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McLeod neuroacanthocytosis syndrome(MCLDS)

MedGen UID:
140765
Concept ID:
C0398568
Disease or Syndrome
Synonyms: MCLDS; MCLEOD PHENOTYPE; McLeod syndrome; NEUROACANTHOCYTOSIS, MCLEOD TYPE; X-linked McLeod syndrome
SNOMED CT: McLeod syndrome (234411007); Blood group deletion syndrome (234411007)
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
 
Gene (location): XK (Xp21.1)
 
Monarch Initiative: MONDO:0018945
OMIM®: 300842
Orphanet: ORPHA59306

Disease characteristics

Excerpted from the GeneReview: McLeod Neuroacanthocytosis Syndrome
McLeod neuroacanthocytosis syndrome (designated as MLS throughout this review) is a multisystem disorder with central nervous system (CNS), neuromuscular, cardiovascular, and hematologic manifestations in males: CNS manifestations are a neurodegenerative basal ganglia disease including movement disorders, cognitive alterations, and psychiatric symptoms. Neuromuscular manifestations include a (mostly subclinical) sensorimotor axonopathy and muscle weakness or atrophy of different degrees. Cardiac manifestations include dilated cardiomyopathy, atrial fibrillation, and tachyarrhythmia. Hematologically, MLS is defined as a specific blood group phenotype (named after the first proband, Hugh McLeod) that results from absent expression of the Kx erythrocyte antigen and weakened expression of Kell blood group antigens. The hematologic manifestations are red blood cell acanthocytosis and compensated hemolysis. Alloantibodies in the Kell and Kx blood group system can cause strong reactions to transfusions of incompatible blood and severe anemia in affected male newborns of Kell-negative mothers. Females heterozygous for XK pathogenic variants have mosaicism for the Kell and Kx blood group antigens. Although they usually lack CNS and neuromuscular manifestations, some heterozygous females may develop clinical manifestations including chorea or late-onset cognitive decline. [from GeneReviews]
Authors:
Hans H Jung  |  Adrian Danek  |  Ruth H Walker, et. al.   view full author information

Additional descriptions

From OMIM
McLeod syndrome (MCLDS) is an X-linked disorder characterized hematologically by the absence of red blood cell Kx antigen, weak expression of Kell red blood cell antigens, acanthocytosis, and compensated hemolysis. Most carriers of this McLeod blood group phenotype have acanthocytosis and elevated serum creatine kinase levels and are prone to develop a severe neurodegenerative disorder. Onset of neurologic symptoms ranges between 25 and 60 years (mean onset, 30-40 years), and penetrance appears to be high. Additional symptoms include generalized seizures, neuromuscular symptoms leading to weakness and atrophy, and cardiomyopathy mainly manifesting with atrial fibrillation, malignant arrhythmias, and dilated cardiomyopathy (summary by Jung et al., 2007).  http://www.omim.org/entry/300842
From MedlinePlus Genetics
McLeod neuroacanthocytosis syndrome is primarily a neurological disorder that occurs almost exclusively in boys and men. This disorder affects movement in many parts of the body. People with McLeod neuroacanthocytosis syndrome also have abnormal star-shaped red blood cells (acanthocytosis). This condition is one of a group of disorders called neuroacanthocytoses that involve neurological problems and abnormal red blood cells.

McLeod neuroacanthocytosis syndrome affects the brain and spinal cord (central nervous system). Affected individuals have involuntary movements, including jerking motions (chorea), particularly of the arms and legs, and muscle tensing (dystonia) in the face and throat, which can cause grimacing and vocal tics (such as grunting and clicking noises). Dystonia of the tongue can lead to swallowing difficulties. Seizures occur in approximately half of all people with McLeod neuroacanthocytosis syndrome. Individuals with this condition may develop difficulty processing, learning, and remembering information (cognitive impairment). They may also develop psychiatric disorders, such as depression, bipolar disorder, psychosis, or obsessive-compulsive disorder.

