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2021-2023 Research Papers

This is where we will share the latest scientific papers on all things NA.

A Case of McLeod's Syndrome Presenting with Severe Decompensated Heart Failure
September 2023

Abstract. McLeod’s syndrome (MLS) is an X-linked disorder caused by mutations in the XK gene with neurological manifestations as well as cardiomyopathy. This is a case of acute exacerbation of heart failure in a 44-year-old White male with a confirmed diagnosis
of MLS, which was managed with guideline-directed medical therapy and placement of an implantable cardioverter defibrillator with recovery in ejection fraction.

Authors: Hemanth K. Boppana, MD, Samarthkumar Thakkar, MD, Harsh P. Patel, MD, Rody G. Bou Chaaya, MD, Scott Feitell, DO

Sphingolipid and Phospholipid Levels Are Altered in Human Brain in Chorea-Acanthocytosis
June 2023

Background: Choreaacanthocytosis (ChAc) is associated with mutations of VPS13A, which encodes for chorein, a protein implicated in lipid transport at intracellular membrane contact sites.
Objectives: The goal of this study was to establish the lipidomic profile of patients with ChAc. 
Methods: We analyzed 593 lipid species in the caudate nucleus (CN), putamen, and dorsolateral prefrontal cortex (DLPFC) from postmortem tissues of four patients with ChAc and six patients without ChAc.
Results: We found increased levels of bis(monoacylglycerol)phosphate, sulfatide, lysophosphatidylserine, and phosphatidylcholine ether in the CN and putamen, but not in the DLPFC, of patients with ChAc. Phosphatidylserine and monoacylglycerol were increased in the CN and N-acyl phosphatidylserine in the putamen. N-acyl serine was decreased in the CN and DLPFC, whereas lysophosphatidylinositol was decreased in the DLPFC.
Conclusions: We present the first evidence of altered sphingolipid and phospholipid levels in the brains of patients with ChAc. Our observations are congruent with recent findings in cellular and animal models, and implicate defects of lipid processing in VPS13A disease pathophysiology.
© 2023 International Parkinson and Movement Disorder Society.
This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Sleep Disorders in McLeod Syndrome

For a limited time (October 3, 2022), we have full access to this article published in the journal Parkinsonism and Related Disorders via this link:

Neuropathology of McLeod Syndrome
December 2021

Background. McLeod syndrome (MLS) is a rare (prevalence: <1/100,000), slowly progressive, X-linked recessive subtype
of neuroacanthocytosis with mean age at onset of 47 years.  Penetrance is high and may be complete after age 60 years. Individuals with MLS show an Xp21-linked Kell blood group variant (depressed Kell erythrocyte antigens including the erythrocyte membrane protein Kx) caused by an XK gene mutation. Neurological features include chorea, involuntary tongue
movements, dysarthria, dysphagia, dystonia, motor/vocal tics, cognitive impairment, neuropsychological disturbances (attention, memory, frontal lobe deficits), axonal sensorimotor neuropathy, myopathy, seizures, and biting of lips/tongue.
Cardiac manifestations and hepatosplenomegaly occur.


We describe two male siblings (61 and 63 years old) who presented with generalized chorea since their early twenties, sensory loss, areflexia, depression, anxiety, seizures, mild personality changes, and, since their mid-40s, cognitive impairment. Distal muscle weakness occurred in the older brother. Acanthocytes were detected. The XK mutation IVS2-2A>G was identified (younger brother).


Authors: Deutschländer, Angela B.,  Dickson, Dennis W., Wszolek, Zbigniew K. Neuropathology of McLeod Syndrome. Movement Disorders. 2021.

