment methods [27], and their absence does not absolutely exclude the diagnosis of ChAc as there are also cases where no acanthocytes may be detected [15,25]. A close monitoring is suggested when suspecting ChAc. ...
Background
Chorea-acanthocytosis (ChAc), as the most common subtype of neuroacanthocytosis syndrome, is characterized by the presence of acanthocytes and neurological symptoms. It is thought to be caused by the VPS13A (vacuolar protein sorting-associated protein 13A) mutations. This article reports two confirmed cases of ChAc and summarizes some suggestive features, which provide direction for the diagnosis and treatment of acanthocytosis in the future.
Case presentation
Here, we present two cases of ChAc diagnosed based on typical clinical symptoms, neuroimaging features, genetic findings of VPS13A, and response to the symptomatic treatment.
Conclusions
Chorea-acanthocytosis is a rare neurodegenerative disease with various early clinical manifestations. The final diagnosis of the ChAc can be established by either genetic analysis or protein expression by Western blotting. Supportive treatments and nursing are helpful to improve the quality of the patient’s life. Nevertheless, it is imperative to investigate the impact of neuroimaging and neuropathological diagnosis in a larger group of ChAc in future studies.
... If negative, further differential diagnosis is complex [68]. Low erythrocyte sedimentation rate, elevated levels of CK, ALT, AST, and LDH, as well as red cell acanthocytosis -that, however is difficult to determine and not even an obligatory finding under routine clinical conditions [69,70] -may lead one to consider the two related conditions of MLS and VPS13A disease. While male sex, older age, and affection also of a brother or maternal uncle support an assumption of MLS, the two conditions cannot, however, be sufficiently distinguished on the basis of clinical phenotype alone. ...
Background:
McLeod syndrome (MLS) is an X-linked multisystemic progressive disorder caused by loss of function mutations in the XK gene. The rare blood group phenotype of MLS patients with absent Kx antigen requires the support of specialized transfusion institutions because of the risk of transfusion complications. Acanthocytosis of red blood cells occurs in almost all patients. Nonhematological manifestations of MLS are very similar to those of VPS13A disease (chorea-acanthocytosis), an autosomal-recessive condition. Their shared phenotype apart from acanthocytosis includes movement disorders such as chorea and dystonia, epilepsy, peripheral neuropathy, and muscle involvement, typically with creatine kinase (CK) elevation, cardiomyopathy included.
Summary:
In this review, we describe the nonhematological manifestations of MLS in comparison with those of VPS13A disease. While there are many similarities, differences such as mode of inheritance, sex distribution, age at manifestation, severity of heart involvement, frequency of feeding dystonia or of involuntary head drops may help to distinguish these disorders in the clinic. Immunohematological demonstration of the McLeod-Kell phenotype or detection of pathogenic mutations of XK (or VPS13A, respectively) is the gold standard for distinction. "Neuroacanthocytosis" was often used as an overarching term, but is potentially misleading, as the term does not refer to a defined disease entity. Its use, if continued, must not prevent clinicians to seek a final diagnosis on the basis of molecular findings. The clinical similarity of MLS and VPS13A disease has long suggested some shared pathophysiology. Evidence for molecular interaction between XK, the McLeod protein, and chorein, the VPS13A gene product, has recently been put forward: XK forms a complex with chorein/VPS13A, a bulk lipid transporter located at various membrane contact sites. The exact role of XK in this complex needs to be further elucidated. Impairment of bulk lipid transport appears as the common denominator of both MLS and VPS13A disease. A variety of further conditions may in time be added to the "bulk lipid transport diseases," such as the recently recognized disorders caused by mutations in the VPS13B, VPS13C, and VPS13D genes.
Key messages:
(1) Patients diagnosed with the rare red cell McLeod phenotype (McLeod syndrome, MLS) require interdisciplinary collaboration of transfusion medicine specialists, neurologists, and cardiologists for both their hematological and nonhematological disease manifestations. (2) The phenotypical similarity of MLS and VPS13A disease, often leading to either confusion or insufficient diagnostic depth (under the label of "neuroacanthocytosis"), is based on interaction of the respective proteins, XK and chorein, within the cellular machinery for bulk lipid transport. (3) Overall, the term "bulk lipid transport diseases" seems useful for further research on a group of conditions that may not only share pathophysiology, but may also share treatment approaches.
... The best procedure requires diluting whole blood samples 1:1 with heparinized saline followed by incubation for 60 minutes at room temperature; wet cell monolayers are then prepared for phase-contrast microscopy. When all RBCs with spicules (corresponding to type AI/AII acanthocytes and echinocytes) are counted, normal controls show fewer than 6.3% acanthocytes/echinocytes [Storch et al 2005]. Acanthocyte count in MLS may vary considerably but usually ranges between 8% and 30%. ...
Clinical characteristics: McLeod neuroacanthocytosis syndrome (designated as MLS throughout this review) is a multisystem disorder with central nervous system (CNS), neuromuscular, cardiovascular, and hematologic manifestations in males:
CNS manifestations are a neurodegenerative basal ganglia disease including movement disorders, cognitive alterations, and psychiatric symptoms.
Neuromuscular manifestations include a (mostly subclinical) sensorimotor axonopathy and muscle weakness or atrophy of different degrees.
Cardiac manifestations include dilated cardiomyopathy, atrial fibrillation, and tachyarrhythmia.
Hematologically, MLS is defined as a specific blood group phenotype (named after the first proband, Hugh McLeod) that results from absent expression of the Kx erythrocyte antigen and weakened expression of Kell blood group antigens. The hematologic manifestations are red blood cell acanthocytosis and compensated hemolysis. Alloantibodies in the Kell and Kx blood group system can cause strong reactions to transfusions of incompatible blood and severe anemia in affected male newborns of Kell-negative mothers.
Females heterozygous for XK pathogenic variants have mosaicism for the Kell and Kx blood group antigens. Although they usually lack CNS and neuromuscular manifestations, some heterozygous females may develop clinical manifestations including chorea or late-onset cognitive decline.
Diagnosis/testing: The diagnosis of MLS is established in a male proband with: suggestive clinical, laboratory, and neuroimaging studies; a family history consistent with X-linked inheritance; and either a hemizygous XK pathogenic variant (90% of affected males) or a hemizygous deletion of Xp21.1 involving XK (10% of affected males) identified on molecular genetic testing.
