Neuroacanthocytosis Syndromes Research Articles

Feeding dystonia, chorea, psychosis, and self-mutilation in an African patient with neuroacanthocytosis syndrome

Feeding dystonia, chorea, psychosis, and self-mutilation in an African patient with neuroacanthocytosis syndrome

Osmotic gradient ektacytometry - a novel diagnostic approach for neuroacanthocytosis syndromes.

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. 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. 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). 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.

A Rare Case of Neuroacanthocytosis with Predominant Dystonia

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Acanthocytosis is irregular spiky red cells on peripheral blood smears, usually associated with neurological and hematological abnormalities. The different types of neuroacanthocytosis (NA) syndromes include core syndromes like chorea-acanthocytosis, McLeod syndrome, Huntington’s disease-like 2, and Pantothenate kinase-associated neurodegeneration, as well as NA associated with lipoprotein disorders such as abetalipoproteinemia (Bassen–Kornzweig syndrome), familial hypobetalipoproteinemia, Anderson disease, and atypical Wolman disease. Here, we describe a case of a 23-year-old man who presented to this hospital with complaints of choriform movements and abnormal dystonic body posturing since childhood. The peripheral smear revealed acanthocytes, and the brain’s MRI was normal.

Neuroacanthocytosis Syndromes: The Clinical Perspective

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.

Erysense, a Lab-on-a-Chip-Based Point-of-Care Device to Evaluate Red Blood Cell Flow Properties With Multiple Clinical Applications.

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.

Two case reports of chorea-acanthocytosis and review of literature

BackgroundChorea-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 presentationHere, we present two cases of ChAc diagnosed based on typical clinical symptoms, neuroimaging features, genetic findings of VPS13A, and response to the symptomatic treatment.ConclusionsChorea-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.

Unmasking of two mutations within XK gene that could be used as diagnostic markers to predict McLeod Syndrome: using in silico analysis

McLeod neuroacanthocytosis syndrome (MSL) is a rare X-linked recessive multisystem disorder affecting the peripheral and central nervous systems, red blood cells, and internal organs. The objective of this study was to identify the most deleterious SNPs within XK gene and to predict their influence on the functional and structural level by a several in silico analysis tools. The raw data of XK gene were recovered from dbSNP database and then used to investigate the damaging effect using SIFT, PolyPhen-2, PROVEAN, SNAP2, SNPs&GO, and PHD-SNP. Furthermore; we submitted the common six damaging results from the previous functional analysis tools to I-mutant 3.0, and MUPro respectively to study their effect on structural perspective. The 3D structure of XK was predicted by RaptorX and visualized using UCSF Chimera to compare the differences between the native and the mutant amino acids. The functional analysis predicted that two SNPs “rs28933690 and rs145996031” have a deleterious effect at functional level. The structural analysis revealed that, the same two mutations predicted a dramatic decrease of the protein stability, thus proposing that the C294R and Y370D mutations within XK could destabilize the amino acid interactions, causing functional abnormalities of XK protein. In this study, the impact of functional mutations in the XK gene was investigated through different computational analysis tool, which determined that (C294R & Y370D) are deleterious SNPs that are a potential responsibility for the functional and structural alterations of XK protein.

Neuroacanthocytosis Syndrome Misdiagnosed as Inflammatory Myopathy: A Case Report

Neuroacanthocytosis syndromes are a category of diseases characterized by progressive basal ganglia degeneration and acanthocytosis. Chorea-acanthocytosis (ChAc), a core neuroacanthocytosis syndrome, is characterized by chorea, psychiatric symptoms, and cognitive decline. It is also associated with neuromuscular abnormalities, including myopathy and axonal neuropathy. Herein, we describe a case of ChAc that was misdiagnosed and inappropriately treated as an inflammatory myopathy due to lower extremity weakness and hyper-creatine kinase (CK)-emia. Careful clinical and laboratory evaluations are always warranted to rule out neuroacanthocytosis in patients with myopathy presenting with chorea and peripheral neuropathy. Although rare, it is necessary to consider ChAc as a potential cause of hyperCKemia. A prompt differential diagnosis can prevent unnecessary treatment with steroids or immunomodulating agents. Keywords: Inflammatory myopathy; Myositis

The Spectrum of Movement Disorders in Neuroacanthocytosis Syndromes: A Video Series.

The Spectrum of Movement Disorders in Neuroacanthocytosis Syndromes: A Video Series.

