Multisystem pathology in McLeod syndrome.

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 chorea-acanthocytosis patient with novel mutations in the VPS13A gene without acanthocyte.

Chorea-acanthocytosis (ChAc) is a rare clinical genetic disorder of the nervous system, which is characterized by choreiform movement disorder, cognitive decline, and psychiatric disorders. ChAc is mostly diagnosed based on its typical clinical manifestations and the increased number of acanthocytes in peripheral blood smears. Here, we report a patient, who has the characteristic clinical manifestations of ChAc with limb choreiform movements, involuntary lip and tongue bites, seizures, and emotional instability. However, her blood smear was negative for acanthocytes with scanning electron microscopy. We later identified two novel pathogenic mutations in the patient's vacuolar protein sorting homolog 13 A (VPS13A) on chromosome 9q21 by targeted gene sequencing, and she was definitively diagnosed with "ChAc." After treatment with carbamazepine, haloperidol, the patient's symptoms gradually improved. We consider that an acanthocyte negative blood smear cannot rule out ChAC diagnosis, and genetic testing is the "gold standard" for the diagnosis. Through a review of previous research, it is rare for a patient to have a clear diagnosis of ChAc by genetic testing, but whose blood smear is negative for acanthocytes with electron microscopy. In addition, in this report, we discovered two novel pathogenic mutations, which have not been reported previously, and extended the genetic characteristics of ChAc.

An Autopsy Series of Seven Cases of VPS13A Disease (Chorea-Acanthocytosis).

BACKGROUND: Vacuolar protein sorting 13 homolog A (VPS13A) disease, historically known as chorea-acanthocytosis, is a rare neurodegenerative disorder caused by biallelic mutations in VPS13A, usually resulting in reduced or absent levels of its protein product, VPS13A. VPS13A localizes to contact sites between subcellular organelles, consistent with its recently identified role in lipid transfer between membranes. Mutations are associated with neuronal loss in the striatum, most prominently in the caudate nucleus, and associated marked astrogliosis. There are no other known disease-specific cellular changes (eg, protein aggregation), but autopsy reports to date have been limited, often lacking genetic or biochemical diagnostic confirmation. OBJECTIVE: The goal of this study was to characterize neuropathological findings in the brains of seven patients with VPS13A disease (chorea-acanthocytosis). METHODS: In this study, we collected brain tissues and clinical data from seven cases of VPS13A for neuropathological analysis. The clinical diagnosis was confirmed by the presence of VPS13A mutations and/or immunoblot showing the loss or reduction of VPS13A protein. Tissues underwent routine, special, and immunohistochemical staining focused on neurodegeneration. Electron microscopy was performed in one case. RESULTS: Gross examination showed severe striatal atrophy. Microscopically, there was neuronal loss and astrogliosis in affected regions. Luxol fast blue staining showed variable lipid accumulation with diverse morphology, which was further characterized by electron microscopy. In some cases, rare degenerating p62- and ubiquitin-positive cells were present in affected regions. Calcifications were present in four cases, being extensive in one. CONCLUSIONS: We present the largest autopsy series of biochemically and genetically confirmed VPS13A disease and identify novel histopathological findings implicating abnormal lipid accumulation. © 2023 International Parkinson and Movement Disorder Society.

Acupuncture for treating symptoms associated with chorea-acanthocytosis: A CARE-compliant case report.

BACKGROUND: Chorea-acanthocytosis (ChAc) is the most common type of neuroacanthocytosis syndromes. Characteristic movement disorders of ChAc are choreiform movements affecting both trunk and extremities. Acanthocytosis in peripheral blood smear, elevated serum creatine kinase, 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. OBJECTIVE: We aimed to report on the use of acupuncture to successfully improve ChAc symptoms. METHOD: A patient with definite ChAc was admitted, who had suffered from involuntary tongue protrusion for about 10 years. Acupuncture treatment was administrated for 3 times a week for 2 months. The chorea tremor control area, Baihui (GV20), Sishencong (EX-HN1), Shenting (GV24), Benshen (GB13, bilateral), Yintang (GV29), Neiguan (PC6, bilateral), Tongli (HT5, bilateral), Zusanli (ST36, bilateral), Sanyinjiao (SP6, bilateral), Dicang (ST4, bilateral), Chengjiang (CV24), Lianquan (CV23), Jinjin (EX-HN12) and Yuye (EX-HN13) were selected as acupunture points. RESULTS: Previous drug dosage was reduced and the frequency of involuntary tongue protrusion was significantly reduced. Other clinical symptoms were also well controlled. Peripheral blood smear still indicated an increased proportion of red lineage, but blood analyses revealed improvement at follow-up. CONCLUSIONS: For patients who do not response well to conventional medical treatments, acupuncture might be used as an alternative treatment for symptoms related to ChAc.

McLeod syndrome with a novel XK frameshift mutation: A case report.