Management: Treatment of manifestations: The following recommendations apply to affected males (although symptomatic heterozygous females may undergo the same procedures, no scientific data are available): use of dopamine antagonists (e.g., tiapride, clozapine, quetiapine) and the dopamine depletory (tetrabenazine) to ameliorate chorea; assessment of cardiac involvement initially with cardiac MRI (if available), Holter electrocardiogram (EKG), echocardiography, cardiac biomarkers, and specialized electrophysiological investigations (if indicated); consideration of placement of prophylactic cardiac pacemaker / implantable cardioverter-defibrillator; treatment of psychiatric problems and seizures based on clinical findings; long-term and continuous multidisciplinary psychosocial support for affected individuals and their families.
Agents/circumstances to avoid: Blood transfusions with Kx antigens in males with MLS. Kx-negative blood or, if possible, banked autologous or homologous blood should be used.
Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic male and female at-risk relatives of any age in order to identify as early as possible those who would benefit from (1) detailed blood compatibility information to prevent transfusion of Kx+ homologous blood products, (2) possible prophylactic cryopreservation of autologous or homologous blood for use in future transfusions, and (3) interventions to prevent sudden cardiac events.
Surveillance: For those with known cardiac involvement, follow up per treating specialist; for those without known cardiac involvement, Holter EKG, echocardiography, and cardiac biomarkers (e.g., troponin T/I, pro BNP) every two years; monitor for seizures; monitor serum CK concentrations for evidence of rhabdomyolysis if excessive movement disorders are present or if neuroleptic medications are being used.
Genetic counseling: MLS is inherited in an X-linked manner. If the mother of an affected male is heterozygous, the chance of transmitting the XK pathogenic variant in each pregnancy is 50%. Males who inherit the XK variant will be affected; females who inherit the XK variant will be heterozygous and will usually not be affected. Affected males pass the XK pathogenic variant to all of their daughters and none of their sons. Once the XK pathogenic variant has been identified in an affected family member, carrier testing for at-risk females, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
... 4,5 Furthermore, while routine laboratory techniques actually demonstrate limited sensitivity in detecting acanthocytosis, the use of isotonically diluted blood and unfixed wet blood preparation improves sensitivity and specificity. 6 In addition, muscle creatine kinase is another useful blood marker that is almost ubiquitously elevated in affected individuals. 7 Symptoms of ChAc typically begin in the third decade (or less frequently in the fourth decade) with dysphagia, dysarthria, chorea, and unsteady or ''rubber man''' gait. ...
... 4,5 Furthermore, while routine laboratory techniques actually demonstrate limited sensitivity in detecting acanthocytosis, the use of isotonically diluted blood and unfixed wet blood preparation improves sensitivity and specificity. 6 In addition, muscle creatine kinase is another useful blood marker that is almost ubiquitously elevated in affected individuals. 7 Symptoms of ChAc typically begin in the third decade (or less frequently in the fourth decade) with dysphagia, dysarthria, chorea, and unsteady or ''rubber man''' gait. ...
... Remarkably elevated serum CK levels of up to 1442 U/l (normal < 174 U/l) were detected repeatedly as were slightly elevated liver function tests (AST = 62 U/l, ALT = 97 U/l; both normally < 40 U/l). The routine blood film showed acanthocytes next to a wide spectrum of other red cell morphology changes, including ovalocytes, echinocytes, micro-and macrocytes, and poikilocytes (Storch, Kornhass, & Schwarz, 2005) (Figure 1). Serum ceruloplasmin (24 mg/dl) and urinary excretion of copper (<50 µg/24 h) were within normal limits and ophthalmological examination did not reveal Kayser-Fleischer rings. ...
Background:
Chorea-acanthocytosis (ChAc; OMIM #200150) is a rare autosomal recessive condition with onset in early adulthood that is caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene encoding chorein. Several diagnostic genomic DNA (gDNA) sequencing approaches are widely used. However, their limitations appear not to be acknowledged thoroughly enough.
Methods:
Clinically, we deployed magnetic resonance imaging, blood smear analysis, and clinical chemistry for the index patient's characterization. The molecular analysis of the index patient next to his parents covered genomic DNA (gDNA) sequencing approaches, RNA/cDNA sequencing, and chorein specific Western blot.
Results:
We report a 33-year-old male patient without functional protein due to compound heterozygosity for two VPS13A large deletions of 1168 and 1823 base pairs (bp) affecting, respectively, exons 8 and 9, and exon 13. To our knowledge, this represents the first ChAc case with two compound heterozygous large deletions identified so far. Of note, standard genomic DNA (gDNA) Sanger sequencing approaches alone yielded false negative findings.
Conclusion:
Our case demonstrates the need to carry out detection of chorein in patients suspected of having ChAc as a helpful and potentially decisive tool to establish diagnosis. Furthermore, the course of the molecular analysis in this case discloses diagnostic pitfalls in detecting some variations, such as deletions, using only standard genomic DNA (gDNA) Sanger sequencing approaches and exemplifies alternative methods, such as RNA/cDNA sequencing or qRT-PCR analysis, necessary to avoid false negative results.
... Similar to findings in patients with Parkinson's disease, PET scans of patients with NA show a 42% reduction in DOPA re-uptake in the posterior putamen. Using single photon emission computed tomography (SPECT), the hypometabolic areas may be observed as areas of hypoperfusion [18,23]. Further, there have also been reports of cases with cerebellar atrophy [15]. ...
The diagnosis of neuroacanthocytosis (NA) is made by the presence of acanthocytes via peripheral smear and by the accompanying clinical picture. Laboratory tests for diagnosis include blood smears to detect acanthocytosis, creatine kinase, genetic analysis and / or chorein level examination with western blot technique. This paper describes the case of a 34 year-old male patient who presented to the emergency department with acute respiratory failure and loss of consciousness. He was intubated and received mechanical ventilatory support after admission to the intensive care unit, and was diagnosed with Chorea akanthozytose (ChAc). We aim to emphasize the need to consider NA among the differential diagnoses for patients presenting with complex clinic such as acute respiratory failure and altered consciousness.
... 5,6 Red blood cell (RBC) acanthocytosis is an unreliable finding unless specific techniques are used. 7 Although elevated creatine kinase levels are present in almost all MLS patients, this finding is not specific. 4 Furthermore, associated symptoms may be confounding with other neuropsychiatric disorders such as Huntington disease or choreoacanthocytosis, suggesting an unknown number of unreported cases. ...
Background:
McLeod syndrome (MLS) is hematologically defined by the absence of the red blood cell (RBC) antigen Kx on the transmembrane RBC protein, XK, representing a highly specific diagnostic marker. Direct molecular assessment of XK therefore represents a desirable diagnostic tool. Whereas pathogenic point mutations may be simply identified, partial and complete deletions of XK on Xp21.1, eventually covering adjacent genes and causing multifaceted "continuous gene syndromes," are difficult to localize.
