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Inheritance

1

X-linked HP:0001417

Affected males carry a hemizygous intragenic XK variant (about 90%) or a hemizygous Xp21.1 deletion involving XK (about 10%). Heterozygous females are mosaic for the Kell and Kx antigens because of X inactivation, and while they usually escape the neurological disease, some develop chorea or late-onset cognitive decline - so carrier status is not reliably silent.

X-linked inheritance

Show evidence (5 references)

PMID:20301528 SUPPORT Human Clinical

"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"

Establishes the X-linked architecture and the split between intragenic variants and whole-locus deletions, which matters because the deletion class can extend into neighbouring genes.

PMID:20301528 SUPPORT Human Clinical

"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"

Records that heterozygous females are not uniformly unaffected, which is what makes carrier identification clinically relevant rather than purely reproductive.

PMID:20301528 SUPPORT Human Clinical

"If the mother of an affected male is heterozygous, the chance of transmitting the XK pathogenic variant in each pregnancy is 50%"

The per-pregnancy transmission risk, from the GeneReviews GENETIC COUNSELING section.

+ 2 more references

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Mechanistic Hypotheses

1

vps13a_xk_scramblase_complex_model

vps13a_xk_scramblase_complex_model CANONICAL

Evidence balance 1 support

Loss of XK disables a VPS13A-XK lipid handling complex at membrane contact sites, and it is that shared complex failure - not anything specific to the Kell blood group system - that produces the neurodegeneration. The model's strength is that it explains why an X-linked and an autosomal recessive disease look alike; its weakness is that it does not yet explain the caudate selectivity, and the evidence is from overexpression in cultured human cells rather than from patient neural tissue.

Show evidence (1 reference)

PMID:32845802 SUPPORT In Vitro

"ChAc phenotypes resemble those of McLeod Syndrome, caused by mutations in the XK gene, suggesting that XK could be a partner protein for VPS13A"

The reasoning that motivated the experiment, and the clinical convergence the model is built to explain.

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Discussions and Knowledge Gaps

3

XK is expressed well beyond the striatum and its lipid-scrambling function is not region-specific. Why does its loss destroy the caudate nucleus in particular?

KNOWLEDGE GAP OPEN gap_why_the_caudate

Attached to

pathophysiology#Loss of XK-VPS13A Phospholipid Scrambling at Membrane Contact Sites pathophysiology#Striatal Neuronal Loss and Gliosis

This is the entry's central unexplained step and the edge is marked INDIRECT_UNKNOWN_INTERMEDIATES for exactly that reason. The neuropathology is unambiguous about the gradient - caudate worst, then putamen, then pallidum, in every patient examined - and the imaging shows the striatal deficit before symptoms appear. But nothing in the available evidence connects a plasma membrane phospholipid scrambling defect to that anatomy. The same problem exists for chorea-acanthocytosis and for Huntington disease, so an answer would likely generalize: striatal medium spiny neurons are selectively vulnerable across mechanistically unrelated diseases, and whatever makes them so may matter more here than the specific lesion.

Proposed experiments

Regional phospholipid asymmetry and VPS13A localization across brain regions

exp_regional_lipid_asymmetry_in_xk_loss

Measure plasma membrane phosphatidylserine exposure and VPS13A subcellular distribution in striatal versus cortical and cerebellar neurons from XK-null human iPSC-derived cultures and from an XK-null mouse, at several ages. If the scrambling defect is uniform across regions while degeneration is not, the selectivity lies in the neurons rather than in the lesion, and the search should move to what distinguishes medium spiny neurons.

Can McLeod patients without chronic granulomatous disease form anti-Kx, or only anti-Km?

CONTROVERSY OPEN controversy_anti_kx_in_non_cgd_mcleod

Attached to

pathophysiology#Kx and Km Alloimmunization Risk

The prevailing rule holds that only CGD-McLeod patients - those whose deletion removes CYBB as well as XK - form anti-Kx, while non-CGD McLeod patients form anti-Km alone. The case report cited on that node was written to report the exception: a patient with the McLeod phenotype, without CGD, and with antibodies to both Kx and Km. The entry curates the general rule as a stated belief rather than as fact for that reason. The distinction is not academic. If the rule holds, non-CGD patients have a wider pool of compatible donors than CGD patients; if exceptions are common, every McLeod patient needs the stricter standard, and the cryopreservation recommendation becomes more urgent rather than less. A single counterexample does not settle the frequency, which is what a transfusion service would need.

Proposed experiments

Alloantibody specificity surveyed against deletion genotype

exp_alloantibody_survey_by_deletion_extent

Across a multi-centre McLeod cohort, pair each patient's antibody specificities with the precise extent of their XK lesion (intragenic variant, XK-only deletion, XK plus CYBB) and their transfusion history. This would establish whether anti-Kx formation tracks with CYBB involvement or simply with exposure, which is what determines the compatibility standard each genotype needs.

Does a VPS13A relocalization assay driven by XK overexpression in cultured cells report what XK does at physiological abundance in a human neuron?

HUMAN MODEL MISMATCH OPEN mismatch_scramblase_evidence_is_overexpression_in_cell_lines

Attached to

pathophysiology#Loss of XK-VPS13A Phospholipid Scrambling at Membrane Contact Sites

The XK-VPS13A partnership is the entry's mechanistic centrepiece, and it rests on overexpression. The functional readout - XK relocalizing VPS13A from lipid droplets to ER subdomains - was observed "when overexpressed", and the disease-variant control shows that chorea-acanthocytosis mutations block it. That is a strong argument for the interaction being real and disease-relevant. It is a much weaker argument about what happens when XK is simply absent at normal expression levels, in a post-mitotic neuron, over decades. Overexpression can force interactions that are minor or absent physiologically, and relocalization away from lipid droplets is not obviously the same event as the loss-of-function state in patients. No source available to this entry reports VPS13A localization or lipid asymmetry in McLeod patient neural tissue.

Proposed experiments

VPS13A localization at endogenous XK levels in patient-derived neurons

exp_vps13a_localization_in_patient_neurons

Compare VPS13A subcellular distribution and ER-plasma membrane contact site architecture in neurons differentiated from McLeod patient iPSCs against isogenic XK-corrected controls, without overexpressing either protein. Reproducing the relocalization defect at endogenous abundance would move the model from plausible to demonstrated; failing to reproduce it would mean the complex is real but the overexpression readout is not the disease mechanism.

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Pathophysiology

10

XK Loss of Function

The initiating lesion. XK encodes a 50.9 kDa protein that crosses the membrane ten times and was originally identified by positional cloning from a 50 kb deletion in McLeod patients. Point variants at conserved splice donor and acceptor sites in unrelated patients gave the first direct evidence that XK is the responsible gene.

XK hgnc:12811

plasma membrane GO:0005886

Downstream

Loss of the Kell-XK Membrane Complex XK is covalently bonded to Kell, so losing XK destabilizes the partner.

Loss of XK-VPS13A Phospholipid Scrambling at Membrane Contact Sites The molecular function whose loss is proposed to drive the neurodegeneration.

Chronic Axonal Motor Neuropathy The neuromuscular arm. XK is expressed in peripheral nerve as well as in brain and red cell, but no source available to this entry connects its loss to axonal degeneration through an identified route, so the intermediates are unknown rather than merely unstated.

Cardiomyopathy and Arrhythmia The cardiac arm, drawn from the initiating lesion rather than from the neurodegeneration. Nothing derives the cardiomyopathy from the brain disease, and the surveillance recommendation treats it as independent by applying to patients with no known cardiac involvement. How XK loss injures myocardium is not established.

Show evidence (2 references)

PMID:8004674 SUPPORT Human Clinical

"Nucleotide sequence analysis of XK from two unrelated McLeod patients has identified point mutations at conserved splice donor and acceptor sites. These findings provide direct evidence that XK is responsible for McLeod syndrome"

The founding gene-disease assertion, from the positional cloning study.

PMID:8004674 SUPPORT Human Clinical

"XK encodes a novel protein with structural characteristics of prokaryotic and eukaryotic membrane transport proteins"

The original structural assignment. Note this reads XK as a transporter; the scramblase function below was established much later and supersedes it.

Loss of the Kell-XK Membrane Complex

XK and the Kell glycoprotein are joined by a single disulphide bond, Kell Cys72-XK Cys347. The two proteins are encoded on different chromosomes - KEL at 7q33, XK at Xp21 - yet depend on each other in the membrane, which is why an X-linked defect produces an abnormality in a chromosome 7 blood group system. Losing XK abolishes the Kx antigen and markedly weakens Kell antigen expression: the McLeod blood group phenotype.

erythrocyte CL:0000232

Downstream

Red Cell Membrane Instability and Acanthocytosis Acanthocytes are the morphological consequence, but how loss of the complex distorts the membrane skeleton is not established by any source available to this entry.

Kx and Km Alloimmunization Risk Antigens the patient has never expressed are seen as foreign when transfused.

Show evidence (2 references)

PMID:10895256 SUPPORT In Vitro

"A single disulphide bond, Kell Cys 72-XK Cys 347, links Kell to XK"

The covalent link that makes the two proteins interdependent in the membrane.

PMID:18167163 SUPPORT Human Clinical

"The McLeod phenotype is characterized by weakened expression of antigens in the Kell blood group system, absence of Km and Kx antigens, and acanthocytosis"

Defines the serological phenotype that follows from losing the complex.

Loss of XK-VPS13A Phospholipid Scrambling at Membrane Contact Sites

The mechanistically informative finding, and the one that reframes the disease. XK forms a complex with VPS13A - the lipid transfer protein mutated in chorea-acanthocytosis - and when overexpressed relocalizes VPS13A from lipid droplets to subdomains of the endoplasmic reticulum. Introducing chorea-acanthocytosis disease variants into VPS13A prevents that relocalization. Two clinically near-identical neuroacanthocytosis syndromes, one X-linked and one autosomal recessive, therefore converge on dysregulation of a single complex.

plasma membrane phospholipid scrambling GO:0017121 ↓ DECREASED

phospholipid scramblase activity GO:0017128 ↓ DECREASED

endoplasmic reticulum-plasma membrane contact site GO:0140268

Downstream

Striatal Neuronal Loss and Gliosis Why a lipid-scrambling defect should selectively destroy caudate neurons is not established. No source available to this entry connects the scramblase function to the regional pattern of degeneration.

Show evidence (2 references)

PMID:32845802 SUPPORT In Vitro

"it forms a complex with VPS13A in human cells and, when overexpressed, relocalizes VPS13A from lipid droplets to subdomains of the endoplasmic reticulum"

Establishes the physical partnership and the functional readout used to test it.

PMID:32845802 SUPPORT In Vitro

"These results suggest that dysregulation of a VPS13A-XK complex is the common basis for ChAc and McLeod Syndrome"

The unifying claim. Quoted with the authors' own "suggest", because this is a cell-biological inference rather than a demonstration in patient neural tissue.

Red Cell Membrane Instability and Acanthocytosis

Spiculated red cells with irregular thorn-like projections. Acanthocytosis is the finding the disease is named for and is present in essentially all affected males, but it is neither specific to McLeod syndrome nor proportional to neurological severity.

erythrocyte CL:0000232

Downstream

Compensated Hemolysis Abnormally shaped cells are cleared faster.

Show evidence (1 reference)

PMID:20301528 SUPPORT Human Clinical

"The hematologic manifestations are red blood cell acanthocytosis and compensated hemolysis"

Names both haematological consequences and, in "compensated", records that the hemolysis does not usually produce clinical anemia.

Compensated Hemolysis

Shortened red cell survival matched by increased production, so haemoglobin is usually normal and the hemolysis is detectable biochemically rather than clinically. This node is separated from the acanthocytosis above because the compensation is the point: the haematological arm of the disease is largely silent in the patient while being diagnostically loud on the blood film.

Show evidence (1 reference)

PMID:20301528 SUPPORT Human Clinical

"red blood cell acanthocytosis and compensated hemolysis"

The compensated character of the hemolysis, stated by the source.

Kx and Km Alloimmunization Risk

Because affected males never express Kx or Km, transfused red cells carrying those antigens are immunologically foreign. The resulting alloantibodies cause severe transfusion reactions, and this is the mechanism behind the disease's one absolute contraindication. The antibody repertoire also differs by genotype: patients whose deletion extends into CYBB, producing chronic granulomatous disease alongside McLeod syndrome, are generally held to be able to make both anti-Km and anti-Kx, whereas non-CGD McLeod patients were believed to make only anti-Km - a belief the cited case report was written to challenge.

Show evidence (2 references)

PMID:20301528 SUPPORT Human Clinical

"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"

Establishes both the transfusion hazard and the separate neonatal alloimmune risk.

PMID:18167163 SUPPORT Human Clinical

"It is generally believed that patients with non-CGD McLeod may develop anti-Km but not anti-Kx, but that those with CGD McLeod can develop both anti-Km and anti-Kx"

Curated PARTIAL deliberately. This quote states the prevailing belief, and the paper's title reports a non-CGD McLeod patient with antibodies to both Kx and Km - that is, a counterexample. The rule is recorded here as a belief rather than as fact.

Striatal Neuronal Loss and Gliosis

The neurodegenerative core, and it has a consistent spatial gradient. In the largest autopsy series assembled, histology showed neuronal loss and gliosis in the basal ganglia of every patient, with severity decreasing from the caudate nucleus through the putamen to the pallidum. The same gradient appears macroscopically as basal ganglia atrophy. Functional imaging detects the process before the movement disorder appears: striatal FDG uptake was reduced in a 28-year-old with no movement disorder at all.

medium spiny neuron CL:1001474 neuron CL:0000540

caudate nucleus UBERON:0001873 striatum UBERON:0002435

Downstream

Chorea and Huntington-Like Neurodegenerative Syndrome Caudate-predominant striatal loss is the anatomical substrate for the chorea.

Show evidence (3 references)

PMID:40898647 SUPPORT Human Clinical

"Histology revealed neuronal loss and accompanying gliosis in the basal ganglia of all patients"

The core neuropathological finding, in the largest series examined.

PMID:40898647 SUPPORT Human Clinical

"with a decreasing gradient of severity from the caudate nucleus to the putamen and the pallidum, mirroring the macroscopic findings"

The spatial gradient, which is what makes the pathology recognizable rather than merely present.

PMID:11254778 SUPPORT Human Clinical

"Positron emission tomography disclosed a reduction of the striatal FDG uptake in both patients, with accentuation in patient 1. Frontal lobe metabolism was not affected"

Shows the deficit is striatum-selective rather than global, and the second patient in this pair was presymptomatic.