RATIONALE: McLeod syndrome (MLS) is a rare X-linked neurohematologic disorder caused by loss-of-function mutations in the XK gene. However, variations in the XK gene remain to be elucidated. Here, we report the clinical phenotype and genetic features of a patient with MLS caused by a novel frameshift mutation in the XK gene. PATIENT CONCERNS: A 44-year-old man presented with chorea, cognitive impairment, mental disorders, and seizures accompanied by peripheral neuropathy, hyperCKemia, and acanthocytosis. The proband's mother had a mild chorea. One older brother who died 10 years ago without a confirmed diagnosis showed symptoms of both chorea and mental disorders, while the other brother also developed mild chorea. DIAGNOSIS: The patient was diagnosed with MLS based on the family history, clinical manifestations, and accessory examinations. Whole-exome sequencing studies revealed a novel frameshift mutation resulting from a nucleotide variation in exon 2 (452delA) that leads to an amino acid residue conversion from Gln to Arg and early termination of the XK protein (Gln151ArgfsTer2). The patient and one of his older brothers were hemizygotes, and his mother was heterozygous. INTERVENTIONS: The patient was treated with haloperidol to control chorea and levetiracetam to control seizures. OUTCOMES: Six months after treatment, the proband was seizure-free, but showed little improvement in chorea and cognitive dysfunction. LESSON: We describe a family with MLS caused by a novel frameshift mutation in the XK gene. The causes of the mild clinical presentation in the proband's mother require further investigation.

Two case reports of chorea-acanthocytosis and review of literature.

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.

Compound Heterozygous VPS13A Variants in a Patient with Neuroacanthocytosis: A Case Report and Review of the Literature.

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by pathogenic variants of the vacuolar protein sorting 13A (VPS13A). Only a few patients with ChAc have been reported to date, and the variant spectrum of VPS13A has not been completely elucidated. We describe the case of a 36-year-old woman who had been experiencing orofacial dyskinesia since age 30 years. In a genetic study using next-generation sequencing, 2 variants of VPS13A, the nonsense variant c.4411C>T (p.Arg1471Ter) and the splicing variant c.145-2A>T, were identified. The splicing variant c.145-2A>T was newly classified as a pathogenic variant through a literature review. Consequently, the patient was diagnosed with ChAc based on the typical clinical manifestations, laboratory findings, and imaging results.

Orofacial manifestations of chorea-acanthocytosis: case presentation and literature review.

Chorea-acanthocytosis is a rare neurological disorder that produces involuntary body movements, along with a condition of misshapen red blood cells that is characterized by appearing in early adulthood. There are numerous orofacial manifestations linked to chorea-acanthocytosis that the dental practitioner must consider in early and late stages of the disease, such as chronic oral ulcerations, chronic mouth grinding, difficulty swallowing, and biting the lip and tongue, among others. This case, the first to the authors' knowledge to address the area of orofacial pain, provides general signs and symptoms of the disorder and management following a multidisciplinary approach. The life span of patients with this disorder is generally shortened, and correct management is essential to improve the quality of life.

[Case-report of neuroacanthocytosis associated with a compound mutation in the VPS13A gene]. / Sluchai neiroakantotsitoza, svyazannyi s mutatsiei VPS13A.

Neuroacanthocytosis is a group of neurodegenerative diseases manifested by a combition of neurological symptoms (most often choreic hyperkinesis) and the presence of an increased number of acanthocytes (erythrocytes with horns) in the peripheral blood. This group includes chorea-acanthocytosis, MacLeod's syndrome, pantothenate kinase-associated neurodegeneration, Huntington-like disease type 2, and some other very rare diseases. This article presents a genetically confirmed clinical case of chorea-acanthocytosis associated with a compound mutation in the VPS13A gene, discusses in detail the stages of a diagnostic search, presents an algorithm for examining patients with chorea.

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 (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.

"Neuroacanthocytosis" - Overdue for a Taxonomic Update.

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.

Neurofilament light chain in serum is significantly increased in chorea-acanthocytosis.

INTRODUCTION: Chorea-acanthocytosis (ChAc) is a rare hereditary neurodegenerative disease, characterized by hyper- and hypokinetic movement disorders, peripheral neuropathy and acanthocytosis. Biomarkers are not established; possible candidates include neurofilament reflecting neuroaxonal damage. METHODS: We studied serum neurofilament light chain (sNfL) of six ChAc patients compared to two healthy control cohorts (A, six age/sex matched and B, historical cohort of 59 healthy adult subjects) and in two patients with the very similar condition of McLeod syndrome (MLS), the second core syndrome of neuroacanthocytosis. sNfL was quantified using single-molecule array analysis. RESULTS: sNfL concentration was significantly higher in the ChAc cohort (18.73 pg/ml; IQR 15.65-27.70) compared to both healthy control cohorts (A, 7.37 pg/ml; IQR 5.60-9.05; B, 3.10 pg/ml; IQR 2.43-3.98). In MLS patients, a similar sNfL increase was observed. CONCLUSIONS: sNfL is significantly increased in ChAc and MLS and seems to reflect neuroaxonal damage in the peripheral as well as the central nervous system.

Chronic Granulomatous Disease with the McLeod Phenotype: a French National Retrospective Case Series.