Study design and methods:
Three different McLeod patient samples were tested using 16 initial positional polymerase chain reaction (PCR) procedures distributed over an approximately 2.8-Mbp Xp-chromosomal region, ranging telomeric from MAGEB16 to OTC, centromeric of XK. The molecular breakpoint of one sample with an apparent large Xp deletion was iteratively narrowed down by stepwise positioning further PCR procedures and sequenced. Two mutant XK genes, one previously published and serving as a positive control, were also sequenced.
Results:
We confirmed the positive control as previously published and listed as XK*N.20 by the International Society of Blood Transfusion (ISBT). The other XK showed a novel four-nucleotide deletion in Exon 1, 195-198delCCGC (newly listed as XK*N.39 by the ISBT). The third sample had an approximately 151-kbp X-chromosomal deletion, reaching from Exon 2 of LANCL3, across XK to Exon 3 of CYBB (newly listed as XK*N.01.016 by the ISBT). Carrier status of the patients' sister was diagnosed using a diagnostic "gap-PCR."
Conclusions:
The stepwise partitioning of Xp21.1 is pragmatic and cost-efficient in comparison to other diagnostic techniques such as "massive parallel sequencing" given the rarity of MLS. All males with suspected MLS should be considered for molecular XK profiling.
... Acanthocytes may not be detected in a peripheral blood smear in some cases with a final diagnosis of neuroacanthocytosis, possibly due to either low sensitivity of blood films or variability in acanthocyte manifestation (28). Furthermore, between 1 and 5% of acanthocytes per 100 red blood cells in a peripheral blood smear may be a normal finding (29,30). The MRI brain scan in patients with chorea-acanthocytosis can share similarities with HD in that there may be degeneration and atrophy of the caudate nucleus (26,31). ...
Chorea, cognitive, behavioural and psychiatric disturbance occur in varying combinations in Huntington's disease (HD). This is often easy to recognise particularly in the presence of an autosomal dominant history. Whilst HD may be the most common aetiology of such a presentation, several HD phenocopies should be considered if genetic testing for HD is negative. We searched PubMed and the Cochrane Database from January 1, 1946 up to January 1, 2016, combining the search terms: 'chorea', 'Huntington's disease', 'HDL' and 'phenocopies'. HD phenocopies frequently display additional movement disorders such as myoclonus, dystonia, parkinsonism and tics. Here, we discuss the phenotypes, investigations and management of HD-like disorders where the combination of progressive chorea and cognitive impairment is obvious, but HD gene test result is negative. Conditions presenting with sudden onset chorea such as vascular, infectious and autoimmune causes are not the primary focus of our discussion, but we will make a passing reference to these as some of these conditions are potentially treatable. Hereditary forms of chorea are a heterogeneous group of conditions and this number is increasing. While most of these conditions are not curable, molecular genetic testing has enabled many of these disorders to be distinguished from HD. Getting a precise diagnosis may enable patients and their families to better understand the nature of their condition.
... Blood samples without EDTA (5 mL) were immediately mixed with 5 mL of isotonic sodium chloride solution containing 10 units of heparin per milliliter, and blood was mounted between a glass object slide and a glass cover slip [6]. ...
Chorea-acanthocytosis (ChAc) is an autosomal recessive hereditary disease characterized by neurodegeneration in the striatum and acanthocytosis that is caused by mutations in the VPS13A gene. We previously produced a ChAc model mice encoding a human disease mutation with deletion of exons 60-61 in the VPS13A gene. The behavioral and pathological phenotypes of the model mice varied a good deal from individual to individual, indicating that differences between individuals may be caused by the content of a genetic hybrid 129/Sv and C57BL/6J strain background. To establish the effect of the genetic background on phenotype, we backcrossed the ChAc-model mice to different inbred strains: C57BL/6J and 129S6/Sv. Although no significant difference between ChAc-mutant mice and wild-type mice on the C57BL/6J background was observed, the ChAc-mutant mice on the 129S6/Sv showed abnormal motor function and behavior. Furthermore, we produced ChAc-mutant mice on two different inbred strains: BALB/c and FVB. Significant reduction in weight was observed in ChAc mutant mice on the FVB and 129S6 backgrounds. We found a marked increase in the osmotic fragility of red blood cells in the ChAc mutant mice backcrossed to 129S6/Sv and FVB. The phenotypes varied according to strain, with ChAc mutant mice on the FVB and 129S6 backgrounds showing remarkably abnormal motor function and behavior. These results indicate that there are modifying genetic factors of ChAc symptoms.
... The detection of acanthocytes often remains elusive, although the probability to detect the characteristic deformed erythrocytes can be increased by using a 1:1 dilution with physiological saline and phase contrast microscopy. 63 However, many hematology laboratories no longer prepare wet blood films due to health and safety policies, 64 and analysis of the protein (chorein) levels is therefore recommended. The function of the protein is not fully understood, but a yet unknown role of chorein in the regulation of secretion and the aggregation of blood platelets has recently been suggested. ...
Background:
The differential diagnosis of chorea syndromes is complex. It includes inherited forms, the most common of which is autosomal dominant Huntington's disease (HD). In addition, there are disorders mimicking HD, the so-called HD-like (HDL) syndromes.
Methods and results:
Here we review main clinical, genetic, and pathophysiological characteristics of HD and the rare HD phenocopies in order to familiarize clinicians with them. Molecular studies have shown that HD phenocopies account for about 1% of suspected HD cases, most commonly due to mutations in C9orf72 (also the main cause of frontotemporal dementia and amyotrophic lateral sclerosis syndromes), TATA box-binding protein (spinocerebellar ataxia type 17 [SCA17]/HDL4), and JPH3 (HDL2). Systematic screening studies also revealed mutations in PRNP (prion disease), VPS13A (chorea-acanthocytosis), ATXN8OS-ATXN8 (SCA8), and FXN (late-onset Friedreich's Ataxia) in single cases. Further differential diagnoses to consider in patients presenting with a clinical diagnosis consistent with HD, but without the HD expansion, include dentatorubral-pallidoluysian atrophy and benign hereditary chorea (TITF1), as well as the recently described form of ADCY5-associated neurodegeneration. Lastly, biallelic mutations in RNF216 and FRRS1L have recently been reported as autosomal recessive phenocopies of HD.
Conclusion:
There is a growing list of genes associated with chorea, yet a substantial percentage of patients remain undiagnosed. It is likely that more genes will be discovered in the future and that the clinical spectrum of the described disorders will broaden.
... Despite being invoked in the name and definition of the disorder, acanthocytosis on peripheral blood smear is helpful, but is not a consistent finding, for reasons which are not known. 81 This fact, and the logistical challenges to having this study performed in a standardized manner, 82 mean that acanthocytosis should not be relied upon to make the diagnosis. ...