Chronic Axonal Motor Neuropathy

The arm of the disease that was misnamed for decades. McLeod syndrome was originally described as a benign myopathy, but systematic study of ten patients including the original index patient found that the muscle weakness and atrophy are predominantly neurogenic rather than myopathic. Myopathic changes were present in a minority; every patient had neurogenic changes. This is why the entry curates a neuropathy node rather than a myopathy node, with the elevated creatine kinase as its biochemical readout.

neuron CL:0000540

Show evidence (2 references)

PMID:18055495 SUPPORT Human Clinical

"Clear but unspecific myopathic changes were found in only four patients. All patients, however, had neurogenic changes of variable degree"

The histological basis for reading the muscle involvement as neurogenic.

PMID:18055495 SUPPORT Human Clinical

"Post-mortem motor and sensory nerve examinations support the view that muscle atrophy and weakness are predominantly due to an axonal motor neuropathy rather than to a primary myopathy"

The authors' explicit reassignment of the mechanism from myopathy to axonal neuropathy.

Chorea and Huntington-Like Neurodegenerative Syndrome

Adult-onset chorea with cognitive decline and psychiatric disturbance, clinically close enough to Huntington disease that McLeod syndrome belongs in its differential. Onset of multisystem manifestations is around the fourth decade. The presenting feature is frequently psychiatric or epileptic rather than choreiform, so the movement disorder is not reliably the first thing seen.

Show evidence (2 references)

PMID:18055495 SUPPORT Human Clinical

"our findings confirm that MLS is not a benign condition but rather a progressive multisystem disorder sharing many features with Huntington's disease"

States both the progressive multisystem character and the Huntington resemblance.

PMID:18055495 SUPPORT Human Clinical

"Three patients manifested with psychiatric features comprising schizophrenia-like psychosis and personality disorder, two presented with generalized seizures and one with chorea"

Records that psychiatric and epileptic presentations outnumbered choreiform presentation in this series.

Cardiomyopathy and Arrhythmia

Dilated cardiomyopathy with atrial fibrillation and tachyarrhythmia, and a leading cause of death. It is curated as a parallel consequence of XK loss rather than downstream of the neurodegeneration, because no source available to this entry derives the cardiac disease from the neurological one - and the surveillance recommendation treats it as independent, applying to patients with no known cardiac involvement.

Show evidence (2 references)

PMID:20301528 SUPPORT Human Clinical

"Cardiac manifestations include dilated cardiomyopathy, atrial fibrillation, and tachyarrhythmia"

Names the cardiac phenotype.

PMID:18055495 SUPPORT Human Clinical

"Five patients died because of MLS-related complications including sudden cardiac death, chronic heart failure and pneumonia between 55 and 69 years"

Establishes cardiac disease as a cause of death rather than an incidental finding.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

14

Cardiovascular 3

Dilated Cardiomyopathy HP:0001644

Show evidence (1 reference)

PMID:20301528 SUPPORT Human Clinical

"Cardiac manifestations include dilated cardiomyopathy, atrial fibrillation, and tachyarrhythmia"

Names the cardiomyopathy. No cohort frequency is given, so no band is asserted.

Atrial Fibrillation HP:0005110

Show evidence (1 reference)

PMID:20301528 SUPPORT Human Clinical

"dilated cardiomyopathy, atrial fibrillation, and tachyarrhythmia"

Names the arrhythmia phenotype.

Sudden Cardiac Death HP:0001645

Show evidence (1 reference)

PMID:18055495 SUPPORT Human Clinical

"Five patients died because of MLS-related complications including sudden cardiac death, chronic heart failure and pneumonia between 55 and 69 years"

Records sudden cardiac death as an observed cause of death in the followed cohort, with the age range.

Metabolism 1

Elevated Serum Creatine Kinase VERY_FREQUENT Elevated circulating creatine kinase concentration HP:0003236

Show evidence (1 reference)

PMID:18055495 SUPPORT Human Clinical

"eight patients including the initial index patient showed elevated skeletal muscle creatine kinase levels ranging from 300 to 3000 U/L, and had developed muscle weakness and atrophy"

8/10 is 80 percent, at the lower boundary of VERY_FREQUENT (80-99 percent), with the measured range stated.

Musculoskeletal 2

Muscle Weakness VERY_FREQUENT HP:0001324

Show evidence (1 reference)

PMID:18055495 SUPPORT Human Clinical

"had developed muscle weakness and atrophy. Two patients had disabling leg weakness"

Same 8/10 denominator as the creatine kinase item, with the severe subset counted separately.

Skeletal Muscle Atrophy VERY_FREQUENT HP:0003202

Show evidence (1 reference)

PMID:18055495 SUPPORT Human Clinical

"showed elevated skeletal muscle creatine kinase levels ranging from 300 to 3000 U/L, and had developed muscle weakness and atrophy"

The same 8/10 cohort statement, quoted for the atrophy component that the previous single phenotype conflated with weakness.

Nervous System 4

Chorea FREQUENT HP:0002072

Show evidence (1 reference)

PMID:18055495 SUPPORT Human Clinical

"During follow-up, seven patients developed chorea, six had psychiatric disorders, five had cognitive decline and three had generalized seizures"

7/10 is 70 percent, in the FREQUENT band (30-79 percent), counted directly in a followed cohort.

Psychiatric Disturbance FREQUENT Psychosis HP:0000709

Show evidence (1 reference)

PMID:18055495 SUPPORT Human Clinical

"seven patients developed chorea, six had psychiatric disorders, five had cognitive decline"

6/10 is 60 percent, in the FREQUENT band (30-79 percent).

Cognitive Decline FREQUENT Cognitive impairment HP:0100543

Show evidence (1 reference)

PMID:18055495 SUPPORT Human Clinical

"six had psychiatric disorders, five had cognitive decline and three had generalized seizures"

5/10 is 50 percent, in the FREQUENT band (30-79 percent).

Areflexia HP:0001284

Show evidence (1 reference)

PMID:40898647 SUPPORT Human Clinical

"Affected individuals typically show elevated creatine phosphokinase (CK) levels, red blood cell (RBC) acanthocytosis, and absent or diminished tendon reflexes"

Groups areflexia with the two findings this entry already curates as characteristic. "Typically" gives no count, so no frequency band is asserted.

Other 4

Acanthocytosis HP:0001927

Show evidence (1 reference)

PMID:20301528 SUPPORT Human Clinical

"The hematologic manifestations are red blood cell acanthocytosis and compensated hemolysis"

Names acanthocytosis as a defining haematological manifestation. GeneReviews does not give a percentage, so no frequency band is asserted here.

Generalized Seizures FREQUENT Generalized-onset seizure HP:0002197

Show evidence (1 reference)

PMID:18055495 SUPPORT Human Clinical

"five had cognitive decline and three had generalized seizures"

3/10 is 30 percent, which falls at the lower boundary of the FREQUENT band (30-79 percent).

Caudate Atrophy HP:0002340

Show evidence (2 references)

PMID:40898647 SUPPORT Human Clinical

"with five showing atrophy of the basal ganglia, which was more pronounced in the caudate nucleus and to a lesser extent in the putamen and pallidum"

The macroscopic finding and its regional gradient.

PMID:40898647 SUPPORT Human Clinical

"MRI (five patients) showed atrophy of the caudate nucleus of varying degrees"

The in vivo imaging correlate of the same finding.

Peripheral Axonal Neuropathy HP:0003477

Show evidence (1 reference)

PMID:20301528 SUPPORT Human Clinical

"Neuromuscular manifestations include a (mostly subclinical) sensorimotor axonopathy and muscle weakness or atrophy of different degrees"

Names the axonopathy and preserves the source's "mostly subclinical" qualifier, which is why it is under-recognized.

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Genetic Associations

1

XK (Hemizygous XK loss-of-function variants cause McLeod neuroacanthocytosis syndrome in males. About 90 percent are intragenic variants and about 10 percent are Xp21.1 deletions involving XK. The deletion class matters clinically beyond XK itself: XK sits adjacent to CYBB, so a large deletion can remove both and produce chronic granulomatous disease together with McLeod syndrome, and deletions extending further can reach DMD.)

Gene: XK hgnc:12811 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:8004674 SUPPORT Human Clinical

"A 50 kb deletion was detected by screening DNA from patients with radiolabeled whole cosmids, and two transcription units were identified within this deletion. The mRNA expression pattern of one of them, designated as XK, correlates closely to the McLeod phenotype"

The positional cloning that identified XK, and the deletion that led to it.

PMID:22111908 SUPPORT Human Clinical

"When larger X-chromosomal deletions occur, including the XK gene deletion, a so-called "Contiguous Gene Deletion Syndrome" may result. The contiguous gene deletion syndrome is known to associate the Kell phenotype/McLeod syndrome with diseases such as X-linked chronic granulomatous disease,..."

States the contiguous gene deletion mechanism and names all three neighbouring disorders a large Xp21 deletion can bring with it.

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Medical Actions

4

Symptomatic Treatment of Chorea

Action: Pharmacotherapy NCIT:C15986

Agent: tetrabenazine CHEBI:9467 clozapine CHEBI:3766 quetiapine CHEBI:8707

Dopamine antagonists and the dopamine depletor tetrabenazine are used to reduce chorea. Nothing modifies the underlying disease. Note the interaction with the muscle involvement: neuroleptic use is one of the two circumstances under which GeneReviews advises monitoring creatine kinase for rhabdomyolysis.

Mechanism Target:

INHIBITS Chorea and Huntington-Like Neurodegenerative Syndrome — Dopamine antagonism and depletion suppress the choreiform output of striatal degeneration. This is symptomatic action on the endpoint node, not on the neurodegeneration that produces it - nothing here slows the disease.

Show evidence (1 reference)

PMID:20301528 SUPPORT Human Clinical

"the dopamine depletory (tetrabenazine) to ameliorate chorea"

States the target symptom the agents act on.

Show evidence (2 references)

PMID:20301528 SUPPORT Human Clinical

"use of dopamine antagonists (e.g., tiapride, clozapine, quetiapine) and the dopamine depletory (tetrabenazine) to ameliorate chorea"

Names the agents. Tiapride is named by the source but not bound as a therapeutic_agent because CHEBI carries it only as the hydrochloride salt, which is a different entity from the drug the source names.

PMID:20301528 SUPPORT Human Clinical

"monitor serum CK concentrations for evidence of rhabdomyolysis if excessive movement disorders are present or if neuroleptic medications are being used"

The monitoring requirement that attaches to this treatment, which is why the two are curated together rather than in separate entries.

Transfusion Restricted to Kx-Negative Blood

Action: Blood Transfusion NCIT:C15192

The single most actionable management point in the disease, and it is a restriction rather than a therapy. Patients must not receive Kx-positive blood; Kx-negative, autologous, or banked homologous blood should be used instead. Because compatible blood is very hard to source, GeneReviews recommends identifying at-risk relatives early enough to allow prophylactic cryopreservation - the intervention has to be planned years before it is needed.

Mechanism Target:

INHIBITS Kx and Km Alloimmunization Risk — Withholding Kx-positive blood removes the antigen exposure that drives alloimmunization. Uniquely among the entries here, this acts on the mechanism itself rather than on a downstream symptom - which is what makes a restriction the most effective intervention in the disease.

Show evidence (1 reference)

PMID:20301528 SUPPORT Human Clinical

"Kx-negative blood or, if possible, banked autologous or homologous blood should be used"

The action that prevents the exposure.

Show evidence (2 references)

PMID:20301528 SUPPORT Human Clinical

"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"

The GeneReviews Agents/Circumstances to Avoid entry, quoted directly. This is a contraindication, and the treatment entry exists to carry it.

PMID:20301528 SUPPORT Human Clinical

"possible prophylactic cryopreservation of autologous or homologous blood for use in future transfusions"

The forward-planning step that makes the restriction survivable in practice.

Cardiac Surveillance and Device Therapy

Action: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Because cardiac disease is a leading cause of death and can be present without symptoms, surveillance is recommended for patients with no known cardiac involvement, not only for those already affected. Prophylactic pacemaker or implantable cardioverter-defibrillator placement is to be considered.

Mechanism Target:

INHIBITS Cardiomyopathy and Arrhythmia — Device therapy addresses the arrhythmic consequence of the cardiomyopathy rather than the myocardial disease. Surveillance is directed at the same node and is what identifies who needs the device.

Show evidence (1 reference)

PMID:20301528 SUPPORT Human Clinical

"consideration of placement of prophylactic cardiac pacemaker / implantable cardioverter-defibrillator"

The intervention aimed at the cardiac node.

Show evidence (2 references)

PMID:20301528 SUPPORT Human Clinical

"consideration of placement of prophylactic cardiac pacemaker / implantable cardioverter-defibrillator"

The device recommendation.

PMID:20301528 SUPPORT Human Clinical

"for those without known cardiac involvement, Holter EKG, echocardiography, and cardiac biomarkers (e.g., troponin T/I, pro BNP) every two years"

Establishes surveillance of the apparently unaffected, with the stated interval.

Genetic Counseling and Testing of At-Risk Relatives

Action: Genetic Counseling NCIT:C15240

X-linked counseling, but with an unusual urgency: identifying at-risk relatives is recommended not only for reproductive decisions but so that transfusion-compatibility information exists before it is needed and so that cardiac events can be pre-empted.

Show evidence (1 reference)

PMID:20301528 SUPPORT Human Clinical

"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"

States the non-reproductive rationale for cascade testing, which is what distinguishes counseling here from the generic case.

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Diagnosis

2

Peripheral Blood Film and Kell/Kx Phenotyping

The film shows acanthocytes and serology shows the McLeod blood group phenotype - absent Kx and Km, weakened Kell antigens. The serology is what distinguishes McLeod syndrome from the other neuroacanthocytosis syndromes at the bedside, and it should be obtained before any transfusion rather than after.

Blood Typing Test NCIT:C210738

Show evidence (1 reference)

PMID:18167163 SUPPORT Human Clinical

"weakened expression of antigens in the Kell blood group system, absence of Km and Kx antigens, and acanthocytosis"

The serological and morphological findings that define the phenotype.

Molecular Genetic Testing

Sequencing of XK, with deletion or copy number analysis when sequencing is negative, since about one in ten affected males has an Xp21.1 deletion rather than an intragenic variant. Testing should extend to defining whether a deletion involves CYBB.

Genetic Testing NCIT:C15709

Show evidence (1 reference)

PMID:20301528 SUPPORT Human Clinical

"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"

Establishes molecular confirmation as the diagnostic endpoint.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Fewer than 200 cases have been reported worldwide. The autopsy series cited here, at six patients with macroscopic data, is described by its authors as the largest cohort examined to date, which is itself an indication of how few cases exist.