Cardiac manifestation is evident in chorea-acanthocytosis but different from McLeod syndrome

IntroductionWe aimed to study the various cardiac manifestations of the two core neuroacanthocytosis (NA) syndromes, namely chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS). So far, cardiac involvement has been described as specific feature only for MLS. MethodsWe studied six patients with ChAc (mean age 44.5 years, five men, one woman) and six patients with MLS (mean age 57.1 years, all men). Cardiac evaluation included echocardiography and/or cardiac magnetic resonance imaging (cardiac MRI), 24-h ECG-recording and examination of cardiac biomarkers. ResultsCardiac involvement of ChAc was found in four of six patients. Two patients showed mildly reduced left ventricular ejection fraction (LVEF), two other patients mild to moderate left ventricular (LV) dilatation. Neither an increase in ventricular ectopic beats nor ventricular tachycardia were evident in ChAc. Four of five MLS patients showed left ventricle dilatation and reduced left ventricular ejection fraction (LVEF). Two of these, in addition, had critical ventricular tachycardia. High sensitive troponin T was elevated in all patients, for whom data were available (n = 10). In contrast, elevation of high sensitive troponin I was found in one of six ChAc and one of two MLS patients. ConclusionFor the first time, we reveal cardiac involvement in a cohort of six ChAc patients, while the risk to develop heart failure seems lower than in MLS. Our study confirms the malignant nature of MLS in terms of ventricular arrhythmias and progression to advanced heart failure. Herein, we define disease-specific recommendations for cardiac assessment in both conditions.

Proceedings of the Tenth International Meeting on Neuroacanthocytosis Syndromes.

The 10th International Meeting on Neuroacanthocytosis Syndromes was held online on March 10th12th, 2021. The COVID19 pandemic situation made our planned meeting in Barcelona on March 2020 to be suspended by one year, and finally took place online. The meeting followed the previous nine international symposia, the last of which was held in Dresden, Germany in March, 2018. The setting of the meeting encouraged interactions, exchange of ideas and networking opportunities among the high number of participants from around the globe, including scientists, neurologists and specially patients and caregivers. A total of 27 oral communications were distributed in 8 sessions with topics ranging from molecular and cellular functions of VPS13 genes and proteins, their involvement in Neuroacanthocytosis Syndromes and finally clinical aspects and patients care. In addition, 5 posters were presented. Altogether, scientists and neurologists discussed recent advances and set the bases for next steps, action points, and future studies in close collaboration with the patients associations, which are always actively involved in the whole process.

Irregular Case of Neuroacanthocytosis Presenting with Late Onset Attention Deficit Hyperactivity Disorder: A Case Report

Neuroacanthocytosis (NA) syndromes are characterized by various neurological abnormalities accompanied by abnormal red blood cells called acanthocytes. Neuroacanthocytosis syndromes may be divided into 4 main subgroups. These subgroups are named as; Core NA syndromes, Degenerative disorders where acanthocytosis is occasionally seen, Paroxysmal dyskinetic disorders and Disorders with reduced blood lipoproteins and acanthocytosis. This report focuses on a patient with Chorea-acanthocytosis who presented with motor signs in the 3rd decade of life. In the later course of disease, the patient developed attention deficit hyperactivity disorder and various tic disorders. We wanted to emphasize the importance of multidisciplinary care in the management of chorea-acanthocytosis.

Acanthocyte Sedimentation Rate as a Diagnostic Biomarker for Neuroacanthocytosis Syndromes: Experimental Evidence and Physical Justification.

(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 (, ). (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.

Neuroacanthocytosis, a rare and challenging diagnosis

Neuroacanthocytosis syndromes are a heterogeneous group of genetically defined neurological disorders characterized by progressive degeneration of the basal ganglia, along with red blood cell acanthocytosis. Despite its likelihood of being under-diagnosed, its reported prevalence is approximately 1–5 per 1,000,000 individuals. Its onset is usually by the third or fourth decade of life, and it's classically manifested by orolingual action-induced dystonia, generalised chorea, vocal tics, and stereotypies. Other manifestations include dysphagia, dysarthria, peripheral neuropathy, cognitive decline, areflexia, and parkinsonism. We herein report a rare case of neuroacanthocytosis in a 40 years old male who presented with a 3 years history of multiple falls, along with difficulty in swallowing and speaking that resulted in a weight loss of 71 kg. In addition, he suffered an apparent cognitive decline and some psychiatric disturbances, on top of his baseline obsessive-compulsive behavior. He was initially misdiagnosed and investigated for Huntington's disease, Huntington-like diseases, and malnutrition but the workup denied these diagnoses. The patient underwent several investigations including laboratory investigations, a brain MRI, and electrodiagnostic studies. His lab tests revealed red blood cell acanthocytosis of more than 5% on the peripheral smear, in addition to elevated lactate dehydrogenase and creatinine phosphokinase. His brain MRI was unremarkable. Nerve conduction studies and electromyography performed on all four limbs and paraspinal muscles revealed findings suggestive of chronic polyneuropathy. In view of the absence of targeted treatment for neuroacanthocytosis, the prognosis was explained to the family and the importance of follow-up was emphasized to optimize symptomatic management.

Proceedings of the Ninth International Meeting on Neuroacanthocytosis Syndromes.