People with McLeod neuroacanthocytosis syndrome also have problems with their muscles, including muscle weakness (myopathy) and muscle degeneration (atrophy). Sometimes, nerves that connect to muscles atrophy (neurogenic atrophy), leading to loss of muscle mass and impaired movement. Individuals with McLeod neuroacanthocytosis syndrome may also have reduced sensation and weakness in their arms and legs (peripheral neuropathy). Life-threatening heart problems such as irregular heartbeats (arrhythmia) and a weakened and enlarged heart (dilated cardiomyopathy) are common in individuals with this disorder.

The signs and symptoms of McLeod neuroacanthocytosis syndrome usually begin in mid-adulthood. Behavioral changes, such as lack of self-restraint, the inability to take care of oneself, anxiety, depression, and changes in personality may be the first signs of this condition. While these behavioral changes are typically not progressive, the movement and muscle problems and intellectual impairments tend to worsen with age.  https://medlineplus.gov/genetics/condition/mcleod-neuroacanthocytosis-syndrome

Clinical features

From HPO
Absent Achilles reflex
MedGen UID:
108240
Concept ID:
C0558845
Finding
Absence of the Achilles reflex (also known as the ankle jerk reflex), which can normally be elicited by tapping the tendon is tapped while the foot is dorsiflexed.
Areflexia of upper limbs
MedGen UID:
388832
Concept ID:
C2674177
Finding
Inability to elicit tendon reflexes in the upper limbs.
Atrial fibrillation
MedGen UID:
445
Concept ID:
C0004238
Finding
An atrial arrhythmia characterized by disorganized atrial activity without discrete P waves on the surface EKG, but instead by an undulating baseline or more sharply circumscribed atrial deflections of varying amplitude an frequency ranging from 350 to 600 per minute.
Primary dilated cardiomyopathy
MedGen UID:
2880
Concept ID:
C0007193
Disease or Syndrome
Familial dilated cardiomyopathy is a genetic form of heart disease. It occurs when heart (cardiac) muscle becomes thin and weakened in at least one chamber of the heart, causing the open area of the chamber to become enlarged (dilated). As a result, the heart is unable to pump blood as efficiently as usual. To compensate, the heart attempts to increase the amount of blood being pumped through the heart, leading to further thinning and weakening of the cardiac muscle. Over time, this condition results in heart failure.\n\nIt usually takes many years for symptoms of familial dilated cardiomyopathy to cause health problems. They typically begin in mid-adulthood, but can occur at any time from infancy to late adulthood. Signs and symptoms of familial dilated cardiomyopathy can include an irregular heartbeat (arrhythmia), shortness of breath (dyspnea), extreme tiredness (fatigue), fainting episodes (syncope), and swelling of the legs and feet. In some cases, the first sign of the disorder is sudden cardiac death. The severity of the condition varies among affected individuals, even in members of the same family.
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Anxiety
MedGen UID:
1613
Concept ID:
C0003467
Finding
Intense feelings of nervousness, tension, or panic often arise in response to interpersonal stresses. There is worry about the negative effects of past unpleasant experiences and future negative possibilities. Individuals may feel fearful, apprehensive, or threatened by uncertainty, and they may also have fears of falling apart or losing control.
Chorea
MedGen UID:
3420
Concept ID:
C0008489
Disease or Syndrome
Chorea (Greek for 'dance') refers to widespread arrhythmic involuntary movements of a forcible, jerky and restless fashion. It is a random-appearing sequence of one or more discrete involuntary movements or movement fragments. Movements appear random because of variability in timing, duration or location. Each movement may have a distinct start and end. However, movements may be strung together and thus may appear to flow randomly from one muscle group to another. Chorea can involve the trunk, neck, face, tongue, and extremities.
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