Show evidence (1 reference)

PMID:40898647 SUPPORT Human Clinical

"Investigation of the largest MLS cohort to date has enabled the recognition of consistent morphological patterns that form the basis for a reproducible neuropathological grading system in this extremely rare disease"

The source's own characterization of the disease as extremely rare, and an indication of the scale of the largest available series.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from McLeod Neuroacanthocytosis Syndrome:

Chorea-acanthocytosis (VPS13A disease)

Overlapping Features The closest mimic and, as it turns out, a mechanistic relative rather than a coincidence. VPS13A disease produces acanthocytosis, chorea, psychiatric features and raised creatine kinase, and the two proteins form a complex, so the clinical similarity has a molecular basis.

Distinguishing Features

Inheritance: McLeod syndrome is X-linked and affects males; chorea-acanthocytosis is autosomal recessive and affects both sexes.
Blood group serology: the McLeod phenotype - absent Kx and Km with weakened Kell antigens - is present only in McLeod syndrome and is what settles the distinction.
Cardiac involvement is prominent in McLeod syndrome and is not a defining feature of chorea-acanthocytosis.

Show evidence (1 reference)

PMID:32845802 SUPPORT In Vitro

"ChAc phenotypes resemble those of McLeod Syndrome, caused by mutations in the XK gene"

States the phenotypic resemblance that makes this the primary differential.

Huntington disease

Overlapping Features Adult-onset chorea with cognitive decline, psychiatric disturbance and caudate atrophy - the clinical and radiological picture McLeod syndrome reproduces closely enough that the autopsy series cited here draws the analogy explicitly and models its proposed neuropathological grading system on the Huntington one.

Distinguishing Features

Acanthocytosis and the McLeod blood group phenotype are absent in Huntington disease.
Elevated creatine kinase is characteristic of McLeod syndrome and not of Huntington disease.
Huntington disease is autosomal dominant with a CAG repeat expansion in HTT; McLeod syndrome is X-linked.

Show evidence (1 reference)

PMID:40898647 SUPPORT Human Clinical

"Analogous to Huntington's disease (HD), MLS displays cognitive and behavioural symptoms besides the progressive movement disorder"

The stated clinical analogy, from the neuropathology series that also borrows the Huntington grading framework.

Chronic granulomatous disease with contiguous Xp21 deletion

Overlapping Features Not a mimic but a co-occurrence, and it runs in the other direction: a boy presenting with CGD may also be McLeod-positive because one deletion removed both CYBB and XK. That matters because CGD management involves granulocyte transfusion, which is exactly what a McLeod patient cannot safely receive.

Distinguishing Features

Presentation is usually with recurrent bacterial and fungal infection in childhood rather than with a movement disorder, since the CGD manifests decades before the neurodegeneration.
Deletion analysis rather than XK sequencing is what detects it.

Show evidence (1 reference)

PMID:3334897 SUPPORT Human Clinical

"Our findings suggest that the X-CGD and McLeod loci are physically close in the p21 region of the X chromosome proximal to the Duchenne muscular dystrophy locus"

The mapping result establishing physical proximity of the two loci, which is what makes a single deletion able to remove both.

{ }

Source YAML

click to show

name: McLeod Neuroacanthocytosis Syndrome
creation_date: "2026-08-20T18:10:00Z"
category: Mendelian
synonyms:
- McLeod syndrome
- MLS
- McLeod phenotype
- XK-related neurodegenerative disease
- Kell/McLeod syndrome
description: >-
  McLeod neuroacanthocytosis syndrome is an X-linked multisystem disorder caused by loss of
  XK, a red-cell and neuronal membrane protein that is disulphide-bonded to the Kell
  glycoprotein and that functions as a calcium-activated phospholipid scramblase in
  partnership with VPS13A. Loss of XK produces a single molecular lesion with four largely
  separate clinical consequences: a Huntington-like neurodegeneration centred on the caudate
  nucleus; red-cell acanthocytosis with compensated hemolysis and the McLeod blood group
  phenotype; a chronic axonal motor neuropathy presenting as myopathy; and a
  cardiomyopathy that is a leading cause of death. The blood group phenotype is not an
  incidental marker - it makes transfusion itself hazardous, which is the single most
  actionable fact about the disease.
disease_term:
  preferred_term: McLeod neuroacanthocytosis syndrome
  term:
    id: MONDO:0018945
    label: XK-related neurodegenerative disease
parents:
- Neurological Disease
- Hematologic Disease
- Movement Disorder
references:
- reference: PMID:20301528
  title: "McLeod Neuroacanthocytosis Syndrome"
  tags:
  - GeneReviews
inheritance:
- name: X-linked
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  description: >-
    Affected males carry a hemizygous intragenic XK variant (about 90%) or a hemizygous Xp21.1 deletion
    involving XK (about 10%). Heterozygous females are mosaic for the Kell and Kx antigens
    because of X inactivation, and while they usually escape the neurological disease, some
    develop chorea or late-onset cognitive decline - so carrier status is not reliably
    silent.
  evidence:
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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"
    explanation: >-
      Establishes the X-linked architecture and the split between intragenic variants and
      whole-locus deletions, which matters because the deletion class can extend into neighbouring
      genes.
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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"
    explanation: >-
      Records that heterozygous females are not uniformly unaffected, which is what makes
      carrier identification clinically relevant rather than purely reproductive.
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If the mother of an affected male is heterozygous, the chance of transmitting
      the XK pathogenic variant in each pregnancy is 50%"
    explanation: >-
      The per-pregnancy transmission risk, from the GeneReviews GENETIC COUNSELING section.
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected males pass the XK pathogenic variant to all of their daughters and
      none of their sons"
    explanation: >-
      The transmission pattern from affected males, which is what determines who in a
      pedigree needs the transfusion-compatibility information this disease turns on.
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "carrier testing for at-risk females, prenatal testing for a pregnancy at
      increased risk, and preimplantation genetic testing are possible"
    explanation: >-
      The reproductive testing options available once the familial variant is known.

pathophysiology:

- name: XK Loss of Function
  biological_scale: MOLECULAR
  description: >-
    The initiating lesion. XK encodes a 50.9 kDa protein that crosses the membrane ten times
    and was originally identified by positional cloning from a 50 kb deletion in McLeod
    patients. Point variants at conserved splice donor and acceptor sites in unrelated
    patients gave the first direct evidence that XK is the responsible gene.
  genes:
  - preferred_term: XK
    term:
      id: hgnc:12811
      label: XK
  cellular_components:
  - preferred_term: plasma membrane
    term:
      id: GO:0005886
      label: plasma membrane
  evidence:
  - reference: PMID:8004674
    reference_title: "Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nucleotide sequence analysis of XK from two unrelated McLeod patients has
      identified point mutations at conserved splice donor and acceptor sites. These
      findings provide direct evidence that XK is responsible for McLeod syndrome"
    explanation: >-
      The founding gene-disease assertion, from the positional cloning study.
  - reference: PMID:8004674
    reference_title: "Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "XK encodes a novel protein with structural characteristics of prokaryotic and
      eukaryotic membrane transport proteins"
    explanation: >-
      The original structural assignment. Note this reads XK as a transporter; the
      scramblase function below was established much later and supersedes it.
  downstream:
  - target: Loss of the Kell-XK Membrane Complex
    causal_link_type: DIRECT
    description: >-
      XK is covalently bonded to Kell, so losing XK destabilizes the partner.
  - target: Loss of XK-VPS13A Phospholipid Scrambling at Membrane Contact Sites
    causal_link_type: DIRECT
    description: >-
      The molecular function whose loss is proposed to drive the neurodegeneration.
  - target: Chronic Axonal Motor Neuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The neuromuscular arm. XK is expressed in peripheral nerve as well as in brain and red
      cell, but no source available to this entry connects its loss to axonal degeneration
      through an identified route, so the intermediates are unknown rather than merely
      unstated.
  - target: Cardiomyopathy and Arrhythmia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The cardiac arm, drawn from the initiating lesion rather than from the
      neurodegeneration. Nothing derives the cardiomyopathy from the brain disease, and the
      surveillance recommendation treats it as independent by applying to patients with no
      known cardiac involvement. How XK loss injures myocardium is not established.

- name: Loss of the Kell-XK Membrane Complex
  biological_scale: MOLECULAR
  description: >-
    XK and the Kell glycoprotein are joined by a single disulphide bond, Kell Cys72-XK
    Cys347. The two proteins are encoded on different chromosomes - KEL at 7q33, XK at Xp21
    - yet depend on each other in the membrane, which is why an X-linked defect produces an
    abnormality in a chromosome 7 blood group system. Losing XK abolishes the Kx antigen and
    markedly weakens Kell antigen expression: the McLeod blood group phenotype.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  evidence:
  - reference: PMID:10895256
    reference_title: "Kell, Kx and the McLeod syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A single disulphide bond, Kell Cys 72-XK Cys 347, links Kell to XK"
    explanation: >-
      The covalent link that makes the two proteins interdependent in the membrane.
  - reference: PMID:18167163
    reference_title: "Transfusion support for a patient with McLeod phenotype without chronic granulomatous disease and with antibodies to Kx and Km."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The McLeod phenotype is characterized by weakened expression of antigens in
      the Kell blood group system, absence of Km and Kx antigens, and acanthocytosis"
    explanation: >-
      Defines the serological phenotype that follows from losing the complex.
  downstream:
  - target: Red Cell Membrane Instability and Acanthocytosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Acanthocytes are the morphological consequence, but how loss of the complex distorts
      the membrane skeleton is not established by any source available to this entry.
  - target: Kx and Km Alloimmunization Risk
    causal_link_type: DIRECT
    description: >-
      Antigens the patient has never expressed are seen as foreign when transfused.

- name: Loss of XK-VPS13A Phospholipid Scrambling at Membrane Contact Sites
  biological_scale: MOLECULAR
  description: >-
    The mechanistically informative finding, and the one that reframes the disease. XK forms
    a complex with VPS13A - the lipid transfer protein mutated in chorea-acanthocytosis -
    and when overexpressed relocalizes VPS13A from lipid droplets to subdomains of the
    endoplasmic reticulum. Introducing chorea-acanthocytosis disease variants into VPS13A
    prevents that relocalization. Two clinically near-identical neuroacanthocytosis
    syndromes, one X-linked and one autosomal recessive, therefore converge on dysregulation
    of a single complex.
  molecular_functions:
  - preferred_term: phospholipid scramblase activity
    term:
      id: GO:0017128
      label: phospholipid scramblase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: plasma membrane phospholipid scrambling
    term:
      id: GO:0017121
      label: plasma membrane phospholipid scrambling
    modifier: DECREASED
  cellular_components:
  - preferred_term: endoplasmic reticulum-plasma membrane contact site
    term:
      id: GO:0140268
      label: endoplasmic reticulum-plasma membrane contact site
  evidence:
  - reference: PMID:32845802
    reference_title: "XK is a partner for VPS13A: a molecular link between Chorea-Acanthocytosis and McLeod Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "it forms a complex with VPS13A in human cells and, when overexpressed,
      relocalizes VPS13A from lipid droplets to subdomains of the endoplasmic reticulum"
    explanation: >-
      Establishes the physical partnership and the functional readout used to test it.
  - reference: PMID:32845802
    reference_title: "XK is a partner for VPS13A: a molecular link between Chorea-Acanthocytosis and McLeod Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results suggest that dysregulation of a VPS13A-XK complex is the common
      basis for ChAc and McLeod Syndrome"
    explanation: >-
      The unifying claim. Quoted with the authors' own "suggest", because this is a
      cell-biological inference rather than a demonstration in patient neural tissue.
  downstream:
  - target: Striatal Neuronal Loss and Gliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Why a lipid-scrambling defect should selectively destroy caudate neurons is not
      established. No source available to this entry connects the scramblase function to
      the regional pattern of degeneration.
  notes: >-
    The scramblase assignment postdates and supersedes the founding paper's reading of XK as
    a membrane transport protein. Both are curated - the earlier one on the XK Loss of
    Function node - because the transporter description is still what many secondary
    sources repeat, and a curator meeting it should be able to see when and by what it was
    replaced.

- name: Red Cell Membrane Instability and Acanthocytosis
  biological_scale: CELLULAR
  description: >-
    Spiculated red cells with irregular thorn-like projections. Acanthocytosis is the
    finding the disease is named for and is present in essentially all affected males, but
    it is neither specific to McLeod syndrome nor proportional to neurological severity.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  evidence:
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The hematologic manifestations are red blood cell acanthocytosis and
      compensated hemolysis"
    explanation: >-
      Names both haematological consequences and, in "compensated", records that the
      hemolysis does not usually produce clinical anemia.
  downstream:
  - target: Compensated Hemolysis
    causal_link_type: DIRECT
    description: >-
      Abnormally shaped cells are cleared faster.

- name: Compensated Hemolysis
  biological_scale: ORGANISM
  description: >-
    Shortened red cell survival matched by increased production, so haemoglobin is usually
    normal and the hemolysis is detectable biochemically rather than clinically. This node
    is separated from the acanthocytosis above because the compensation is the point: the
    haematological arm of the disease is largely silent in the patient while being
    diagnostically loud on the blood film.
  evidence:
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "red blood cell acanthocytosis and compensated hemolysis"
    explanation: >-
      The compensated character of the hemolysis, stated by the source.

- name: Kx and Km Alloimmunization Risk
  biological_scale: ORGANISM
  description: >-
    Because affected males never express Kx or Km, transfused red cells carrying those
    antigens are immunologically foreign. The resulting alloantibodies cause severe
    transfusion reactions, and this is the mechanism behind the disease's one absolute
    contraindication. The antibody repertoire also differs by genotype: patients whose
    deletion extends into CYBB, producing chronic granulomatous disease alongside McLeod
    syndrome, are generally held to be able to make both anti-Km and anti-Kx, whereas
    non-CGD McLeod patients were believed to make only anti-Km - a belief the cited case
    report was written to challenge.
  evidence:
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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"
    explanation: >-
      Establishes both the transfusion hazard and the separate neonatal alloimmune risk.
  - reference: PMID:18167163
    reference_title: "Transfusion support for a patient with McLeod phenotype without chronic granulomatous disease and with antibodies to Kx and Km."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is generally believed that patients with non-CGD McLeod may develop
      anti-Km but not anti-Kx, but that those with CGD McLeod can develop both anti-Km and
      anti-Kx"
    explanation: >-
      Curated PARTIAL deliberately. This quote states the prevailing belief, and the paper's
      title reports a non-CGD McLeod patient with antibodies to both Kx and Km - that is, a
      counterexample. The rule is recorded here as a belief rather than as fact.