There have been significant advances in neuroacanthocytosis (NA) syndromes in the past 20 years, however, confusion still exists regarding the precise nature of these disorders and the correct nomenclature. This article seeks to clarify these issues and to summarise the recent literature in the field. The four key NA syndromes are described here-chorea-acanthocytosis, McLeod syndrome, Huntington's disease-like 2, and pantothenate kinase- associated neurodegeneration. In the first two, acanthocytosis is a frequent, although not invariable, finding; in the second two, it occurs in approximately 10% of patients. Degeneration affecting the basal ganglia is the key neuropathologic finding, thus the clinical presentations can be remarkably similar. The characteristic phenotype comprises a variety of movement disorders, including chorea, dystonia, and parkinsonism, and also psychiatric and cognitive symptoms attributable to basal ganglia dysfunction. The age of onset, inheritance patterns, and ethnic background differ in each condition, providing diagnostic clues. Other investigations, including routine blood testing and neuroimaging can be informative. Genetic diagnosis, if available, provides a definitive diagnosis, and is important for genetic counseling, and hopefully molecular therapies in the future. In this article I provide a historical perspective on each NA syndrome. The first 3 disorders, chorea-acanthocytosis, McLeod syndrome, Huntington's disease-like 2, are discussed in detail, with a comprehensive review of the literature to date for each, while pantothenate kinase-associated neurodegeneration is presented in summary, as this disorder has recently been reviewed in this journal. Therapy for all of these diseases is, at present, purely symptomatic.
Chorea is a hyperkinetic movement disorder characterized by random and flowing movements. The phenomenology of chorea can vary from mild forms to severe forms such as hemiballism. Motor impersistence is also one of the phenomenological features of chorea, and co-existing neurological features can serve as an important clue. Diagnosis leans heavily on the neurologic history and potentially involves an array of investigative measures including magnetic resonance imaging (MRI) of the brain, serological and genetic testing. Symptomatic treatment, when chorea is severe or affects patients’ daily activities, varies from the application of neuroleptics or vesicular monoamine transporter 2 (VMAT2) inhibitors, to a comprehensive multidisciplinary approach in chronic cases, ensuring both patient and caregiver are adequately supported and treated. The chapter prompts critical diagnostic questions, outlines possible diagnostic scenarios, and details therapeutic approaches, offering a coherent guide to management.
Diagnostic procedures for the manifestations of neuromuscular diseases (NMD) as emergencies or in critically ill patients in ICU, as well as for the acute worsening of patients with known NMD, must meet the challenge to resolve complex situations within a short time. They must overcome the limitations of the ICU setting and take into account the patient’s vulnerability concerning stressful exams. The combined use of standard laboratory parameters, imaging techniques, and specific electrodiagnostic tests can provide the basis for a rapid diagnostic assessment with timely initiation of further, more time-consuming testing and for the decision about necessity, time, and location of a biopsy. Most importantly, they form the foundation of the therapeutic decisions beyond basic support. This chapter looks into the strengths and weaknesses of established tests and recent developments in the neuromuscular field that may be applied to the emergency situation in detail.KeywordsNeuromuscular emergencyLaboratory testsElectrodiagnostic testsNeuromuscular imagingMuscle biopsyNerve biopsyBlood smearCritical illness myopathyCritical illness polyneuropathyIntensive care unit
Purpose of review:
This article provides an overview of the approach to chorea in clinical practice, beginning with a discussion of the phenomenologic features of chorea and how to differentiate it from other movement disorders. The diagnostic approach, clinical features of important acquired and genetic choreas, and therapeutic principles are also discussed. Practical clinical points and caveats are included.
Recent findings:
C9orf72 disease is the most common Huntington disease phenocopy, according to studies in the European population. Anti-IgLON5 disease can present with chorea. The role of immunotherapies in Sydenham chorea has increased, and further clinical studies may be useful. Benign hereditary chorea is a syndrome or phenotype due to mutations in several genes, including NKX2-1, ADCY5, GNAO1, and PDE10A. New-generation presynaptic dopamine-depleting agents provide more options for symptomatic treatment of chorea with fewer adverse effects. Deep brain stimulation has been performed in several choreic disorders, but features other than chorea and the neurodegenerative nature should be taken into consideration. Studies on genetic interventions for Huntington disease are ongoing.
Summary:
Clinical features remain crucial in guiding the differential diagnosis and appropriate investigations in chorea. Given the complexity of most choreic disorders, treating only the chorea is not sufficient. A comprehensive and multidisciplinary approach is required.
Background:
Huntington Disease-like 2 (HDL2) is a neurodegenerative disorder similar to Huntington Disease (HD) in its clinical phenotype, genetic characteristics, neuropathology and longitudinal progression. Proposed specific differences include an exclusive African ancestry, lack of eye movement abnormalities, increased Parkinsonism, and acanthocytes in HDL2.
Objective:
The objective was to determine the similarities and differences between HD and HDL2 by establishing the clinical phenotype of HDL2 with the published cases.
Methods:
A literature review of all clinically described cases of HDL2 until the end of 2016 was performed and a descriptive analysis was carried out.
Results:
Sixty-nine new cases were described between 2001 and 2016. All cases had likely African ancestry, and most were found in South Africa and the USA. Many features were found to be similar to HD, including a strong negative correlation between repeat length and age of onset. Chorea was noted in 48/57 cases (84%). Dementia was reported in 74% patients, and Parkinsonism in 37%. Psychiatric features were reported in 44 out of 47 cases. Patients with chorea had lower expanded repeat lengths compared to patients without chorea. Eye movements were described in 19 cases, 8 were abnormal. Acanthocytes were detected in 4 of the 13 patients tested. There were 19 out of 20 MRIs reported abnormal with findings similar to HD.
Conclusion:
This review clarifies some aspects of the HDL2 phenotype and highlights others which require further investigation. Features that are unique to HDL2 have been documented in a minority of subjects and require prospective validation.