The 9th International Meeting on Neuroacanthocytosis Syndromes was held on March 23th–25th, 2018 in Dresden, Germany. The conference followed the tradition of the previous eight international symposia, the last of which was held in Ann Arbor, USA in May, 2016. Following the positive response to the previous meeting, a major component of this year’s symposium was the participation of patients, their families, and caregivers. The conference focused primarily on chorea-acanthocytosis as one of the “core” diseases of neuroacanthocytosis syndromes, with some discussion also of McLeod syndrome. These neurodegenerative diseases lead to chorea, epilepsy, cognitive and behavioral problems, and acanthocytosis of red blood cells. While chorea-acanthocytosis is caused by mutations in the VPS13A gene, other “VPS13opathies” (VPS13B-D) were also topic of the meeting. At present there are no treatments that can halt or slow down the progression of these diseases. However, two pathways seem to be prominently involved in chorea-acanthocytosis – namely the PI3K (phosphoinositide 3-kinase) pathway and the Lyn kinase pathway – both of which are potential “druggable” targets. Model organisms including Dictyostelium , Drosophila , yeast, and mice, and human cell models were presented. Finally, clinical translation and clinical trial readiness in such a rare disease were extensively discussed.

The first case report of neuroacanthocytosis in Vietnam

Background: Neuroacanthocytosis (NA) syndromes are a group of rare diseases characterized by the presence of acanthocytes and neuromuscular manifestations that includes chorea-acanthocytosis (ChAc), McLeod syndrome (MLS), Huntington’s disease-like 2 (HDL-2), and pantothenate kinase-associated neu- rodegeneration (PKAN).

Progress in the Diagnosis and Management of Chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is the most common subtype of neuroacanthocytosis syndrome, characterized by the presence of acanthocytes and neurological disorders. It is thought to be caused by VPS13A mutations. Characteristic movement disorders in ChAc is choreiform movements affecting both trunk and extremities and prominent orolingual dyskinesia is pathognomonic. Acanthocytosis in peripheral blood smear, elevated serum creatine kinase and atrophy of heads of caudate nuclei and dilation of the anterior horn of the lateral ventricles in magnetic resonance imaging could assist the diagnosis of ChAc. Botulinum toxin injection is a possible treatment for the typical orofacial dystonia. Deep brain stimulation is a novel surgical treatment modality. Most cases chose globus pallidus internus as target. Patients with dystonia as a major manifestation will benefit more from high-frequency stimulation and those with major findings of chorea and dysarthria are suitable for low-frequency stimulation. More evidence of long-term outcomes is warranted.

Absence of Acanthocytosis in Huntington’s Disease-like 2: A Prospective Comparison with Huntington’s Disease

<strong>Background:</strong> 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). <strong>Methods:</strong> 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. <strong>Results:</strong> 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. <strong>Discussion:</strong> 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 First Genetically Confirmed McLeod Syndrome in Korea

McLeod syndrome is a rare X-linked multisystem disorder which forms the core of neuroacanthocytosis syndrome. Neurological symptoms characterized by chorea, seizure, cognitive impairment, and psychosis mostly develop around the 5-6th decades, accompanied by multisystem involvement comprising neuropathy, myopathy, acanthocytosis and hepatosplenomegaly. We hereby present a 60-year-old male who is the first genetically confirmed Korean McLeod syndrome patient. Genetic analysis of his XK gene revealed a previously reported 5 base pair deletion of exon 3 (c.856_860delCTCTA). Key Words: McLeod syndrome, Neuroacanthocytosis

Neuroacanthocytosis syndromes and neuropsychiatry symptoms associated

IntroductionNeuroacanthocytosis is an infrequent cause of both neurological and psychiatric manifestations, and acanthocytes, which are a special form of spiculated red blood cells. Clinically significant psychopathology, ranging from behavioural disturbance to frank psychiatric illness, has been reported to occur in up to 60% of ChAc patients.MethodsA review was conducted aiming to clarify the physiopathology of this illness and its clinical features in order to distinguish neuroacanthocytosis from other neurological or psychiatric diseases. The literature search was conducted in PubMed data reviewing articles dating between 2010 and 2016.Results– Neuroacanthocytosis autosomal recessive disorder associated with mutations or deletions in the VPS13A gene on chromosome 9q, which codes for the membrane protein chorein. Chorein is strongly expressed in the brain. Chorein loss particularly affects the basal ganglia, especially the caudate nucleus and putamen;– Dysexecutive syndromes, OCD, depression and possibly psychosis, which may precede the frank motor and cognitive impairment;– The most recently developed treatment for neuroacanthocytoses is the use of deep-brain stimulation (DBS), with stimulation of the globus pallidus internus.ConclusionsWhile conducting a neurological exam, secondary causes of psychosis have to be included in the differential diagnosis. It is important to notice the possible confusion between tardive dyskinesia and a primary movement disorder. It should be necessary to investigate all de novo movement disorders in psychotic patients in order to eliminate etiologies other than iatrogenic ones.Disclosure of interestThe authors have not supplied their declaration of competing interest.