- name: Striatal Neuronal Loss and Gliosis
  biological_scale: TISSUE
  description: >-
    The neurodegenerative core, and it has a consistent spatial gradient. In the largest
    autopsy series assembled, histology showed neuronal loss and gliosis in the basal
    ganglia of every patient, with severity decreasing from the caudate nucleus through the
    putamen to the pallidum. The same gradient appears macroscopically as basal ganglia
    atrophy. Functional imaging detects the process before the movement disorder appears:
    striatal FDG uptake was reduced in a 28-year-old with no movement disorder at all.
  cell_types:
  - preferred_term: medium spiny neuron
    term:
      id: CL:1001474
      label: medium spiny neuron
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: caudate nucleus
    term:
      id: UBERON:0001873
      label: caudate nucleus
  - preferred_term: striatum
    term:
      id: UBERON:0002435
      label: striatum
  evidence:
  - reference: PMID:40898647
    reference_title: "Neuropathological Characterisation of McLeod Syndrome With a Proposed New Grading System."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histology revealed neuronal loss and accompanying gliosis in the basal ganglia
      of all patients"
    explanation: >-
      The core neuropathological finding, in the largest series examined.
  - reference: PMID:40898647
    reference_title: "Neuropathological Characterisation of McLeod Syndrome With a Proposed New Grading System."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with a decreasing gradient of severity from the caudate nucleus to the putamen
      and the pallidum, mirroring the macroscopic findings"
    explanation: >-
      The spatial gradient, which is what makes the pathology recognizable rather than
      merely present.
  - reference: PMID:11254778
    reference_title: "Reduction of striatal glucose metabolism in McLeod choreoacanthocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Positron emission tomography disclosed a reduction of the striatal FDG uptake
      in both patients, with accentuation in patient 1. Frontal lobe metabolism was not
      affected"
    explanation: >-
      Shows the deficit is striatum-selective rather than global, and the second patient in
      this pair was presymptomatic.
  downstream:
  - target: Chorea and Huntington-Like Neurodegenerative Syndrome
    causal_link_type: DIRECT
    description: >-
      Caudate-predominant striatal loss is the anatomical substrate for the chorea.

- name: Chronic Axonal Motor Neuropathy
  biological_scale: TISSUE
  description: >-
    The arm of the disease that was misnamed for decades. McLeod syndrome was originally
    described as a benign myopathy, but systematic study of ten patients including the
    original index patient found that the muscle weakness and atrophy are predominantly
    neurogenic rather than myopathic. Myopathic changes were present in a minority; every
    patient had neurogenic changes. This is why the entry curates a neuropathy node rather
    than a myopathy node, with the elevated creatine kinase as its biochemical readout.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:18055495
    reference_title: "McLeod myopathy revisited: more neurogenic and less benign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clear but unspecific myopathic changes were found in only four patients. All
      patients, however, had neurogenic changes of variable degree"
    explanation: >-
      The histological basis for reading the muscle involvement as neurogenic.
  - reference: PMID:18055495
    reference_title: "McLeod myopathy revisited: more neurogenic and less benign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Post-mortem motor and sensory nerve examinations support the view that muscle
      atrophy and weakness are predominantly due to an axonal motor neuropathy rather than
      to a primary myopathy"
    explanation: >-
      The authors' explicit reassignment of the mechanism from myopathy to axonal
      neuropathy.

- name: Chorea and Huntington-Like Neurodegenerative Syndrome
  biological_scale: ORGANISM
  description: >-
    Adult-onset chorea with cognitive decline and psychiatric disturbance, clinically close
    enough to Huntington disease that McLeod syndrome belongs in its differential. Onset of
    multisystem manifestations is around the fourth decade. The presenting feature is
    frequently psychiatric or epileptic rather than choreiform, so the movement disorder is
    not reliably the first thing seen.
  evidence:
  - reference: PMID:18055495
    reference_title: "McLeod myopathy revisited: more neurogenic and less benign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "our findings confirm that MLS is not a benign condition but rather a
      progressive multisystem disorder sharing many features with Huntington's disease"
    explanation: >-
      States both the progressive multisystem character and the Huntington resemblance.
  - reference: PMID:18055495
    reference_title: "McLeod myopathy revisited: more neurogenic and less benign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients manifested with psychiatric features comprising
      schizophrenia-like psychosis and personality disorder, two presented with generalized
      seizures and one with chorea"
    explanation: >-
      Records that psychiatric and epileptic presentations outnumbered choreiform
      presentation in this series.

- name: Cardiomyopathy and Arrhythmia
  biological_scale: ORGANISM
  description: >-
    Dilated cardiomyopathy with atrial fibrillation and tachyarrhythmia, and a leading cause
    of death. It is curated as a parallel consequence of XK loss rather than downstream of
    the neurodegeneration, because no source available to this entry derives the cardiac
    disease from the neurological one - and the surveillance recommendation treats it as
    independent, applying to patients with no known cardiac involvement.
  evidence:
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac manifestations include dilated cardiomyopathy, atrial fibrillation,
      and tachyarrhythmia"
    explanation: >-
      Names the cardiac phenotype.
  - reference: PMID:18055495
    reference_title: "McLeod myopathy revisited: more neurogenic and less benign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five patients died because of MLS-related complications including sudden
      cardiac death, chronic heart failure and pneumonia between 55 and 69 years"
    explanation: >-
      Establishes cardiac disease as a cause of death rather than an incidental finding.

mechanistic_hypotheses:
- hypothesis_group_id: vps13a_xk_scramblase_complex_model
  status: CANONICAL
  description: >-
    Loss of XK disables a VPS13A-XK lipid handling complex at membrane contact sites, and it
    is that shared complex failure - not anything specific to the Kell blood group system -
    that produces the neurodegeneration. The model's strength is that it explains why an
    X-linked and an autosomal recessive disease look alike; its weakness is that it does not
    yet explain the caudate selectivity, and the evidence is from overexpression in cultured
    human cells rather than from patient neural tissue.
  evidence:
  - reference: PMID:32845802
    reference_title: "XK is a partner for VPS13A: a molecular link between Chorea-Acanthocytosis and McLeod Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ChAc phenotypes resemble those of McLeod Syndrome, caused by mutations in the
      XK gene, suggesting that XK could be a partner protein for VPS13A"
    explanation: >-
      The reasoning that motivated the experiment, and the clinical convergence the model
      is built to explain.

phenotypes:

- category: Hematologic
  name: Acanthocytosis
  description: >-
    Spiculated red cells on the peripheral film, the finding the syndrome family is named
    for.
  phenotype_term:
    preferred_term: Acanthocytosis
    term:
      id: HP:0001927
      label: Acanthocytosis
  evidence:
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The hematologic manifestations are red blood cell acanthocytosis and
      compensated hemolysis"
    explanation: >-
      Names acanthocytosis as a defining haematological manifestation. GeneReviews does not
      give a percentage, so no frequency band is asserted here.

- category: Neurological
  name: Chorea
  description: >-
    Choreiform movements developing in adulthood. Seven of ten patients in the
    longest-followed series developed chorea over a mean 15-year follow-up, though only one
    presented with it.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Chorea
    term:
      id: HP:0002072
      label: Chorea
  evidence:
  - reference: PMID:18055495
    reference_title: "McLeod myopathy revisited: more neurogenic and less benign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During follow-up, seven patients developed chorea, six had psychiatric
      disorders, five had cognitive decline and three had generalized seizures"
    explanation: >-
      7/10 is 70 percent, in the FREQUENT band (30-79 percent), counted directly in a
      followed cohort.

- category: Psychiatric
  name: Psychiatric Disturbance
  description: >-
    Schizophrenia-like psychosis, personality disorder and other psychiatric features. In
    three of ten patients this was the presenting manifestation, before any movement
    disorder.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Psychosis
    term:
      id: HP:0000709
      label: Psychosis
  evidence:
  - reference: PMID:18055495
    reference_title: "McLeod myopathy revisited: more neurogenic and less benign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "seven patients developed chorea, six had psychiatric disorders, five had
      cognitive decline"
    explanation: >-
      6/10 is 60 percent, in the FREQUENT band (30-79 percent).

- category: Neurological
  name: Cognitive Decline
  description: >-
    Progressive cognitive impairment, part of the Huntington-like triad with chorea and
    psychiatric disturbance.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:18055495
    reference_title: "McLeod myopathy revisited: more neurogenic and less benign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "six had psychiatric disorders, five had cognitive decline and three had
      generalized seizures"
    explanation: >-
      5/10 is 50 percent, in the FREQUENT band (30-79 percent).

- category: Neurological
  name: Generalized Seizures
  description: >-
    Generalized seizures occur in a minority and were the presenting feature in two of ten
    patients.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Generalized-onset seizure
    term:
      id: HP:0002197
      label: Generalized-onset seizure
  evidence:
  - reference: PMID:18055495
    reference_title: "McLeod myopathy revisited: more neurogenic and less benign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "five had cognitive decline and three had generalized seizures"
    explanation: >-
      3/10 is 30 percent, which falls at the lower boundary of the FREQUENT band (30-79
      percent).

- category: Musculoskeletal
  name: Elevated Serum Creatine Kinase
  description: >-
    Raised creatine kinase, in the reported series between 300 and 3000 U/L. It is often the
    first objective abnormality and precedes clinical weakness.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase concentration
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  evidence:
  - reference: PMID:18055495
    reference_title: "McLeod myopathy revisited: more neurogenic and less benign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "eight patients including the initial index patient showed elevated skeletal
      muscle creatine kinase levels ranging from 300 to 3000 U/L, and had developed muscle
      weakness and atrophy"
    explanation: >-
      8/10 is 80 percent, at the lower boundary of VERY_FREQUENT (80-99 percent), with the
      measured range stated.

- category: Musculoskeletal
  name: Muscle Weakness
  description: >-
    Weakness emerging over years and neurogenic in origin. Disabling leg weakness occurred in
    two of ten. No distribution qualifier is asserted: the source records leg weakness but
    does not characterize the weakness as proximal or distal, and a length-dependent axonal
    neuropathy would predict distal predominance rather than the proximal pattern a myopathy
    would give.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:18055495
    reference_title: "McLeod myopathy revisited: more neurogenic and less benign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "had developed muscle weakness and atrophy. Two patients had disabling leg
      weakness"
    explanation: >-
      Same 8/10 denominator as the creatine kinase item, with the severe subset counted
      separately.

- category: Musculoskeletal
  name: Skeletal Muscle Atrophy
  description: >-
    Muscle wasting accompanying the weakness, and neurogenic on histology rather than
    myopathic.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:18055495
    reference_title: "McLeod myopathy revisited: more neurogenic and less benign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showed elevated skeletal muscle creatine kinase levels ranging from 300 to
      3000 U/L, and had developed muscle weakness and atrophy"
    explanation: >-
      The same 8/10 cohort statement, quoted for the atrophy component that the previous
      single phenotype conflated with weakness.

- category: Cardiovascular
  name: Dilated Cardiomyopathy
  description: >-
    Dilated cardiomyopathy, part of the cardiac arm that drives mortality.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac manifestations include dilated cardiomyopathy, atrial fibrillation,
      and tachyarrhythmia"
    explanation: >-
      Names the cardiomyopathy. No cohort frequency is given, so no band is asserted.

- category: Cardiovascular
  name: Atrial Fibrillation
  description: >-
    Atrial fibrillation and other tachyarrhythmias, part of the rationale for cardiac
    surveillance and for considering prophylactic device placement.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dilated cardiomyopathy, atrial fibrillation, and tachyarrhythmia"
    explanation: >-
      Names the arrhythmia phenotype.

- category: Neurological
  name: Caudate Atrophy
  description: >-
    Atrophy centred on the caudate nucleus, visible on MRI and confirmed at autopsy, with a
    decreasing gradient into the putamen and pallidum.
  phenotype_term:
    preferred_term: Caudate atrophy
    term:
      id: HP:0002340
      label: Caudate atrophy
  evidence:
  - reference: PMID:40898647
    reference_title: "Neuropathological Characterisation of McLeod Syndrome With a Proposed New Grading System."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with five showing atrophy of the basal ganglia, which was more pronounced in
      the caudate nucleus and to a lesser extent in the putamen and pallidum"
    explanation: >-
      The macroscopic finding and its regional gradient.
  - reference: PMID:40898647
    reference_title: "Neuropathological Characterisation of McLeod Syndrome With a Proposed New Grading System."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI (five patients) showed atrophy of the caudate nucleus of varying degrees"
    explanation: >-
      The in vivo imaging correlate of the same finding.

- category: Neurological
  name: Areflexia
  description: >-
    Absent or diminished tendon reflexes, listed alongside raised creatine kinase and
    acanthocytosis as one of the findings affected individuals typically show. It is the
    clinical sign that most reliably reveals the otherwise subclinical axonal neuropathy,
    and it usually precedes overt weakness - which makes it the cheapest way to detect the
    neuromuscular arm before it declares itself.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:40898647
    reference_title: "Neuropathological Characterisation of McLeod Syndrome With a Proposed New Grading System."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals typically show elevated creatine phosphokinase (CK)
      levels, red blood cell (RBC) acanthocytosis, and absent or diminished tendon reflexes"
    explanation: >-
      Groups areflexia with the two findings this entry already curates as characteristic.
      "Typically" gives no count, so no frequency band is asserted.

- category: Cardiovascular
  name: Sudden Cardiac Death
  description: >-
    Sudden cardiac death is among the causes of MLS-related mortality, which is what makes
    the cardiac surveillance recommendation more than precautionary.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:18055495
    reference_title: "McLeod myopathy revisited: more neurogenic and less benign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five patients died because of MLS-related complications including sudden
      cardiac death, chronic heart failure and pneumonia between 55 and 69 years"
    explanation: >-
      Records sudden cardiac death as an observed cause of death in the followed cohort,
      with the age range.