BACKGROUND: X-linked chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the CYBB gene (located on Xp21.1). Patients with large deletions on chromosome Xp21.1 can present with the McLeod phenotype and also Duchenne muscular dystrophy or retinitis pigmentosa. The objective of the present study was to describe a series of French patients with CGD and the McLeod phenotype. METHODS: We retrospectively collected data from the medical records of 8 patients with CGD and the McLeod phenotype registered at the French National Reference Center for blood types. RESULTS: The median age at diagnosis of CGD was 1.2 years, the median age at diagnosis of the McLeod phenotype was 4.5 years, and the median length of follow-up was 15.2 years. Four patients displayed allo-immunization, with anti-KEL20 and anti-XK1 (formerly known as anti-KL) antibodies. Five of the 6 patients with available blood smears had acanthocytosis. Neuropsychiatric, muscle-related, and ocular manifestations were present in 4, 2, and 1 of the patients, respectively. Three of the 4 patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT) are alive. Overall, 5 patients are alive, and 3 are alive and well. CONCLUSION: This is the largest yet descriptive study of a series of patients with X-linked CGD and the McLeod phenotype. Although this disease combination is rare, the timely, accurate diagnosis of the McLeod phenotype is critical because of the serious post-transfusion complications. However, HSCT can be considered in these patients.

Identification of two compound heterozygous VPS13A large deletions in chorea-acanthocytosis only by protein and quantitative DNA analysis.

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.

A patient with McLeod syndrome showing involvement of the central sensorimotor tracts for the legs.

BACKGROUND: McLeod syndrome is a rare X-linked recessive acanthocytosis associated with neurological manifestations including progressive chorea, cognitive impairment, psychiatric disturbances, seizures, and sensorimotor axonal polyneuropathy. However, no studies have investigated the functioning of central sensorimotor tracts in patients with McLeod syndrome. CASE PRESENTATION: A 66-year-old man had experienced slowly progressive chorea and gait disturbance due to lower limb muscle weakness since his early fifties. Blood examinations showed erythrocyte acanthocytosis and the reduction of Kell antigens in red blood cells. Brain magnetic resonance imaging showed atrophy of the bilateral caudate nuclei and putamen. The diagnosis of McLeod syndrome was confirmed by the presence of a mutation of the XK gene on the X chromosome. Somatosensory-evoked potential and transcranial magnetic stimulation studies demonstrated that the central sensory and motor conduction times were abnormally prolonged for the lower extremity but normal for the upper extremity. CONCLUSIONS: This is the first report of the involvement of the central sensorimotor tracts for the legs in a patient with McLeod syndrome. The clinical neurophysiological technique revealed the central sensorimotor tracts involvements clinically masked by neuropathy.

Neuroacanthocytosis: a case report of chorea-acanthocytosis.

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.

Neuroacanthocytosis with unusual clinical features: A case report.

RATIONALE: Neuroacanthocytosis (NA) is a heterogeneous group of inherited neurodegenerative disorders characterized by misshapen spiculated erythorcytes and symptoms that resemble Huntington's disease. PATIENT CONCERNS: A 59-year-old female who developed hyperkinetic involuntary movements that became progressively more obvious during the course of a year. DIAGNOSES: Acanthocytes were observed in a peripheral blood smear. The patient had elevated levels of serum creatine kinase (CK). Gene sequencing did not reveal a genetic mutation. INTERVENTIONS: The patient was administered oral tiapride, alprazolam, B1 and B12 Vitamins. OUTCOMES: After 2 months of treatment the patient's symptoms were obviously alleviated. At the 6 month follow-up, the patient could feed herself and walk without assistance. LESSONS: The NA syndrome is extremely rare. It may be identified in the clinic based on abnormal orofacial movement, chorea, cognitive decline, elevated CK levels, and acanthocytosis. If available, protein- or genetic-based testing may provide a confirmatory diagnosis.

O'Sullivan-McLeod syndrome: Unmasking a rare atypical motor neuron disease.

Atypical motor neuron disease represents a rare heterogeneous group of neurodegenerative disorders with clinical, genetic and neuroimaging features distinct from those of the classic spinal or bulbar-onset amyotrophic lateral sclerosis (ALS). O'Sullivan-McLeod syndrome represents an extremely rare lower motor neuronopathy with early adult-onset distal amyotrophy and weakness in the upper limbs with asymmetrical involvement. To add to the few case series and epidemiological and genetic studies describing this variant syndrome, our team here presents a series of seven unrelated Brazilian patients with O'Sullivan-McLeod syndrome in a detailed review of their clinical, neuroimaging, laboratory and neurophysiological findings. A male-to-female ratio of 2.5 to 1 and a mean age at onset of 34.3years was observed, with a mean time delay of 6.6years between symptom-onset and a definitive diagnosis. A positive family history was observed in one case, yet whole-exome sequencing results were negative. Neuroimaging studies were unremarkable. All cases presented with chronic denervation restricted to cervical myotomes and normal sensory nerve conduction studies. This case series, one of the largest groups of patients with O'Sullivan-McLeod syndrome reported in the literature, confirms the sporadic nature of the condition and the difficulties faced in arriving at a definite diagnosis, and also expands the age limit in late adult-onset cases.