Frequently experiencing feelings of being down, miserable, and/or hopeless; struggling to recover from these moods; having a pessimistic outlook on the future; feeling a pervasive sense of shame; having a low self-worth; experiencing thoughts of suicide and engaging in suicidal behavior.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Dyskinesia
MedGen UID:
8514
Concept ID:
C0013384
Disease or Syndrome
A movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Personality disorder
MedGen UID:
45827
Concept ID:
C0031212
Mental or Behavioral Dysfunction
A personality disorder is a deeply ingrained pattern of behavior of a specified kind that deviates markedly from the norms of generally accepted behavior. It is typically apparent by the time of adolescence and causes long-term difficulties in personal relationships or functioning in society.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Generalized-onset seizure
MedGen UID:
115963
Concept ID:
C0234533
Disease or Syndrome
A generalized-onset seizure is a type of seizure originating at some point within, and rapidly engaging, bilaterally distributed networks. The networks may include cortical and subcortical structures but not necessarily the entire cortex.
Compulsive behaviors
MedGen UID:
109373
Concept ID:
C0600104
Mental or Behavioral Dysfunction
Behavior that consists of repetitive acts, characterized by the feeling that one "has to" perform them, while being aware that these acts are not in line with one's overall goal.
Impaired vibration sensation at ankles
MedGen UID:
343107
Concept ID:
C1854372
Finding
A decrease in the ability to perceive vibration at the ankles. Clinically, this is usually tested with a tuning fork which vibrates at 128 Hz and is applied to the malleoli of the ankles.
Motor axonal neuropathy
MedGen UID:
413108
Concept ID:
C2749625
Disease or Syndrome
Progressive impairment of function of motor axons with muscle weakness, atrophy, and cramps. The deficits are length-dependent, meaning that muscles innervated by the longest nerves are affected first, so that for instance the arms are affected at a later age than the onset of deficits involving the lower leg.
Acanthocytosis
MedGen UID:
195801
Concept ID:
C0687751
Disease or Syndrome
Acanthocytosis is a type of poikilocytosis characterized by the presence of spikes on the cell surface. The cells have an irregular shape resembling many-pointed stars.
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Rhabdomyolysis
MedGen UID:
19775
Concept ID:
C0035410
Pathologic Function
Breakdown of muscle fibers that leads to the release of muscle fiber contents (myoglobin) into the bloodstream.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Elevated circulating aspartate aminotransferase concentration
MedGen UID:
57497
Concept ID:
C0151904
Finding
The concentration of aspartate aminotransferase (AST) in the blood circulation is above the upper limit of normal.
Elevated circulating alanine aminotransferase concentration
MedGen UID:
57740
Concept ID:
C0151905
Finding
An abnormally high concentration in the circulation of alanine aminotransferase (ALT).
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Elevated gamma-glutamyltransferase level
MedGen UID:
1370086
Concept ID:
C4476869
Finding
Increased level of the enzyme gamma-glutamyltransferase (GGT). GGT is mainly present in kidney, liver, and pancreatic cells, but small amounts are present in other tissues.
Increased circulating lactate dehydrogenase concentration
MedGen UID:
1377250
Concept ID:
C4477095
Finding
An elevated level of the enzyme lactate dehydrogenase in the blood circulation.
Reduced haptoglobin level
MedGen UID:
1686017
Concept ID:
C5209264
Finding
An abnormally low concentration of haptoglobin in the blood circulation. Decreased haptoglobin in conjunction with increased reticulocyte count and anemia may indicate hemolysis. Decreased haptoglobin levels can also occur in the absence of hemolysis, due to cirrhosis of the liver, disseminated ovarian carcinomatosis, pulmonary sarcoidosis, and elevated estrogen state.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMcLeod neuroacanthocytosis syndrome
Follow this link to review classifications for McLeod neuroacanthocytosis syndrome in Orphanet.