Neurodegeneration with brain iron accumulation (NBIA) designates a heterogeneous group of inherited diseases characterized by excessive brain iron accumulation. Aceruloplasminemia, resulting from mutations of the ceruloplasmin gene, is an autosomal recessive member of NBIA. Common clinical features of aceruloplasminemia are cognitive impairment, craniofacial dyskinesia, cerebellar ataxia, and retinal degeneration as well as cerebellar signs and tremor; mean age at neurological diagnosis is 51 years. We report a 72-year-old female patient who was admitted for a first depressive episode after her husband died. Neurological examination showed subtle bilateral rigidity of arms and legs, and intermittent bilateral low-amplitude resting tremor. Laboratory findings, including complete absence of ceruloplasmin, markedly increased ferritin in the presence of normal iron and transferrin, and neuroimaging findings suggested the diagnosis of aceruloplasminemia. Genetic analysis confirmed a homozygous missense mutation of the ceruloplasmin gene, p.Ala350Asp. Notably, the patient was only insignificantly affected despite massive iron deposits in brain and liver, indicating the possibility of a benign course of aceruloplasminemia. In addition, we found distinct acanthocytosis on the blood smear which, in view of the observation of acanthocytosis in PKAN (formerly Hallervorden-Spatz disease), might imply a connection between acanthocytosis and iron metabolism disorders.
Neuroacanthocytosis (NA) syndromes are a group of rare disorders displaying neurodegeneration and misshaped spiky red blood cells (acanthocytes) including chorea-acanthocytosis (ChAc), McLeod syndrome (MLS), Huntington’s disease-like 2, and pantothenate kinase-associated neurodegeneration (PKAN). The major clinical manifestations are movement disorders most often showing involuntary movements as the main symptom and thus being a differential diagnosis to Huntington’s disease. Additionally, cognitive decline, psychiatric disturbances, peripheral neuropathy, epilepsy, and parkinsonism appear together with blood cell acanthocytosis and elevated creatine kinase and liver enzymes. There is currently no cure for the diseases; treatment is purely symptomatic. Recent data suggests chorein being involved in actin cytoskeleton disturbances and different kinase pathways. This book chapter briefly summarizes the clinical phenotype, neuropathology, and the current state of pathophysiology of NA syndromes.
Objective:
To provide clinical clues to differential diagnosis in patients with chorea and other movement disorders with blood acanthocytes.
Methods:
We present a long-term video accompanied follow-up of six Caucasian patients with neuroacanthocytosis from several centers, three diagnosed with chorea-acanthocytosis (ChAc): 34-y.o.(no.1), 36-y.o.(no.2), 43-y.o.(no.3), two diagnosed with McLeod Syndrome (MLS): 52-y.o.(no.4), 61-y.o.(no.5) and one 63-y.o.(no.6), a brother of no.5, with clinical suspicion of MLS. Additionally we report pathological findings of the mother of two brothers with MLS reported in our series with acanthocytes on peripheral blood smear RESULTS: The patients had an unremarkable family history and were asymptomatic until adulthood. Patients no. 1,2,4,5,6 developed generalized chorea and patient no. 3 had predominant bradykinesia. Patients no. 1,2,3 had phonic and motor tics, additionally patients no. 1 and 2 exhibited peculiar oromandibular dystonia with tongue thrusting. In patients no. 2 and 3 dystonic supination of feet was observed, patient no. 3 subsequently developed bilateral foot drop. Patients no. 2 and 4 had signs of muscle atrophy. Tendon reflexes were decreased or absent and electroneurography demonstrated sensorimotor neuropathy in patients no. 1,2,3,4,5, except no. 6. Generalized seizures were seen in patients no. 2,3,5,6 and myoclonic jerks in patient no. 1. Cognitive deterioration was reported in patients no. 1,2,3,5,6. Serum creatine kinase levels were elevated in all six patients.
Conclusion:
We highlight the variability of clinical presentation of neuroacanthocytosis syndromes and the long time from the onset to diagnosis with the need to screen the blood smears in uncertain cases, however, as in one of our cases acanthocytes may even be not found. Based on our observations and data from the literature we propose several red flags that should raise the suspicion of an NA syndrome in a patient with a movement disorder: severe orofacial dyskinesia with tongue and lip-biting (typical of ChAc), feeding dystonia, psychiatric and cognitive disturbances, seizures, peripheral neuropathy, elevation of creatine kinase, elevation of transaminases, hepatosplenomegaly, cardiomyopathy and arrhythmias, and an X-linked pattern of inheritance (McLeod Syndrome, MLS).
Neuroacanthocytosis is a group of rare disorders. We report a 36-year-old right-handed female who presented with gradually progressive abnormal facial movements, generalized weakness, and lower-lip biting starting 4 years ago. On examination, she had lower-lip ulcer, orofacial dyskinesias, and peripheral neuropathy. Her peripheral blood smears showed acanthocytosis and magnetic resonance imaging revealed atrophied head of caudate nuclei and putaminal hyperintensities on T2-weighted and fluid attenuated inversion recovery images. Work-up for autoimmune and metabolic causes was negative. She was diagnosed with chorea-acanthocytosis, an entity under neuroacanthocytosis syndrome and the patient was offered symptomatic treatment.
Chorea-acanthocytosis is a rare disease presenting with chorea, dystonia, tics, amyotrophy, areflexia, dementia and oro-lingual self-mutilation. The presence of acanthocytes in blood smear and elevated creatin kinase levels are the most common laboratory findings. However, there are instances of late-appearing acanthocytes or of choreaacanthocytosis without acanthocytes. We report a 52-year-old patient with a 12-year history of chorea and orofacial dyskinesia. On neurological examination, he had facial, perioral and lingual hyperkinesias as well as dystonic trunk movements with severe limb chorea. Magnetic resonance imaging of the brain showed bilateral atrophy of the caudate nuclei. Peripheral blood smear, which failed to show any abnormality on all repeated evaluations, revealed abundant acanthocytes. Based on this, the patient was diagnosed with choreaacanthocytosis with late appearance of acantocytes in the course of the disease. In this paper, we underlined the significance of examination for acanthocytosis with special techniques to increase the diagnostic yield.
Choreoacanthocytosis or Levine-Critchley syndrome (MIM 200150) is a progressive multisystem disease with autosomal recessive transmission and a wide range of symptoms including: involuntary movements, lesion of peripheral nervous system, myopathy, behavioural and intellectual abnormalities, epilepsy, acanthocytosis and absence of any lipid abnormality. This disease is caused by mutation in VPS13A gene (CHAC) which is located on ch9q21. VPS13A gene spanning a 250 kbp region and consists of 73 exons. This gene encodes a large protein of unknown function, named chorein. Treatment for choreoacanthocytosis is aimed at the problematic symptoms of the sufferer but may not result in modification of natural history of this disease. Herein we report the case of a patient with positive familial history, choreiform movements in the arms, involuntary movements of the face and tongue, which was associated with vocalizations, dysarthria and dysphagia, progressing intellectual abnormalities, depression, clinical sign of peripheral nervous system lesion or/and myopathy, epilepsy with tonic-clonic fits and acanthocytosis. Creatine kinase was raised at - 387 U/l (N: 0-145 U/l) with LDH - 244 U/l (N: 80-240 U/l). Direct bilirubin and indirect bilirubin was slightly elevated. The MRI of the brain showed typical atrophy of the caudate nucleus (left) and seldom observed atrophy of hippocampus (right). As far as we know, it is the first observation of a patient with familial choreoacanthocytosis in Poland.