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Three new XK alleles; two associated with a McLeod RBC phenotype
September 2021

Background. The Kx antigen is the product of the XK gene on the X chro- mosome and the only known antigen in the XK blood group system.1 The Kx and Kell proteins are covalently linked on the red blood cells (RBC) membrane, and changes in the XK gene that abolish expression of Kx antigen are associated with very weak expression of Kell system antigens, known as the McLeod phenotype, found almost exclusively in males. The phenotype may be fortuitously detected when screening healthy blood donors.2 Importantly, XK null and missense mutations can cause the McLeod syndrome which is associated with acanthocytes, a late onset of neurological impairment, chorea-like disease, cardiomyopathy, and various degrees of muscular atrophy.1,3 Large deletions in the X chromosome can also cause McLeod syndrome, X-linked Chronic Granulomatous Disorder, and the contiguous gene deletion syndrome.4,5 Here, we report the molecular basis of the McLeod phenotype in a healthy male blood donor found by random screening for depressed Kell expression, a patient referred for a family history of a McLeod phenotype, and a patient referred for testing as part of a neurological workup.

Authors: Floch A, Lomas-Francis C, Vege S, Westhoff CM. Three new XK alleles; two associated with a McLeod RBC
phenotype. Transfusion. 2021;1–2. 10.1111/trf.16650

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Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis
May 2021

Abstract. Chorea-Acanthocytosis (ChAc) is a devastating, little understood, and currently untreatable neurodegenerative disease caused by VPS13A mutations. Based on our recent demonstration that accumulation of activated Lyn tyrosine kinase is a key pathophysiological event in human ChAc cells, we took advantage of Vps13a−/− mice, which phenocopied human ChAc. Using proteomic approach, we found accumulation of active Lyn, γ-synuclein and phospho-tau proteins in Vps13a−/− basal ganglia secondary to impaired autophagy leading to neuroinflammation. Mice double knockout Vps13a−/− Lyn−/− showed normalization of red cell morphology and improvement of autophagy in basal ganglia. We then in vivo tested pharmacologic inhibitors of Lyn: dasatinib and nilotinib. Dasatinib failed to cross the mouse brain blood barrier (BBB), but the more specific Lyn kinase inhibitor nilotinib, crosses the BBB. Nilotinib ameliorates both Vps13a−/− hematological and neurological phenotypes, improving autophagy and preventing neuroinflammation. Our data support the proposal to repurpose nilotinib as new therapeutic option for ChAc patients.

Authors: Peikert K*, Federti E*, Matte A, Constantin G, Pietronigro EC, Fabene PF, Defilippi P, Turco E, Del Gallo F, Pucci P, Amoresano A, Illiano A, Cozzolino F, Monti M, Garello F, Terreno E, Alper SL, Glaß H, Pelzl L, Akgün K, Ziemssen T, Ordemann R, Lang F, Brunati AM, Tibaldi E, Andolfo I, Iolascon A, Bertini G, Buffelli M, Zancanaro C, Lorenzetto E, Siciliano A, Bonifacio M, Danek A, Walker RH, Hermann A*, De Franceschi L*. https://doi:10.1186/s40478-021-01181-y

*contributed equally

Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in a Rare Disease

May 2021

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

Authors: Peikert K, Glaß H, Federti E, Matte A, Pelzl L, Akgün K, Ziemssen T, Ordemann R, Lang F. The Network for Translational Research for Neuroacanthocytosis Patients, De Franceschi L*, Hermann A*. May 2021. Journal of Personalized Medicine 11(5):392.

*contributed equally

The Erythrocyte Sedimentation Rate and Its Relation to Cell Shape and Rigidity of Red Blood Cells from Chorea-Acanthocytosis Patients in an Off-Label Treatment with Dasatinib

May 2021

Abstract: 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.

Authors: Rabe A*, Kihm A*, Darras A*, Peikert K*, Simionato G*, Dasanna AK*, Glaß H, Geisel J, Quint S, Danek A, Wagner C, Fedosov DA, Hermann A, Kaestner L. May 2021. Biomolecules 11(5):727.


*contributed equally.

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

April 2021

Abstract: (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.

Authors: Darras A*, Peikert K*, Rabe A, Yaya F, Simionato G, John T, Dasanna AK, Buvalyy S, Geisel J, Hermann A, Fedosov DA, Danek A, Wagner C, Kaestner L. April 2021. Cells 10(4):788.


*contributed equally.

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