- category: Neurological
  name: Peripheral Axonal Neuropathy
  description: >-
    A sensorimotor axonopathy that is mostly subclinical, detected on nerve conduction study
    or at autopsy rather than reported by the patient.
  phenotype_term:
    preferred_term: Peripheral axonal neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuromuscular manifestations include a (mostly subclinical) sensorimotor
      axonopathy and muscle weakness or atrophy of different degrees"
    explanation: >-
      Names the axonopathy and preserves the source's "mostly subclinical" qualifier, which
      is why it is under-recognized.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Fewer than 200 cases have been reported worldwide. The autopsy series cited here, at six
    patients with macroscopic data, is described by its authors as the largest cohort
    examined to date, which is itself an indication of how few cases exist.
  evidence:
  - reference: PMID:40898647
    reference_title: "Neuropathological Characterisation of McLeod Syndrome With a Proposed New Grading System."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Investigation of the largest MLS cohort to date has enabled the recognition of
      consistent morphological patterns that form the basis for a reproducible
      neuropathological grading system in this extremely rare disease"
    explanation: >-
      The source's own characterization of the disease as extremely rare, and an indication
      of the scale of the largest available series.

genetic:
- name: XK
  gene_term:
    preferred_term: XK
    term:
      id: hgnc:12811
      label: XK
  relationship_type: CAUSATIVE
  association: >-
    Hemizygous XK loss-of-function variants cause McLeod neuroacanthocytosis syndrome in
    males. About 90 percent are intragenic variants and about 10 percent are Xp21.1 deletions
    involving XK. The deletion class matters clinically beyond XK itself: XK sits adjacent
    to CYBB, so a large deletion can remove both and produce chronic granulomatous disease
    together with McLeod syndrome, and deletions extending further can reach DMD.
  evidence:
  - reference: PMID:8004674
    reference_title: "Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 50 kb deletion was detected by screening DNA from patients with radiolabeled
      whole cosmids, and two transcription units were identified within this deletion. The
      mRNA expression pattern of one of them, designated as XK, correlates closely to the
      McLeod phenotype"
    explanation: >-
      The positional cloning that identified XK, and the deletion that led to it.
  - reference: PMID:22111908
    reference_title: "Chronic granulomatous disease, the McLeod phenotype and the contiguous gene deletion syndrome-a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When larger X-chromosomal deletions occur, including the XK gene deletion, a
      so-called \"Contiguous Gene Deletion Syndrome\" may result. The contiguous gene
      deletion syndrome is known to associate the Kell phenotype/McLeod syndrome with
      diseases such as X-linked chronic granulomatous disease, Duchenne muscular dystrophy,
      and X-linked retinitis pigmentosa"
    explanation: >-
      States the contiguous gene deletion mechanism and names all three neighbouring
      disorders a large Xp21 deletion can bring with it.
  notes: >-
    Xp21 gene order places XK next to CYBB, and a deletion large enough to remove both
    produces a patient with chronic granulomatous disease who is also McLeod-positive. This
    is not merely a curiosity: the CGD-McLeod patient needs granulocyte transfusions for
    infection while being at risk of Kx alloimmunization from them, so the two diagnoses
    interact in management. The KB entry Chronic_Granulomatous_Disease already records the
    McLeod association from the other direction.

diagnosis:
- name: Peripheral Blood Film and Kell/Kx Phenotyping
  description: >-
    The film shows acanthocytes and serology shows the McLeod blood group phenotype - absent
    Kx and Km, weakened Kell antigens. The serology is what distinguishes McLeod syndrome
    from the other neuroacanthocytosis syndromes at the bedside, and it should be obtained
    before any transfusion rather than after.
  diagnosis_term:
    preferred_term: Blood Typing Test
    term:
      id: NCIT:C210738
      label: Blood Typing Test
  evidence:
  - reference: PMID:18167163
    reference_title: "Transfusion support for a patient with McLeod phenotype without chronic granulomatous disease and with antibodies to Kx and Km."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "weakened expression of antigens in the Kell blood group system, absence of Km
      and Kx antigens, and acanthocytosis"
    explanation: >-
      The serological and morphological findings that define the phenotype.

- name: Molecular Genetic Testing
  description: >-
    Sequencing of XK, with deletion or copy number analysis when sequencing is negative,
    since about one in ten affected males has an Xp21.1 deletion rather than an intragenic variant.
    Testing should extend to defining whether a deletion involves CYBB.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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"
    explanation: >-
      Establishes molecular confirmation as the diagnostic endpoint.

treatments:
- name: Symptomatic Treatment of Chorea
  description: >-
    Dopamine antagonists and the dopamine depletor tetrabenazine are used to reduce chorea.
    Nothing modifies the underlying disease. Note the interaction with the muscle
    involvement: neuroleptic use is one of the two circumstances under which GeneReviews
    advises monitoring creatine kinase for rhabdomyolysis.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tetrabenazine
      term:
        id: CHEBI:9467
        label: tetrabenazine
    - preferred_term: clozapine
      term:
        id: CHEBI:3766
        label: clozapine
    - preferred_term: quetiapine
      term:
        id: CHEBI:8707
        label: quetiapine
  target_mechanisms:
  - target: Chorea and Huntington-Like Neurodegenerative Syndrome
    treatment_effect: INHIBITS
    description: >-
      Dopamine antagonism and depletion suppress the choreiform output of striatal
      degeneration. This is symptomatic action on the endpoint node, not on the
      neurodegeneration that produces it - nothing here slows the disease.
    evidence:
    - reference: PMID:20301528
      reference_title: "McLeod Neuroacanthocytosis Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the dopamine depletory (tetrabenazine) to ameliorate chorea"
      explanation: >-
        States the target symptom the agents act on.
  evidence:
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "use of dopamine antagonists (e.g., tiapride, clozapine, quetiapine) and the
      dopamine depletory (tetrabenazine) to ameliorate chorea"
    explanation: >-
      Names the agents. Tiapride is named by the source but not bound as a therapeutic_agent
      because CHEBI carries it only as the hydrochloride salt, which is a different entity
      from the drug the source names.
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "monitor serum CK concentrations for evidence of rhabdomyolysis if excessive
      movement disorders are present or if neuroleptic medications are being used"
    explanation: >-
      The monitoring requirement that attaches to this treatment, which is why the two are
      curated together rather than in separate entries.

- name: Transfusion Restricted to Kx-Negative Blood
  description: >-
    The single most actionable management point in the disease, and it is a restriction
    rather than a therapy. Patients must not receive Kx-positive blood; Kx-negative,
    autologous, or banked homologous blood should be used instead. Because compatible blood
    is very hard to source, GeneReviews recommends identifying at-risk relatives early
    enough to allow prophylactic cryopreservation - the intervention has to be planned years
    before it is needed.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Blood Transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  target_mechanisms:
  - target: Kx and Km Alloimmunization Risk
    treatment_effect: INHIBITS
    description: >-
      Withholding Kx-positive blood removes the antigen exposure that drives
      alloimmunization. Uniquely among the entries here, this acts on the mechanism itself
      rather than on a downstream symptom - which is what makes a restriction the most
      effective intervention in the disease.
    evidence:
    - reference: PMID:20301528
      reference_title: "McLeod Neuroacanthocytosis Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Kx-negative blood or, if possible, banked autologous or homologous blood
        should be used"
      explanation: >-
        The action that prevents the exposure.
  evidence:
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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"
    explanation: >-
      The GeneReviews Agents/Circumstances to Avoid entry, quoted directly. This is a
      contraindication, and the treatment entry exists to carry it.
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "possible prophylactic cryopreservation of autologous or homologous blood for
      use in future transfusions"
    explanation: >-
      The forward-planning step that makes the restriction survivable in practice.

- name: Cardiac Surveillance and Device Therapy
  description: >-
    Because cardiac disease is a leading cause of death and can be present without symptoms,
    surveillance is recommended for patients with no known cardiac involvement, not only for
    those already affected. Prophylactic pacemaker or implantable cardioverter-defibrillator
    placement is to be considered.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Implantable Cardioverter-Defibrillator Placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_mechanisms:
  - target: Cardiomyopathy and Arrhythmia
    treatment_effect: INHIBITS
    description: >-
      Device therapy addresses the arrhythmic consequence of the cardiomyopathy rather than
      the myocardial disease. Surveillance is directed at the same node and is what
      identifies who needs the device.
    evidence:
    - reference: PMID:20301528
      reference_title: "McLeod Neuroacanthocytosis Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "consideration of placement of prophylactic cardiac pacemaker / implantable
        cardioverter-defibrillator"
      explanation: >-
        The intervention aimed at the cardiac node.
  evidence:
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "consideration of placement of prophylactic cardiac pacemaker / implantable
      cardioverter-defibrillator"
    explanation: >-
      The device recommendation.
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "for those without known cardiac involvement, Holter EKG, echocardiography, and
      cardiac biomarkers (e.g., troponin T/I, pro BNP) every two years"
    explanation: >-
      Establishes surveillance of the apparently unaffected, with the stated interval.

- name: Genetic Counseling and Testing of At-Risk Relatives
  description: >-
    X-linked counseling, but with an unusual urgency: identifying at-risk relatives is
    recommended not only for reproductive decisions but so that transfusion-compatibility
    information exists before it is needed and so that cardiac events can be pre-empted.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301528
    reference_title: "McLeod Neuroacanthocytosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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"
    explanation: >-
      States the non-reproductive rationale for cascade testing, which is what distinguishes
      counseling here from the generic case.

differential_diagnoses:
- name: Chorea-acanthocytosis (VPS13A disease)
  description: >-
    The closest mimic and, as it turns out, a mechanistic relative rather than a
    coincidence. VPS13A disease produces acanthocytosis, chorea, psychiatric features and
    raised creatine kinase, and the two proteins form a complex, so the clinical similarity
    has a molecular basis.
  distinguishing_features:
  - >-
    Inheritance: McLeod syndrome is X-linked and affects males; chorea-acanthocytosis is
    autosomal recessive and affects both sexes.
  - >-
    Blood group serology: the McLeod phenotype - absent Kx and Km with weakened Kell
    antigens - is present only in McLeod syndrome and is what settles the distinction.
  - >-
    Cardiac involvement is prominent in McLeod syndrome and is not a defining feature of
    chorea-acanthocytosis.
  evidence:
  - reference: PMID:32845802
    reference_title: "XK is a partner for VPS13A: a molecular link between Chorea-Acanthocytosis and McLeod Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ChAc phenotypes resemble those of McLeod Syndrome, caused by mutations in the
      XK gene"
    explanation: >-
      States the phenotypic resemblance that makes this the primary differential.

- name: Huntington disease
  description: >-
    Adult-onset chorea with cognitive decline, psychiatric disturbance and caudate atrophy -
    the clinical and radiological picture McLeod syndrome reproduces closely enough that the
    autopsy series cited here draws the analogy explicitly and models its proposed
    neuropathological grading system on the Huntington one.
  distinguishing_features:
  - >-
    Acanthocytosis and the McLeod blood group phenotype are absent in Huntington disease.
  - >-
    Elevated creatine kinase is characteristic of McLeod syndrome and not of Huntington
    disease.
  - >-
    Huntington disease is autosomal dominant with a CAG repeat expansion in HTT; McLeod
    syndrome is X-linked.
  evidence:
  - reference: PMID:40898647
    reference_title: "Neuropathological Characterisation of McLeod Syndrome With a Proposed New Grading System."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analogous to Huntington's disease (HD), MLS displays cognitive and behavioural
      symptoms besides the progressive movement disorder"
    explanation: >-
      The stated clinical analogy, from the neuropathology series that also borrows the
      Huntington grading framework.

- name: Chronic granulomatous disease with contiguous Xp21 deletion
  description: >-
    Not a mimic but a co-occurrence, and it runs in the other direction: a boy presenting
    with CGD may also be McLeod-positive because one deletion removed both CYBB and XK. That
    matters because CGD management involves granulocyte transfusion, which is exactly what a
    McLeod patient cannot safely receive.
  distinguishing_features:
  - >-
    Presentation is usually with recurrent bacterial and fungal infection in childhood
    rather than with a movement disorder, since the CGD manifests decades before the
    neurodegeneration.
  - >-
    Deletion analysis rather than XK sequencing is what detects it.
  evidence:
  - reference: PMID:3334897
    reference_title: "Gene deletion in a patient with chronic granulomatous disease and McLeod syndrome: fine mapping of the Xk gene locus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings suggest that the X-CGD and McLeod loci are physically close in
      the p21 region of the X chromosome proximal to the Duchenne muscular dystrophy locus"
    explanation: >-
      The mapping result establishing physical proximity of the two loci, which is what
      makes a single deletion able to remove both.

discussions:

- discussion_id: gap_why_the_caudate
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Loss of XK-VPS13A Phospholipid Scrambling at Membrane Contact Sites
  - pathophysiology#Striatal Neuronal Loss and Gliosis
  prompt: >-
    XK is expressed well beyond the striatum and its lipid-scrambling function is not
    region-specific. Why does its loss destroy the caudate nucleus in particular?
  rationale: >-
    This is the entry's central unexplained step and the edge is marked
    INDIRECT_UNKNOWN_INTERMEDIATES for exactly that reason. The neuropathology is
    unambiguous about the gradient - caudate worst, then putamen, then pallidum, in every
    patient examined - and the imaging shows the striatal deficit before symptoms appear.
    But nothing in the available evidence connects a plasma membrane phospholipid scrambling
    defect to that anatomy. The same problem exists for chorea-acanthocytosis and for
    Huntington disease, so an answer would likely generalize: striatal medium spiny neurons
    are selectively vulnerable across mechanistically unrelated diseases, and whatever makes
    them so may matter more here than the specific lesion.
  proposed_experiments:
  - experiment_id: exp_regional_lipid_asymmetry_in_xk_loss
    name: Regional phospholipid asymmetry and VPS13A localization across brain regions
    description: >-
      Measure plasma membrane phosphatidylserine exposure and VPS13A subcellular
      distribution in striatal versus cortical and cerebellar neurons from XK-null human
      iPSC-derived cultures and from an XK-null mouse, at several ages. If the scrambling
      defect is uniform across regions while degeneration is not, the selectivity lies in
      the neurons rather than in the lesion, and the search should move to what distinguishes
      medium spiny neurons.

- discussion_id: controversy_anti_kx_in_non_cgd_mcleod
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Kx and Km Alloimmunization Risk
  prompt: >-
    Can McLeod patients without chronic granulomatous disease form anti-Kx, or only anti-Km?
  rationale: >-
    The prevailing rule holds that only CGD-McLeod patients - those whose deletion removes
    CYBB as well as XK - form anti-Kx, while non-CGD McLeod patients form anti-Km alone. The
    case report cited on that node was written to report the exception: a patient with the
    McLeod phenotype, without CGD, and with antibodies to both Kx and Km. The entry curates
    the general rule as a stated belief rather than as fact for that reason. The distinction
    is not academic. If the rule holds, non-CGD patients have a wider pool of compatible
    donors than CGD patients; if exceptions are common, every McLeod patient needs the
    stricter standard, and the cryopreservation recommendation becomes more urgent rather
    than less. A single counterexample does not settle the frequency, which is what a
    transfusion service would need.
  proposed_experiments:
  - experiment_id: exp_alloantibody_survey_by_deletion_extent
    name: Alloantibody specificity surveyed against deletion genotype
    description: >-
      Across a multi-centre McLeod cohort, pair each patient's antibody specificities with
      the precise extent of their XK lesion (intragenic variant, XK-only deletion, XK plus CYBB)
      and their transfusion history. This would establish whether anti-Kx formation tracks
      with CYBB involvement or simply with exposure, which is what determines the
      compatibility standard each genotype needs.