History The term neuroacanthocytosis (NA) refers to a group of syndromes in which nervous system abnormalities occur together with acanthocytosis, i.e., contracted and deformed erythrocytes that show spikelike protrusions (Figure 26.1). This description has been used to refer to a number of genetically distinct disorders, hence use of the term can be somewhat confusing and imprecise.There are two broad groups of NA disorders. The present chapter refers to those in which there is neurodegeneration of the basal ganglia, resulting in the development of movement disorders, with prominent cognitive impairment and psychiatric features. The “core” NA syndromes can now be classified as autosomal recessive chorea-acanthocytosis (ChAc), due to mutation of VPS13A [1–3], and X-linked McLeod syndrome (MLS), due to mutation of the XK gene on the X chromosome [4]. Despite being caused by distinct genes, whose functions appear to be unrelated, these two disorders share a number of similarities, including central and peripheral nervous system manifestations, hepatosplenomegaly and acanthocytosis. This striking phenotypic overlap has resulted in confusion in the literature. In this chapter the two disorders are discussed together, with emphasis upon the distinctive features of each.It could be argued that “chorea-acanthocytosis” is an inaccurate term as neither chorea nor acanthocytosis is a necessary or invariant feature of the disorder. However, we find this term preferable as it is now associated with a single genetically defined disorder, whereas “neuroacanthocytosis” has historically been a diagnostically imprecise term.
Neuroacanthocytosis (NA) syndromes are genetically defi ned neurodegenerative disorders characterized by the association of red blood cell acanthocytosis and progressive striatal neurodegeneration. The so-called core NA syndromes include autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome. These two disorders have a Huntington disease-like phenotype consisting of a hyperkinetic, mostly choreatic, movement disorders, psychiatric manifestations, and cognitive decline with a relentlessly progressive course over several decades. In addition, they may have multisystem involvement including motor-dominant axonal neuropathy, myopathy, and cardiomyopathy. McLeod syndrome (MLS) is exceptionally rare with an estimated prevalence of less than 1-5 per 1,000,000 inhabitants. It is caused by mutations in the XK gene. Although the mechanism by which these mutations cause striatal neurodegeneration is not known, the association of the acanthocytic membrane abnormality with selective striatal degeneration suggests a common pathogenetic pathway. Useful diagnostic laboratory tests, besides blood smears to detect acanthocytosis, encompass determination of serum creatine kinase, since virtually all patients with McLeod syndrome reported to date have elevated levels. Cerebral magnetic resonance imaging may demonstrate striatal atrophy. Kell and Kx blood group antigens are reduced or absent, thus delivering an accurate diagnosis of McLeod syndrome, and identifi cation of a distinct mutation in the XK gene is confi rmatory. The course of McLeod syndrome is relentlessly progressive, and there is no curative therapy known yet. However, regular cardiologic studies and avoidance of transfusion complications are mandatory. The hyperkinetic movement disorder may be treated as in Huntington disease. Other symptoms including psychiatric manifestations should be managed in a symptom-oriented manner.
Neuroacanthocytosis (NA) syndromes are a group of rare disorders displaying neurodegeneration and misshaped spiky red blood cells (acanthocytes). NA syndromes include chorea-acanthocytosis (ChAc), McLeod syndrome (MLS), Huntington's disease-like 2, and pantothenate kinase-associated neurodegeneration (PKAN) with ChAc as the prototype of this disease family. ChAc is caused by lossof- function mutations within the gene VPS13A encoding for a protein of unknown function named chorein. This leads to movement disorders most often showing involuntary movements as the main symptom and thus being a differential to Huntington's disease. Additional symptoms are cognitive decline, psychiatric disturbances, peripheral neuropathy, epilepsy, parkinsonism, and blood cell acanthocytosis together with elevated creatine kinase and liver enzymes. Interestingly, the non-neurological changes do not translate in relevant clinical symptoms in the respective system. There is no cure for the disease, and treatment is purely symptomatic. Recent data hints towards chorein being involved in different kinase pathways and actin cytoskeleton disturbances. This book chapter tries to shed light into the clinical phenotype, treatment, neuroimaging, neuropathology, and the current state of pathophysiology of ChAc.
Acanthocytes are atypical erythrocytes with sharp membrane protrusions. The range of diseases classified as neuroacanthocytosis (NA) includes a variety of disorders characterised by the occurrence of acanthocytes together with neurological symptoms. The detection of acanthocytes is, however, not specific and may not necessarily be a symptom of NA. The text describes both the most frequent and rare forms of NA, their etiology, and clinical and laboratory picture. The authors propose their own differential diagnostic approach based on the incidence of atrophy of the caput nuclei caudati which can make diagnosis faster and cheaper.
The presence of acanthocytes in the blood is characteristic of patients suffering from neuroacanthocytosis (NA). Recent studies have described abnormal phosphorylation of the proteins involved in connecting the membrane and cytoskeleton in patient-derived erythrocytes. The involvement of lipids in the underlying signaling pathways and recent reports on in vitro disease-associated lipid alterations support renewed research into lipid composition, signal transduction, and metabolism in patient erythrocytes. In addition to morphology, changes in membrane organization affect erythrocyte function and survival. Patient erythrocytes may have a decreased ability to deform, and this may contribute to accelerated erythrocyte removal and a decreased oxygen supply, especially in vulnerable brain regions. The presently available data indicate that acanthocytes are likely to originate in the bone marrow, making erythropoiesis an obvious new focus in NA research. Moreover, new, detailed morphological observations indicate that acanthocytes may be the tip of the iceberg with regard to misshapen erythrocytes in the circulation of patients with NA.
A systematic assessment of patient erythrocyte morphology, deformability, oxygen delivery, and metabolism will be instrumental in determining the putative contribution of erythrocyte function to NA clinical symptoms.
Movement disorders can be defined as neurologic syndromes in which there is either an excess of movement (commonly referred to as hyperkinesia, dyskinesia, and abnormal involuntary movement) or a paucity of voluntary and automatic movements unrelated to weakness or spasticity. The latter group can be referred to as hypokinesia (decreased amplitude of movement), but bradykinesia (slowness of movement) and akinesia (loss of movement) are common alternatives. The parkinsonian syndromes are the most common cause of paucity of movement; other hypokinetic disorders represent only a small group of patients. Movement disorders are conveniently divided into parkinsonism and all other types. Gait is affected by most types of movement disorders, including parkinsonism, dystonia, chorea, myoclonus, and cerebellar ataxia.