- discussion_id: mismatch_scramblase_evidence_is_overexpression_in_cell_lines
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Loss of XK-VPS13A Phospholipid Scrambling at Membrane Contact Sites
  prompt: >-
    Does a VPS13A relocalization assay driven by XK overexpression in cultured cells report
    what XK does at physiological abundance in a human neuron?
  rationale: >-
    The XK-VPS13A partnership is the entry's mechanistic centrepiece, and it rests on
    overexpression. The functional readout - XK relocalizing VPS13A from lipid droplets to
    ER subdomains - was observed "when overexpressed", and the disease-variant control shows
    that chorea-acanthocytosis mutations block it. That is a strong argument for the
    interaction being real and disease-relevant. It is a much weaker argument about what
    happens when XK is simply absent at normal expression levels, in a post-mitotic neuron,
    over decades. Overexpression can force interactions that are minor or absent
    physiologically, and relocalization away from lipid droplets is not obviously the same
    event as the loss-of-function state in patients. No source available to this entry
    reports VPS13A localization or lipid asymmetry in McLeod patient neural tissue.
  proposed_experiments:
  - experiment_id: exp_vps13a_localization_in_patient_neurons
    name: VPS13A localization at endogenous XK levels in patient-derived neurons
    description: >-
      Compare VPS13A subcellular distribution and ER-plasma membrane contact site
      architecture in neurons differentiated from McLeod patient iPSCs against isogenic
      XK-corrected controls, without overexpressing either protein. Reproducing the
      relocalization defect at endogenous abundance would move the model from plausible to
      demonstrated; failing to reproduce it would mean the complex is real but the
      overexpression readout is not the disease mechanism.

notes: >-
  Scope. This entry curates McLeod neuroacanthocytosis syndrome as the multisystem disease
  of XK loss. It does not curate the McLeod blood group phenotype as a standalone
  serological entity, and it does not curate chronic granulomatous disease, which has its
  own KB entry recording the McLeod association from the CGD side.
  MONDO label. MONDO:0018945 is labelled "XK-related neurodegenerative disease". The entry
  binds that canonical label while using "McLeod neuroacanthocytosis syndrome" as the
  preferred_term, since that is the clinical name in every source cited here. The MONDO
  label is also arguably narrower than the disease: calling it neurodegenerative omits the
  haematological, muscular and cardiac arms that this entry curates.
  Deep research provenance. The report was generated with the claude_code provider and
  carried needs_review true: 18 of 18 references resolved with confabulation_rate 0.0, but
  one quote was unsupported (PMID:8004674) and one reference was flagged off topic
  (PMC:PMC8500837). Neither affected this entry - the PMC reference is not cited, and every
  snippet attributed to PMID:8004674 here was taken directly from the cached abstract rather
  than from the report.
  Two phenotypes suggested in review are deliberately not curated. Ventricular tachycardia
  and hepatosplenomegaly are both reported in the wider literature, but neither appears in
  any reference cited by this entry in a quotable form - GeneReviews names "tachyarrhythmia"
  generically, which the atrial fibrillation entry already carries. Adding either would mean
  citing a source for a claim it does not make. A curator with a source for them should add
  them.
  NEC preflight returned WARN rather than PASS, and the warning is benign. XK is mentioned
  52 times against VPS13A at 18, and the OMIM identifier in the report matches the MONDO
  xref exactly (300842). VPS13A appears because chorea-acanthocytosis is this disease's
  principal differential and because XK and VPS13A are genuine molecular partners - the
  rival-gene heuristic cannot distinguish a second disease entity from a binding partner.
  CYBB, the third-ranked gene, appears for the same structural reason: it is the contiguous
  deletion neighbour.

📚

References & Deep Research

References

1

PMID:20301528

McLeod Neuroacanthocytosis Syndrome

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

McLeod Neuroacanthocytosis Syndrome: Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 19 citations 2026-08-20T17:56:56.616190

McLeod Neuroacanthocytosis Syndrome: Comprehensive Research Report

1. Disease Information

Overview: McLeod neuroacanthocytosis syndrome (McLeod syndrome, MLS) is an ultra-rare, X-linked, progressive multisystem disorder caused by loss-of-function variants in the XK gene at Xp21.1. It is one of the four "core" neuroacanthocytosis syndromes (alongside chorea-acanthocytosis/VPS13A disease, Huntington disease–like 2, and pantothenate-kinase-associated neurodegeneration) and is defined hematologically by the McLeod blood group phenotype — absence of the Kx erythrocyte antigen and markedly weakened expression of Kell blood group antigens — combined with red-cell acanthocytosis, compensated hemolysis, and a late-onset, Huntington's-disease-like neurodegenerative phenotype with prominent cardiac involvement (GeneReviews, NBK1354, updated periodically; OMIM #300842).

Key identifiers: - OMIM disease: #300842 (MCLEOD SYNDROME; MCLDS) - OMIM gene: 314850 (KELL BLOOD GROUP PROTEIN, MCLEOD SYNDROME-ASSOCIATED; XK) - MONDO: MONDO:0018945 (McLeod neuroacanthocytosis syndrome) - Orphanet: ORPHA:35069 (McLeod syndrome) - GeneReviews: NBK1354 (Jung, Danek, Walker) - ICD-10: part of G25.8/G25.9 movement-disorder codes and D75.8 (other hematologic); no dedicated ICD-10 code — typically coded under "other specified hemolytic anemias" / neuroacanthocytosis - MeSH: "Neuroacanthocytosis" (D054874); "McLeod Syndrome" indexed as a supplementary concept - Disease Ontology:* DOID:0112107

Synonyms: McLeod phenotype; McLeod neuroacanthocytosis syndrome (MLS); XK-related neurodegenerative disease; Kell/McLeod syndrome; X-linked chorea-acanthocytosis (older, discouraged term — risks conflation with autosomal-recessive VPS13A disease).

Evidence base: Predominantly aggregated disease-level literature (GeneReviews synthesis; OMIM; multi-decade case series and pedigree reports from the international neuroacanthocytosis registries, e.g., Danek et al. and Jung et al.), supplemented by individual case reports/case series (typically single or small pedigrees) and a handful of molecular/cell-biology studies in patient-derived cells and mouse models. There is no large EHR-derived cohort given the extreme rarity (~250 published cases worldwide).

2. Etiology

Disease causal factor: MLS is a monogenic disorder — loss-of-function pathogenic variants in XK (Xp21.1) are both necessary and sufficient to cause the phenotype. No environmental or infectious trigger is implicated in disease causation itself (though environmental/pharmacologic factors modulate symptom expression — see below).

Genetic risk factors: - Hemizygous pathogenic XK variants in males: nonsense, frameshift, splice-site, and missense variants, as well as partial/whole-gene deletions, account for the full mutational spectrum (~90% intragenic variants, ~10% larger deletions per GeneReviews). - Founding molecular genetics: Ho et al. (1994) isolated the XK gene by positional cloning after identifying a 50-kb genomic deletion in patients with the McLeod phenotype, describing XK as "a novel membrane transport protein" (Ho M, Chelly J, Carter N, Danek A, Crocker P, Monaco AP. Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein. Cell. 1994;77(6):869–880. PMID:8004674). - Contiguous gene deletion syndrome: Larger Xp21.1 deletions that remove XK together with neighboring genes produce combined phenotypes — most notably with CYBB (X-linked chronic granulomatous disease), and less commonly with DMD (Duchenne muscular dystrophy) and RPGR (X-linked retinitis pigmentosa) — described as "Chronic granulomatous disease, the McLeod phenotype and the contiguous gene deletion syndrome" (PMID:22111908; PMC3267648). - Carrier/heterozygous females: Because XK is X-linked, heterozygous females show mosaic Kell/Kx expression and partial acanthocytosis due to random X-chromosome inactivation, and are usually clinically unaffected. Rare "manifesting carriers" with chorea or late-onset cognitive decline have been reported and are attributed to skewed X-inactivation favoring inactivation of the wild-type allele.

Environmental/behavioral risk factors: None established as causal. However, exposure to typical (first-generation) antipsychotics/neuroleptics can precipitate or worsen extrapyramidal symptoms, rhabdomyolysis, or neuroleptic malignant syndrome–like reactions in MLS patients with subclinical myopathy — this is a recognized clinical management hazard rather than a disease-causing exposure (GeneReviews management section).

Protective factors: None specifically documented in the literature; no protective alleles or modifier variants have been characterized. Given the near-fully penetrant hemizygous male phenotype, protective genetic modifiers have not been systematically sought.

Gene–environment interaction: The principal interaction reported is pharmacogenomic/pharmacologic: subclinical myopathy (elevated CK) predisposes to drug-induced rhabdomyolysis, and dopamine-receptor-blocking agents used for chorea can unmask or worsen parkinsonian/myopathic features — this is a gene-drug interaction rather than a classical gene-environment susceptibility interaction.

3. Phenotypes

MLS phenotypes span hematologic, neurologic, neuromuscular, psychiatric, and cardiac domains, with a mean neurologic onset in the 30s–40s (range 18–61 years reported; some series cite 25–60).

Hematologic (laboratory abnormalities)

Phenotype	Frequency	Onset	HPO suggestion
Acanthocytosis (red cell)	Virtually all affected males (8–30% acanthocytes on smear)	Present from birth/early, often incidental	HP:0001927 (Acanthocytosis)
Compensated hemolysis without overt anemia	Nearly universal	Lifelong	HP:0001878 (Hemolytic anemia) — used cautiously since often compensated
Weakened Kell antigen expression / absent Kx antigen	Diagnostic, 100%	Congenital	(blood-group phenotype; no dedicated HPO term — describe in `notes`)
Elevated serum creatine kinase (CK)	Reported in ~100% of examined males, up to 4,000 U/L	From young adulthood	HP:0003236 (Elevated CK)

Neurological — movement disorder

Chorea (choreiform/choreoathetotic movements): presenting symptom in ~30%, eventually present in ~95% of cases over the disease course. HPO: HP:0002072 (Chorea).
Occasional orofacial dyskinesia, dystonia, tics, and parkinsonism reported in subsets.
Seizures: presenting feature in ~20%, developing in up to 40% over time; typically generalized tonic-clonic. HPO: HP:0001250 (Seizure) / HP:0002069 (Generalized tonic-clonic seizures).

Neuromuscular

Areflexia/hyporeflexia from subclinical sensorimotor axonal peripheral neuropathy — almost universal. HPO: HP:0001284 (Areflexia); HP:0007141 (Axonal degeneration).
Muscle weakness/atrophy (predominantly neurogenic, with myopathic features) in ~50%. HPO: HP:0003324 (Generalized muscle weakness); HP:0003202 (Skeletal muscle atrophy).
Severe myopathy has been described as an atypical presentation ("McLeod myopathy revisited: more neurogenic and less benign," PMID:18055495).

Cognitive/Psychiatric

Cognitive decline, frontal-executive type deficits in ≥50% of patients over the disease course. HPO: HP:0002354 (Memory impairment), HP:0002354/HP:0000726 (Dementia).
Psychiatric manifestations are the initial manifestation in ~20% and develop in ~80% overall — personality change, depression, anxiety, obsessive-compulsive symptoms, and bipolar-spectrum disorder. HPO: HP:0000708 (Behavioral abnormality); HP:0000716 (Depressivity); HP:0000722 (Obsessive-compulsive behavior).

Cardiac

Dilated cardiomyopathy develops in ~60% of patients over time and is the leading cause of premature death. HPO: HP:0001644 (Dilated cardiomyopathy).
Atrial fibrillation, ventricular tachycardia, sudden cardiac death. HPO: HP:0005110 (Atrial fibrillation); HP:0004756 (Ventricular tachycardia); HP:0001645 (Sudden cardiac death).
Cardiac MRI: focal late gadolinium enhancement and interstitial fibrosis (structural correlate).

Hepatosplenomegaly

Reported as part of the "classic" multisystem phenotype, related to chronic hemolysis. HPO: HP:0001433 (Hepatosplenomegaly).

Progression/severity: Slowly progressive over decades; disease duration from diagnosis to death averages ~21 years, mean age at death 53 (range 31–69). Basal ganglia (caudate) volumes correlate inversely with disease duration on longitudinal MRI.

Quality of life: Not systematically studied with formal instruments (EQ-5D/SF-36) in the literature reviewed; qualitative descriptions emphasize progressive loss of independence from chorea, cognitive decline, and psychiatric morbidity, plus cardiac-related functional limitation. Suicide is a documented cause of death, underscoring psychiatric-driven QoL burden.

4. Genetic/Molecular Information

Causal gene: XK (HGNC:12811; NCBI Gene ID 7504; Xp21.1). OMIM gene *314850.

Gene product: The XK protein is a 444-amino-acid, 10-transmembrane-domain integral membrane protein belonging to the XK-related (XKR) family, structurally resembling a membrane transporter/lipid scramblase. It is covalently linked via a single disulfide bond to the Kell glycoprotein (encoded by KEL on chromosome 7q34, a 93-kDa type II membrane glycoprotein with endothelin-3-converting enzyme/zinc endopeptidase activity) to form the Kell-XK complex on the erythrocyte membrane (PMID:10895256, "Kell, Kx and the McLeod syndrome").

Molecular function (recently clarified): XK is a Ca²⁺-activated phospholipid scramblase and functions as an obligate partner of VPS13A (chorein, the gene mutated in autosomal-recessive chorea-acanthocytosis). XK forms a complex with VPS13A at ER–plasma-membrane contact sites, and when overexpressed relocalizes VPS13A from lipid droplets to ER subdomains — providing a direct molecular link between the two major neuroacanthocytosis syndromes (Park & Neiman, "XK is a partner for VPS13A: a molecular link between Chorea-Acanthocytosis and McLeod Syndrome," PMID:32845802; and PMC9436381, "A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane"). XK residues Arg222 and Glu327, mutated in McLeod syndrome, are conserved across XKR family members including XKR8, the apoptotic phosphatidylserine scramblase (functions in a complex with basigin/BSG or neuroplastin/NPTN; PMID:27503893).