Movement disorders in children are symptoms that can be caused by many different diseases. Movement disorders are typically classified into primary and secondary disorders [1]. Primary movement disorders are conditions in which the movement disorder is the major symptom of a genetic or presumed genetic disorder. Secondary movement disorders are conditions in which the movement disorder is an expression of an underlying disease that may include other signs and symptoms, and which may be due to an acquired injury, infection, toxin, or metabolic process. Most movement disorders in children are secondary. One of the particular complicating factors of movement disorders in childhood is that several different disorders may coexist in the same child, making diagnosis difficult. In addition, many different etiologies can lead to the same disorder, and the same etiology can lead to different movement disorders in different children, or in the same child at a different age. Nevertheless, a thorough understanding of the different types of movement disorder, their possible causes, and the different types of expression that may occur in children is essential to guiding clinical practice for both diagnosis and effective treatment.
Nineteen cases are described, including 12 cases from three different families and 7 nonfamilial cases, in which multisystem neurological disease was associated with acanthocytosis in peripheral blood and normal plasma lipoproteins. Mild acanthocytosis can easily be overlooked, and scanning electron microscopy may be helpful. Some neurologically asymptomatic relatives with significant acanthocytosis were identified during family screening, including some who were clinically affected. The mean age of onset was 32 (range 8-62) yrs and the clinical course was usually progressive but there was marked phenotypic variation. Cognitive impairment, psychiatric features and organic personality change occurred in over half the cases, and more than one-third had seizures. Orofaciolingual involuntary movements and pseudobulbar disturbance commonly caused dysphagia and dysarthria that was sometimes severe, but biting of the lips or tongue was rarely seen. Chorea was seen in almost all symptomatic cases but dystonia, tics, involuntary vocalizations and akinetic-rigid features also occurred. Two cases had no movement disorder at all. Computerized tomography often demonstrated cerebral atrophy. Caudate atrophy was seen less commonly, and nonspecific focal and symmetric signal abnormalities from the caudate or lentiform nuclei were seen by magnetic resonance imaging in 3 out of 4 cases. Depression or absence of tendon reflexes was noted in 13 cases and neurophysiological abnormalities often indicated an axonal neuropathy. Sural nerve biopsies from 3 cases showed evidence of a chronic axonal neuropathy with prominent regenerative activity, predominantly affecting the large diameter myelinated fibres. Serum creatine kinase activity was increased in 11 cases but without clinical evidence of a myopathy. Postmortem neuropathological examination in 1 case revealed extensive neuronal loss and gliosis affecting the corpus striatum, pallidum, and the substantia nigra, especially the pars reticulata. The cerebral cortex appeared spared and the spinal cord showed no evidence of anterior horn cell loss. Two examples of the McLeod phenotype, an X-linked abnormality of expression of Kell blood group antigens, were identified in a single family and included 1 female. The genetics of neuroacanthocytosis are unclear and probably heterogeneous, but the available pedigree data and the association with the McLeod phenotype suggest that there may be a locus for this disorder on the short arm of the X chromosome.
Chorea-acanthocytosis (CHAC, MIM 200150) is an autosomal recessive neurodegenerative disorder characterized by the gradual onset of hyperkinetic movements and abnormal erythrocyte morphology (acanthocytosis). Neurological findings closely resemble those observed in Huntington disease. We identified a gene in the CHAC critical region and found 16 different mutations in individuals with chorea-acanthocytosis. CHAC encodes an evolutionarily conserved protein that is probably involved in protein sorting.
Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. Mutations in the CHAC gene on 9q21 were recently found to cause chorea-acanthocytosis. CHAC encodes a large, novel protein with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in CHAC were screened for mutations by denaturing high-performance liquid chromatography in 43 probands with ChAc. We identified 57 different mutations, 54 of which have not previously been reported, in 39 probands. The novel mutations comprise 15 nonsense, 22 insertion/deletion, 15 splice-site and two missense mutations and are distributed throughout the CHAC gene. Three mutations were found in multiple families within this or our previous study. The preponderance of mutations that are predicted to cause absence of gene product is consistent with the recessive inheritance of this disease. The high proportion of splice-site mutations found is probably a reflection of the large number of exons that comprise the CHAC gene. The CHAC protein product, chorein, appears to have a certain tolerance to amino-acid substitutions since only two out of nine substitutions described here appear to be pathogenic.
The rare McLeod blood group phenotype is characterized by weak Kell antigens, lack of the common Kx antigen, and acanthocytic morphology. Previous studies that did not detect membrane or cytoskeletal protein abnormalities suggested a lipid disturbance. In normal red cells, dimyristoyl phosphatidylserine (DMPS) is transported across the membrane by an enzymatic process and accumulates in the inner leaflet of the membrane bilayer causing discocyte to stomatocyte shape changes. Scanning electron microscopy of McLeod red cells shows a mixture comprised of 15% discocytes, 51% with irregular surfaces, and 34% acanthocytes. On incubation with various concentrations of DMPS at 37 degrees C for periods up to two hours, McLeod red cells transported DMPS across the membrane and caused irregularly shaped and acanthocytic McLeod red cells to attain normal discocyte shape and later to become stomatocytes. Chlorpromazine, which at 0 degrees C preferentially partitions into the inner monolayer of the membrane, had a similar effect on the shape of McLeod red cells. This suggests that in McLeod cells acanthocytosis is due to a lack of lipid in the inner leaflet of the membrane bilayer but that the imbalance is not caused by defective transport of phosphatidylserine across the membrane.
Detailed clinical and neuropathological findings in two unrelated patients with a chorea-acanthocytosis-like phenotype (CA) are reported. One case met all the diagnostic criteria of CA and had a deceased brother with the same disease. The second case had a virtually identical phenotype to the former but without acanthocytes. These findings suggest that both patients are affected by the same disease and that acanthocytes are not essential to the diagnosis. Neuropathological autopsy studies on the brain of the second case showed selective atrophy of the caudate nucleus that seemed to correspond to the movement disorder and behavioural abnormalities prominent in this patient. In both subjects, morphometric and ultrastructural examination of the peripheral nerve showed loss of myelinated fibres, more accentuated distally, and cytoskeletal changes in the axoplasm. These findings support the hypothesis that peripheral neuropathy in CA is caused by distal axonopathy.
Two patients with striatal atrophy and a clinical syndrome consistent with choreoacanthocytosis had normal dried blood smears but their red cells demonstrated an abnormal sensitivity to various conditions known to promote discocyte-echinocyte transformation. Dilution in normal saline, in vitro aging, and contact with glass caused a great proportion of these patients' red cells to develop multiple spiny or rounded projections. Under identical conditions, such shape changes did not occur in normal patients or in those with Huntington's disease. Scanning electron microscopy showed that the age-induced increase in acanthocytic-appearing cells could be reversed with chlorpromazine. These data suggest that the red cells from these patients with striatal degeneration are deficient in their ability to preserve normal shape in the face of echinocytic stress and that this observation has diagnostic and, possibly, pathophysiologic significance.
The rare McLeod blood group phenotype is characterized by weak Kell antigens, lack of the common Kx antigen, and acanthocytic morphology. Previous studies that did not detect membrane or cytoskeletal protein abnormalities suggested a lipid disturbance. In normal red cells, dimyristoyl phosphatidylserine (DMPS) is transported across the membrane by an enzymatic process and accumulates in the inner leaflet of the membrane bilayer causing discocyte to stomatocyte shape changes. Scanning electron microscopy of McLeod red cells shows a mixture comprised of 15% discocytes, 51% with irregular surfaces, and 34% acanthocytes. On incubation with various concentrations of DMPS at 37 degrees C for periods up to two hours, McLeod red cells transported DMPS across the membrane and caused irregularly shaped and acanthocytic McLeod red cells to attain normal discocyte shape and later to become stomatocytes. Chlorpromazine, which at 0 degrees C preferentially partitions into the inner monolayer of the membrane, had a similar effect on the shape of McLeod red cells. This suggests that in McLeod cells acanthocytosis is due to a lack of lipid in the inner leaflet of the membrane bilayer but that the imbalance is not caused by defective transport of phosphatidylserine across the membrane.
Chorea-acanthocytosis (CHA) is a rare inherited neurologic disorder with peripheral red cell acanthocytes and normal serum lipoprotein levels. To date, 8 families with the disorder have been reported outside of Japan. We describe 4 patients in 3 families with CHA and review the clinical presentations in previous reports. In addition, we report magnetic resonance imaging scans in these patients. The pattern of inheritance in these families is most likely autosomal recessive. Obligate heterozygotes do not have acanthocytes on wet preparation under phase microscope.
Two of 3 propositi were initially diagnosed as having Huntington chorea. Chorea-acanthocytosis is an important differential in the diagnosis of Huntington chorea and should be considered in families without a family history. The paucity of families with CHA reported to date may represent lack of recognition.
The involuntary movements in three patients with chorea-acanthocytosis (CA) and three with Huntington's chorea (HC) were studied by polygraphic recordings and jerk-locked averaging technique. Choreic movements in patients with CA were suppressed by mental calculation, voluntary muscle contraction, and instruction to stop them, whereas movements in HC were generally enhanced by these tasks. Backward averaging of the EEG time-locked to the choreic movement of an extremity or the trunk demonstrated a cortical slow negativity before the movement, similar to the Bereitschaftspotential (“readiness potential”), in cases of CA but not those of HC. Involuntary movements in CA appear to differ from those in HC and might be generated at least in part by a mechanism similar to that of voluntary movement.
Detailed clinical and neuropathological findings in two unrelated patients with a chorea-acanthocytosis-like phenotype (CA) are reported. One case met all the diagnostic criteria of CA and had a deceased brother with the same disease. The second case had a virtually identical phenotype to the former but without acanthocytes. These findings suggest that both patients are affected by the same disease and that acanthocytes are not essential to the diagnosis. Neuropathological autopsy studies on the brain of the second case showed selective atrophy of the caudate nucleus that seemed to correspond to the movement disorder and behavioural abnormalities prominent in this patient. In both subjects, morphometric and ultrastructural examination of the peripheral nerve showed loss of myelinated fibres, more accentuated distally, and cytoskeletal changes in the axoplasm. These findings support the hypothesis that peripheral neuropathy in CA is caused by distal axonopathy.
Acanthocytosis occurs because of ultrastructural abnormalities of the erythrocyte membranous skeleton resulting in reduced membrane fluidity. At least three hereditary neurological conditions are associated with it, although as yet the pathogenesis of the neurological features is unknown. In abetalipoproteinaemia, an autosomal recessive condition, vitamin E deficiency results in a progressive spinocerebellar syndrome associated with peripheral neuropathy and retinitis pigmentosa. Neuroacanthocytosis is also probably an autosomal recessive condition and is characterised by chorea, orofaciolingual dyskinesia, dysarthria, areflexia, seizures and dementia. McLeod syndrome is an X-linked recessive disorder usually presenting in males as a benign myopathy with areflexia, in association with a particular abnormality of expression of Kell blood group antigens. However, occasionally the neurological features are more severe and indistinguishable from those of neuroacanthocytosis. Recent advances in molecular genetics may assist better understanding of the disease mechanisms and the search for more effective treatments.
Chorea-acanthocytosis is a neurodegenerative disorder with peripheral red cell acanthocytosis. Linkage of chorea-acanthocytosis to chromosome 9q21 has been found. We refined the locus region and identified a previously unknown, full-length cDNA encoding a presumably structural protein, which we called chorein. We found a deletion in the coding region of the cDNA leading to a frame shift resulting in the production of a truncated protein in both alleles of patients and in single alleles of obligate carriers.
McLeod syndrome is caused by mutations of XK, an X-chromosomal gene of unknown function. Originally defined as a peculiar Kell blood group variant, the disease affects multiple organs, including the nervous system, but is certainly underdiagnosed. We analyzed the mutations and clinical findings of 22 affected men, aged 27 to 72 years. Fifteen different XK mutations were found, nine of which were novel, including the one of the eponymous case McLeod. Their common result is predicted absence or truncation of the XK protein. All patients showed elevated levels of muscle creatine phosphokinase, but clinical myopathy was less common. A peripheral neuropathy with areflexia was found in all but 2 patients. The central nervous system was affected in 15 patients, as obvious from the occurrence of seizures, cognitive impairment, psychopathology, and choreatic movements. Neuroimaging emphasized the particular involvement of the basal ganglia, which was also detected in 1 asymptomatic young patient. Most features develop with age, mainly after the fourth decade. The resemblance of McLeod syndrome with Huntington's disease and with autosomal recessive chorea-acanthocytosis suggests that the corresponding proteins--XK, huntingtin, and chorein--might belong to a common pathway, the dysfunction of which causes degeneration of the basal ganglia.
Acanthocytosis Handbook of Clinical Neurology. Else-vier
- Brin
Brin M (1993) Acanthocytosis. In: Goetz C, Tanner C, Aminoff M (eds) Handbook of Clinical Neurology. Else-vier, Amsterdam, pp 271–299
Acanthocytosis Handbook of Clinical Neurology
- M Brin