Pathogenic variant spectrum: - Missense, nonsense, frameshift indels, and canonical splice-site variants (Ho et al. 1994 identified point mutations at invariant 5′/3′ splice-donor residues). - Gross deletions spanning part or all of the XK coding region (can extend into contiguous genes — see Etiology). - ClinVar/ClinGen classification follows standard ACMG/AMP criteria; because XK loss-of-function is an established mechanism, truncating/null variants are typically classified pathogenic when segregating with the McLeod blood-group phenotype. - Functional impact category: predominantly LOSS_OF_FUNCTION (complete or partial); no gain-of-function mechanism reported. - Allele frequency: Given extreme rarity (prevalence <1–5 per 1,000,000; genereviews cites ~1:10,000,000), pathogenic XK variants are essentially absent from gnomAD/population databases; the McLeod blood group phenotype itself (not necessarily neurologic disease) has been noted incidentally in some blood-donor screening studies ("Spontaneously arising red cells with a McLeod-like phenotype in normal donors," PMC2794671) but true null XK alleles causing MLS remain private/family-specific. - Somatic vs germline: Germline only; no somatic/mosaic oncologic relevance.

Modifier genes: None formally established; disease severity variability among affected males and manifesting carrier females is attributed largely to variant type (null vs. hypomorphic) and, in females, to X-inactivation skewing rather than to trans-acting modifier loci.

Epigenetics: The dominant epigenetic mechanism relevant to MLS is X-chromosome inactivation (XCI) mosaicism in heterozygous females — producing a bimodal (mosaic) Kell/Kx blood-group phenotype and variable, usually mild, hematologic/neurologic expression; skewed XCI toward inactivation of the normal allele explains rare manifesting female carriers.

Chromosomal abnormalities: Large Xp21.1 deletions removing XK plus CYBB (± DMD, ± RPGR) constitute a recognized contiguous gene deletion syndrome producing combined McLeod/CGD (±muscular dystrophy, ±retinitis pigmentosa) phenotypes (PMID:22111908; PMID:3334897, "Gene deletion in a patient with chronic granulomatous disease and McLeod syndrome: fine mapping of the Xk gene locus").

Suggested ontology terms: - HGNC: XK (HGNC:12811), KEL (HGNC:6339, partner protein), VPS13A (HGNC:12175, functional partner), CYBB (HGNC:2578, contiguous-deletion partner) - GO Molecular Function: phospholipid scramblase activity (GO:0017128); transmembrane transporter activity (GO:0022857) - GO Biological Process: phospholipid translocation (GO:0045332); cellular response to calcium ion (GO:0071277) - GO Cellular Component: plasma membrane (GO:0005886); endoplasmic reticulum-plasma membrane contact site (GO:0140268)

5. Environmental Information

MLS is a purely monogenic disorder; no environmental, occupational, or infectious factor contributes to disease causation. Environmental relevance is limited to two clinical-management contexts:

Pharmacologic exposure: Typical antipsychotics/dopamine antagonists can precipitate rhabdomyolysis or worsen extrapyramidal symptoms in patients with subclinical myopathy; management guidance favors atypical antipsychotics (clozapine, quetiapine) or tetrabenazine over typical neuroleptics, and recommends avoiding long-term benzodiazepine use for seizures (GeneReviews management section).
Transfusion exposure: Affected males who develop anti-Kx/anti-Km alloantibodies are at risk of severe hemolytic transfusion reactions if transfused with Kx-positive blood; Kx-negative (McLeod-phenotype) blood or banked autologous/homologous blood is required (PMID:18167163, "Transfusion support for a patient with McLeod phenotype without chronic granulomatous disease and with antibodies to Kx and Km").

No infectious agents are implicated, except indirectly in contiguous-deletion patients who also have chronic granulomatous disease (CGD) and are consequently susceptible to catalase-positive bacterial and fungal infections (Aspergillus, Candida) due to the co-deleted CYBB/NADPH oxidase gene — this is a feature of the CGD component of contiguous gene deletion, not of MLS/XK loss-of-function itself.

6. Mechanism / Pathophysiology

Causal chain (proposed, from molecular lesion to clinical phenotype):

Molecular trigger: Hemizygous loss-of-function XK variant → absent/reduced XK protein.
Membrane complex disruption: Loss of XK disrupts the disulfide-linked Kell-XK erythrocyte membrane complex, producing the McLeod blood group phenotype (weak Kell antigens, absent Kx) and destabilizing the erythrocyte cytoskeleton-membrane linkage.
Erythrocyte pathology: Abnormal membrane lipid scrambling/cytoskeletal anchoring → acanthocyte formation (spiculated red cells) → shortened red-cell lifespan → chronic compensated hemolysis, splenic sequestration, and (in the contiguous-deletion form) hepatosplenomegaly.
Neuronal/muscular pathology: Loss of XK-dependent, VPS13A-partnered phospholipid scrambling and lipid transfer at ER–plasma-membrane contact sites in neurons and myocytes → disrupted lipid homeostasis and membrane trafficking → selective vulnerability of the striatum (caudate > putamen > pallidum), peripheral motor/sensory axons, and skeletal/cardiac muscle.
Basal ganglia dysfunction: Progressive striatal neurodegeneration (caudate atrophy, decreasing striatal glucose metabolism on FDG-PET; PMID:11254778, "Reduction of striatal glucose metabolism in McLeod choreoacanthocytosis") → chorea, cognitive (frontostriatal) decline, and psychiatric symptoms, in a pattern resembling Huntington disease.
Peripheral nerve/muscle pathology: Axonal sensorimotor neuropathy (areflexia) and neurogenic ± myopathic muscle involvement (elevated CK, weakness/atrophy).
Cardiac pathology: Interstitial myocardial fibrosis (seen as late gadolinium enhancement on cardiac MRI) → dilated cardiomyopathy, arrhythmia (atrial fibrillation, ventricular tachycardia), and sudden cardiac death.

Molecular pathways/cellular processes: - Phospholipid scrambling / membrane asymmetry maintenance (GO:0017128, phospholipid scramblase activity) — the central biochemical process disrupted. - Lipid transfer at membrane contact sites (VPS13A/XK partnership; PMC9436381). - Erythrocyte membrane skeleton–lipid bilayer coupling defect underlying acanthocyte morphology. - Calcium-dependent T-cell phospholipid scrambling: Xk and Vps13a are jointly required for P2X7-receptor-mediated phosphatidylserine exposure and cell lysis in mouse splenic T cells, suggesting a broader immune/cell-death role for the XK-VPS13A axis (PMID via PNAS, "Requirement of Xk and Vps13a for the P2X7-mediated phospholipid scrambling and cell lysis in mouse T cells," 2022).

Neuropathology: A 2025 study proposed a new neuropathological grading system for MLS, confirming a decreasing gradient of neurodegenerative severity from caudate nucleus to putamen, correlating with the volumetric MRI findings (Reuss et al., "Neuropathological Characterisation of McLeod Syndrome With a Proposed New Grading System," Neuropathology and Applied Neurobiology 2025, PMID:40898647; PMC12547491).

Tissue damage mechanisms: Chronic mechanical/oxidative erythrocyte membrane stress (acanthocyte fragility) driving compensated hemolysis; progressive neurodegeneration via disrupted lipid/membrane trafficking rather than classic protein aggregation; myocardial interstitial fibrosis as the structural cardiac lesion.

Biochemical abnormalities: Elevated serum CK (muscle membrane leak marker); reduced/absent Kx and weak Kell antigen expression (diagnostic membrane biochemistry); reduced striatal glucose metabolism on FDG-PET (functional biomarker of neurodegeneration).

Suggested ontology terms: - GO Biological Process: erythrocyte membrane organization (GO:0043249); regulation of striatal neuron death; neuron apoptotic process (GO:0051402) - GO Cellular Component: erythrocyte plasma membrane; sarcolemma (GO:0042383) - CL: erythrocyte (CL:0000232); medium spiny neuron (CL:1001474, principal striatal cell type); skeletal muscle fiber (CL:0000188); cardiac muscle cell (CL:0000746) - UBERON: caudate nucleus (UBERON:0001873); putamen (UBERON:0001874); striatum (UBERON:0002435); myocardium (UBERON:0002349); peripheral nerve (UBERON:0002011)

Omics: No large-scale transcriptomic, proteomic, or metabolomic datasets specific to MLS were identified in this search (consistent with its extreme rarity); mechanistic insight to date derives from targeted cell-biology and biochemical studies of the XK-VPS13A partnership and from mouse T-cell scrambling assays rather than unbiased multi-omic profiling.

7. Anatomical Structures Affected

Organ level: - Primary: Central nervous system (basal ganglia — caudate, putamen, pallidum), peripheral nervous system (peripheral nerves), skeletal muscle, heart, erythrocytes/hematopoietic system. - Secondary: Spleen and liver (hepatosplenomegaly from chronic hemolysis); in contiguous-deletion cases, phagocytes (CGD), retina (RP), and skeletal muscle (Duchenne). - Body systems: Nervous system, musculoskeletal system, cardiovascular system, hematologic/immune system.

Tissue/cell level: - Erythrocytes (acanthocytosis) — CL:0000232. - Striatal neurons, particularly medium spiny neurons of the caudate nucleus — CL:1001474. - Peripheral motor and sensory axons — axonal (not demyelinating) pathology. - Skeletal muscle fibers (neurogenic atrophy ± myopathic change). - Cardiac myocytes / interstitial fibroblasts (fibrosis).

Subcellular level: - Plasma membrane (site of Kell-XK complex and phospholipid scrambling; GO:0005886). - Endoplasmic reticulum–plasma membrane contact sites (site of VPS13A-XK lipid transfer; GO:0140268). - Erythrocyte membrane skeleton.

Localization: Bilateral, symmetric basal ganglia involvement (predominantly caudate, decreasing gradient to putamen/pallidum); generalized (non-focal) peripheral neuropathy and myopathy; diffuse/patchy interstitial cardiac fibrosis.

Suggested UBERON terms: caudate nucleus (UBERON:0001873), putamen (UBERON:0001874), globus pallidus (UBERON:0002476), striatum (UBERON:0002435), spleen (UBERON:0002106), liver (UBERON:0002107), heart left ventricle (UBERON:0002084), peripheral nervous system (UBERON:0000010), skeletal muscle tissue (UBERON:0001134).

8. Temporal Development

Onset: Congenital/lifelong hematologic phenotype (acanthocytosis, weak Kell/absent Kx antigens present from birth, often detected incidentally on routine blood typing or crossmatch difficulty). Neurologic/neuromuscular/cardiac disease is adult-onset, typically emerging between ages 18–61 years, with the majority presenting before age 40 and mean onset in the 30s–40s. About 30% of affected males have no CNS/neuromuscular findings at the time their McLeod blood phenotype is first identified, but most develop symptoms on follow-up (Danek et al. 2001).

Progression pattern: Insidious, slowly progressive over years to decades — not episodic or relapsing-remitting. Chorea, cognitive decline, and psychiatric symptoms accumulate progressively; peripheral neuropathy (areflexia) and elevated CK are typically present from early adulthood, often preceding overt weakness. Cardiomyopathy and arrhythmia risk increase with disease duration (develops in ~60% over time).

Disease stages: No formally staged clinical classification exists (unlike, e.g., Huntington disease's Shoulson-Fahn staging), though the new neuropathological grading system (Reuss et al. 2025) proposes histopathologic staging correlating with the caudate>putamen>pallidum severity gradient and disease duration.

Disease course: Chronic, progressive, ultimately fatal — mean age at death 53 years (range 31–69); mean disease duration from diagnosis to death ~21 years. Cause of death includes cardiac tachyarrhythmia/sudden cardiac death, pneumonia, seizures, suicide, and sepsis.

Remission: None reported — MLS is not known to remit spontaneously; symptomatic (not disease-modifying) treatments can improve chorea and psychiatric symptoms but do not alter the underlying neurodegenerative or cardiac trajectory.

Critical periods/intervention windows: Early diagnosis via blood-group phenotyping (often incidental, pre-symptomatic) creates an opportunity window for presymptomatic cardiac surveillance (biennial Holter/echocardiography per GeneReviews) before overt cardiomyopathy develops, and for genetic counseling before neurologic onset.

9. Inheritance and Population

Epidemiology: - Prevalence: Estimated <1 per 1,000,000 to as high as 1:10,000,000 depending on source; GeneReviews cites ~1:10,000,000. Orphanet epidemiology class would correspond to "<1/1,000,000" (BELOW_1_IN_1000000 in dismech's PrevalenceClassEnum). - Cases reported: Only ~250 cases reported worldwide in the literature to date (extremely rare, ultra-orphan disease). - Incidence: Not separately reported (X-linked, essentially a fixed birth-prevalence disorder given no evidence of reduced reproductive fitness before disease onset).

Inheritance pattern: X-linked recessive. Hemizygous males are affected; heterozygous females are typically unaffected carriers with mosaic (bimodal) Kell/Kx blood group expression due to random X-inactivation.

Penetrance: Neurologic/cardiac disease in hemizygous males appears fully penetrant given sufficient lifespan, though age-dependent (subclinical in a subset at the time of blood-group diagnosis, with most developing symptoms on follow-up). The hematologic (McLeod blood-group) phenotype is congenital and fully penetrant in hemizygous males.

Expressivity: Variable — age of neurologic onset, relative prominence of chorea vs. psychiatric vs. cardiac vs. myopathic features, and rate of progression vary between families and even within families, likely influenced by variant type (null vs. partial loss-of-function) and possibly X-linked contiguous deletion extent.

Genetic anticipation: Not reported; MLS is not a repeat-expansion disorder.

Germline mosaicism: Not specifically documented in the reviewed literature, though possible in principle for any X-linked disorder with de novo variants in a carrier mother.

Founder effects: Not established; the mutational spectrum is heterogeneous (private variants per family) rather than showing recurrent founder alleles.

Consanguinity: Not a relevant risk factor given X-linked recessive (not autosomal recessive) inheritance — consanguinity does not increase risk to sons of carrier mothers beyond the standard 50% transmission risk.

Carrier frequency: Not established in population databases given extreme rarity; pathogenic XK alleles are essentially absent from gnomAD.

Population demographics: - Affected populations: No specific ethnic or geographic predilection reported; cases described across European, North American, and Asian cohorts (e.g., Japanese and Chinese case reports of novel XK variants). - Sex ratio: Neurologic disease occurs "almost exclusively in boys and men" — i.e., markedly male-predominant, consistent with X-linked recessive inheritance; rare manifesting female carriers exist due to skewed X-inactivation. - Age distribution: Hematologic phenotype from birth; neurologic disease onset concentrated in the 3rd–5th decades of life.

10. Diagnostics

Clinical/laboratory tests: - Peripheral blood smear: Acanthocytosis (spiculated red cells), typically 8–30% of erythrocytes. - Blood bank serology: McLeod blood group phenotype — weak/absent Kell antigen expression, negativity for Kx antigen — is the diagnostic hallmark, highly specific for MLS. - Serum creatine kinase (CK): Elevated in essentially all affected males (up to 4,000 U/L), useful screening/monitoring biomarker. - Hemolysis markers: Reticulocytosis, elevated LDH/bilirubin consistent with compensated hemolysis (usually without overt anemia). - Cardiac biomarkers/Holter ECG/echocardiography: For surveillance and diagnosis of cardiomyopathy/arrhythmia. - EEG: When seizures are suspected. - Cardiac MRI: Late gadolinium enhancement/interstitial fibrosis pattern. - Brain MRI: Caudate (> putamen > pallidum) atrophy; T2-hyperintense white matter changes in some cases. - FDG-PET: Reduced striatal glucose metabolism, described as an early/obligate finding (PMID:11254778). - Electrophysiology (NCS/EMG): Confirms axonal sensorimotor peripheral neuropathy; can show neurogenic ± myopathic muscle changes.

Genetic testing (per GeneReviews): 1. McLeod blood group phenotyping plus chromosomal microarray analysis (to detect contiguous gene deletions, e.g., co-deletion of CYBB, DMD, RPGR). 2. McLeod blood group phenotyping plus single-gene XK testing — sequence analysis first (~60% detection), followed by gene-targeted deletion/duplication analysis if negative (~40% detection among remaining cases). 3. Multigene panel or comprehensive genomic testing (exome/genome sequencing) for undiagnosed symptomatic individuals presenting with chorea/neuroacanthocytosis of unclear cause.

Differential diagnosis: - Huntington disease: Distinguished by absence of acanthocytosis and normal CK in HD; MLS and HD share the choreatic-cognitive-psychiatric triad ("Huntington's disease-like phenotype"). - Chorea-acanthocytosis (VPS13A disease): Autosomal recessive (vs. MLS's X-linked pattern); VPS13A disease features more prominent orofacial dyskinesia with habitual tongue/lip biting and self-mutilation, and generally less severe cardiac involvement than MLS. - Other HD-phenocopies (HDL2, SCA17, PKAN/NBIA) should also be considered in the neuroacanthocytosis differential.

Screening: No population newborn or carrier screening program exists given extreme rarity; diagnosis typically follows either (a) incidental pre-transfusion blood-bank discovery of the McLeod phenotype, or (b) targeted workup of adult-onset chorea/neuroacanthocytosis. Cascade testing of at-risk female relatives (via blood-group phenotyping and/or XK sequencing) is appropriate for genetic counseling.

Suggested NCIT/LOINC: NCIT clinical-intervention terms for genetic testing (e.g., NCIT:C15709 Genetic Testing), gene panel sequencing, chromosomal microarray; LOINC codes for creatine kinase, reticulocyte count, and blood group phenotyping panels.

11. Outcome/Prognosis

Survival/mortality: Mean age at death 53 years (range 31–69). Disease duration from diagnosis to death averages ~21 years. Causes of death include cardiac tachyarrhythmia/sudden cardiac death, pneumonia (likely aspiration-related in advanced disease), seizure-related death, suicide, and sepsis — indicating that cardiac disease is the leading cause of premature death, with psychiatric morbidity (suicide) a significant secondary contributor.

Morbidity/function: Progressive functional decline driven by the combination of chorea (motor disability), cognitive decline (executive dysfunction), psychiatric illness, and neuromuscular weakness. No formal disability/QoL instrument data were identified in the literature reviewed for this report.

Disease course/complications: Rhabdomyolysis risk (particularly if exposed to typical neuroleptics); transfusion-related hemolytic reactions in alloimmunized patients; progressive cardiomyopathy leading to heart failure, arrhythmia, and candidacy for ICD/pacemaker or transplantation; seizures.

Prognostic factors: Cardiac involvement (dilated cardiomyopathy, arrhythmia) is the strongest driver of mortality; basal ganglia (caudate) volume loss correlates with disease duration and likely with neurologic severity. Variant type (complete vs. partial loss-of-function) and, in the contiguous-deletion form, co-morbid CGD/CYBB status, likely modify overall prognosis, though this is not rigorously quantified in the literature.

Prognostic biomarkers: Serial cardiac MRI/echocardiography and Holter monitoring for early arrhythmia/cardiomyopathy detection; longitudinal caudate volumetric MRI as a neurodegeneration biomarker (used in small longitudinal cohorts, e.g., a 7-year follow-up of three MLS individuals showing decreasing caudate volumes).

12. Treatment

MLS has no disease-modifying or curative therapy; management is entirely symptomatic/supportive, following the multidisciplinary approach detailed in GeneReviews (Jung, Danek, Walker).

Pharmacotherapy: - Chorea: Dopamine-receptor antagonists — tiapride, clozapine, quetiapine — or the VMAT2 inhibitor tetrabenazine; typical (first-generation) neuroleptics are specifically discouraged due to elevated risk of extrapyramidal side effects and precipitating myopathic/rhabdomyolysis complications in patients with subclinical myopathy. - NCIT: Pharmacotherapy (NCIT:C15986); therapeutic_agent candidates — tetrabenazine (CHEBI/NCIT), clozapine, quetiapine. - Seizures: Standard anti-seizure medications selected per seizure type; long-term benzodiazepine use is discouraged. - Psychiatric symptoms: Standard psychiatric pharmacotherapy (antidepressants, mood stabilizers) as clinically indicated, though no MLS-specific trial data exist.

Cardiac management: - Standard guideline-directed dilated cardiomyopathy/heart failure therapy. - Prophylactic pacemaker or implantable cardioverter-defibrillator (ICD) consideration given arrhythmia and sudden-death risk. - Cardiac transplantation as an option in advanced cardiomyopathy. - NCIT: Therapeutic Procedure (NCIT:C49236); Cardiac Pacemaker Implantation; Heart Transplantation (NCIT:C15289, Organ Transplantation).

Hematologic/transfusion management: - Use of Kx-negative (McLeod phenotype) blood, or banked autologous/homologous blood, to avoid severe hemolytic transfusion reactions from anti-Kx/anti-Km alloantibodies.

Supportive/rehabilitative care: - Physical, occupational, and speech therapy as needed for movement-disorder-related functional decline. - Psychosocial support and psychiatric care given the high burden of depression, personality change, and suicide risk.

Experimental/investigational therapy: No gene therapy, cell therapy, or targeted molecular therapy specific to MLS was identified in the literature reviewed; given the loss-of-function XK mechanism and the recently defined XK-VPS13A lipid-scramblase partnership, gene replacement or scramblase-restoring approaches are conceptually plausible future directions but are not yet in clinical development based on available sources. No MLS-specific interventional trials were surfaced in this search (searches of ClinicalTrials.gov specific to MLS were not separately queried in this pass but no trial citations were found via the general literature search).

Treatment strategy/surveillance schedule (per GeneReviews): - Cardiac: Holter ECG, echocardiography, and cardiac biomarkers every 2 years in individuals without known cardiac involvement (more frequently once disease is detected). - Neurologic: EEG when seizures are suspected. - Muscular: Regular serum CK monitoring, with heightened vigilance when neuroleptics are used. - Psychosocial: Evaluation at each clinical visit.

13. Prevention

Primary prevention: Not applicable in the traditional sense (no modifiable risk-factor or vaccination strategy exists for this monogenic disorder). The principal "primary prevention" tool is genetic counseling and reproductive planning for known carrier families (prenatal diagnosis, preimplantation genetic testing) given the X-linked recessive inheritance pattern and 50% transmission risk to sons of carrier mothers.

Secondary prevention (early detection): Presymptomatic identification via blood-bank serologic screening (McLeod phenotype often discovered incidentally during routine blood typing or difficult crossmatch) allows early genetic confirmation and initiation of the surveillance protocols above (biennial cardiac screening) before overt cardiomyopathy or neurologic symptoms develop — this is the single most actionable secondary-prevention strategy documented in the literature.

Tertiary prevention: Avoidance of typical neuroleptics to prevent rhabdomyolysis/extrapyramidal complications; use of Kx-negative blood products to prevent hemolytic transfusion reactions; proactive cardiac rhythm monitoring/device therapy to prevent sudden cardiac death.

Genetic counseling: Central to management — includes carrier testing for at-risk female relatives (with attention to X-inactivation-related variable expressivity), reproductive counseling, and family segregation studies to clarify pathogenicity of novel XK variants.

Public health/screening programs: No population-level newborn or carrier screening program exists for MLS given its extreme rarity; case detection remains opportunistic (via blood banking) or clinically triggered (via chorea/neuroacanthocytosis workup).

14. Other Species / Natural Disease

Taxonomy: No naturally occurring McLeod-syndrome-like disease has been documented in non-human species in the literature reviewed here (unlike some other neuroacanthocytosis-spectrum or lipid-membrane disorders that have recognized veterinary correlates). XK orthologs exist across mammals (used for the mouse knockout studies below), but no spontaneous veterinary McLeod phenotype was identified in this search.

Comparative biology: The XK-VPS13A functional partnership is evolutionarily conserved — XK residues mutated in human McLeod syndrome (Arg222, Glu327) are conserved across the broader XKR gene family (including XKR8), underscoring deep conservation of the phospholipid-scramblase mechanism across paralogs and likely across species.

Transmission: Not applicable — MLS is a purely genetic, non-communicable, non-zoonotic disorder.

15. Model Organisms

Mouse models: - Xk knockout mice: Used to study the requirement of Xk (with its partner Vps13a) for P2X7-receptor-mediated phospholipid scrambling and cell lysis in splenic T cells, demonstrating that Xk is essential for ATP-induced phosphatidylserine exposure and cytolysis in CD25⁺CD4⁺ T cells — establishing an immunologic/cell-biology role for Xk beyond the erythrocyte membrane (PNAS 2022, "Requirement of Xk and Vps13a for the P2X7-mediated phospholipid scrambling and cell lysis in mouse T cells"). - Vps13a knockout mice (the chorea-acanthocytosis/VPS13A-disease model, studied comparatively because of the XK-VPS13A partnership): show increased reticulocytes but notably do NOT reproduce acanthocytosis on peripheral smear, and are valuable primarily for studying male infertility and select hematologic aspects of chorea-acanthocytosis rather than the full neurologic phenotype — illustrating a fidelity gap (HUMAN_MODEL_MISMATCH-type limitation) between rodent knockouts and the human acanthocytic/neurodegenerative phenotype (Yamamoto et al./Ueno et al., "Analysis of Brain, Blood, and Testis Phenotypes Lacking the Vps13a Gene in C57BL/6N Mice," 2024, PMC11277237; and "VPS13A knockdown impairs corticostriatal synaptic plasticity and locomotor behavior in a new mouse model of chorea-acanthocytosis"). - No dedicated Xk-knockout mouse study specifically modeling the full MLS neurodegenerative/cardiomyopathic phenotype (chorea, caudate atrophy, cardiomyopathy) was identified in this search — the existing Xk-KO literature focuses on T-cell/immune phospholipid scrambling rather than CNS or cardiac phenotyping, representing a translational gap: the immunologic Xk-KO mouse work has not yet been extended to systematically recapitulate the human basal-ganglia/cardiac phenotype.

Cellular/in vitro models: - Patient-derived erythrocytes and lymphoblasts have been used to characterize the biochemical Kell-XK complex defect and acanthocyte morphology. - Heterologous overexpression systems (human cell lines) were used to demonstrate the XK-VPS13A physical interaction and ER-relocalization phenotype (PMC9436381). - Structural biology of the related XKR8-Basigin scramblase complex (cryo-EM structure, PMC8500837) provides a structural template for understanding XK's presumed scramblase mechanism, though the McLeod-specific XK structure itself has not yet been solved.

Model limitations: No model to date fully recapitulates the human triad of acanthocytosis + basal ganglia neurodegeneration + dilated cardiomyopathy. Available mouse data are fragmented across an immune/T-cell-focused Xk-KO line and a hematology/reproduction-focused Vps13a-KO line, neither of which is a complete phenocopy — this is a HUMAN_MODEL_MISMATCH-worthy gap for a future dismech entry: rodent Vps13a loss does not reproduce acanthocytosis despite being the direct genetic/molecular partner of XK, suggesting species-specific differences in erythrocyte membrane biology or compensatory mechanisms that limit translational inference from mouse hematologic data to human MLS.

Resources: MGI (Mouse Genome Informatics) records for Xk and Vps13a alleles; no dedicated Xk-KO strain repository entry with a validated MLS-recapitulating phenotype was surfaced in this search.

Summary Table: Key Ontology Term Suggestions for KB Curation

Category	Term
MONDO	MONDO:0018945 (McLeod neuroacanthocytosis syndrome)
OMIM	#300842 (disease); *314850 (XK gene)
Gene (HGNC)	XK (HGNC:12811); partner: KEL (HGNC:6339), VPS13A (HGNC:12175)
Inheritance (HP)	HP:0001417 (X-linked recessive inheritance)
Key phenotypes (HP)	HP:0001927 (Acanthocytosis), HP:0002072 (Chorea), HP:0001284 (Areflexia), HP:0001644 (Dilated cardiomyopathy), HP:0003236 (Elevated CK), HP:0001878 (Hemolytic anemia), HP:0001250 (Seizures), HP:0000708 (Behavioral abnormality)
GO	GO:0017128 (phospholipid scramblase activity), GO:0140268 (ER-PM contact site)
CL	CL:0000232 (erythrocyte), CL:1001474 (medium spiny neuron), CL:0000746 (cardiac muscle cell)
UBERON	UBERON:0001873 (caudate nucleus), UBERON:0002435 (striatum), UBERON:0002106 (spleen)
NCIT (treatment)	NCIT:C15986 (Pharmacotherapy), NCIT:C15289 (Organ Transplantation), NCIT:C15709 (Genetic Testing)

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	18
Resolved	18
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	3
Quoted claims found in source	2
Quoted claims not found in source	1
References weighed for topical relevance	18
On topic	15
Off topic	1

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:8004674 (abstract only): "a novel membrane transport protein"
closest text in source: "XK encodes a novel protein with structural characteristics of prokaryotic and eukaryotic membrane transport proteins"

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

PMC:PMC8500837 (1 mention) - The tertiary structure of the human Xkr8-Basigin complex that scrambles phospholipids at plasma membranes.
shared terms: cell

Weighed against this report's own most characteristic terms: phenotype, disease, mcleod, cardiac, mls, chorea, blood, gene, cell, syndrome, genetic, cardiomyopathy, kell, symptom, hematologic, caudate, neurologic, vps13a, psychiatric, risk.

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McLeod Neuroacanthocytosis Syndrome: Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

Hematologic (laboratory abnormalities)

Neurological — movement disorder

Neuromuscular

Cognitive/Psychiatric

Cardiac

Hepatosplenomegaly

4. Genetic/Molecular Information

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7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary Table: Key Ontology Term Suggestions for KB Curation

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Quotes not found in the cited source

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