Professional guidelines

PubMed

Cardoso F
Neurodegener Dis Manag 2014;4(1):67-72. doi: 10.2217/nmt.13.78. PMID: 24640980
Danek A, Rubio JP, Rampoldi L, Ho M, Dobson-Stone C, Tison F, Symmans WA, Oechsner M, Kalckreuth W, Watt JM, Corbett AJ, Hamdalla HH, Marshall AG, Sutton I, Dotti MT, Malandrini A, Walker RH, Daniels G, Monaco AP
Ann Neurol 2001 Dec;50(6):755-64. doi: 10.1002/ana.10035. PMID: 11761473

Recent clinical studies

Etiology

Schon KR, O'Donovan DG, Briggs M, Rowe JB, Wijesekera L, Chinnery PF, van den Ameele J
Neuropathology 2024 Apr;44(2):109-114. Epub 2023 Jul 12 doi: 10.1111/neup.12935. PMID: 37438874
Denomme GA
Immunohematology 2015;31(1):14-9. PMID: 26308465
Hewer E, Danek A, Schoser BG, Miranda M, Reichard R, Castiglioni C, Oechsner M, Goebel HH, Heppner FL, Jung HH
Brain 2007 Dec;130(Pt 12):3285-96. doi: 10.1093/brain/awm269. PMID: 18055495
Jung HH, Danek A, Frey BM
Vox Sang 2007 Aug;93(2):112-21. doi: 10.1111/j.1423-0410.2007.00949.x. PMID: 17683354
Walker RH, Danek A, Uttner I, Offner R, Reid M, Lee S
Transfusion 2007 Feb;47(2):299-305. doi: 10.1111/j.1537-2995.2007.01106.x. PMID: 17302777

Diagnosis

Schon KR, O'Donovan DG, Briggs M, Rowe JB, Wijesekera L, Chinnery PF, van den Ameele J
Neuropathology 2024 Apr;44(2):109-114. Epub 2023 Jul 12 doi: 10.1111/neup.12935. PMID: 37438874
Helander L, McKinney C, Kelly K, Mack S, Sanders M, Gurley J, Dumont LJ, Annen K
Front Immunol 2022;13:994321. Epub 2022 Aug 23 doi: 10.3389/fimmu.2022.994321. PMID: 36081507Free PMC Article
Jung HH, Danek A, Frey BM
Vox Sang 2007 Aug;93(2):112-21. doi: 10.1111/j.1423-0410.2007.00949.x. PMID: 17683354
Miranda M, Castiglioni C, Frey BM, Hergersberg M, Danek A, Jung HH
Mov Disord 2007 Jul 15;22(9):1358-61. doi: 10.1002/mds.21536. PMID: 17469188
Jung HH, Hergersberg M, Vogt M, Pahnke J, Treyer V, Röthlisberger B, Kollias SS, Russo D, Frey BM
Transfusion 2003 Jul;43(7):928-38. doi: 10.1046/j.1537-2995.2003.t01-1-00434.x. PMID: 12823753

Therapy

Jung HH, Brandner S
Muscle Nerve 2002 Sep;26(3):424-7. doi: 10.1002/mus.10199. PMID: 12210375

Prognosis

Helander L, McKinney C, Kelly K, Mack S, Sanders M, Gurley J, Dumont LJ, Annen K
Front Immunol 2022;13:994321. Epub 2022 Aug 23 doi: 10.3389/fimmu.2022.994321. PMID: 36081507Free PMC Article
Hewer E, Danek A, Schoser BG, Miranda M, Reichard R, Castiglioni C, Oechsner M, Goebel HH, Heppner FL, Jung HH
Brain 2007 Dec;130(Pt 12):3285-96. doi: 10.1093/brain/awm269. PMID: 18055495
Jung HH, Hergersberg M, Vogt M, Pahnke J, Treyer V, Röthlisberger B, Kollias SS, Russo D, Frey BM
Transfusion 2003 Jul;43(7):928-38. doi: 10.1046/j.1537-2995.2003.t01-1-00434.x. PMID: 12823753
Jung HH, Brandner S
Muscle Nerve 2002 Sep;26(3):424-7. doi: 10.1002/mus.10199. PMID: 12210375

Clinical prediction guides

Valko PO, Hänggi J, Meyer M, Jung HH
Eur J Neurol 2010 Apr;17(4):612-8. Epub 2009 Nov 24 doi: 10.1111/j.1468-1331.2009.02872.x. PMID: 19968700
Jung HH, Hergersberg M, Vogt M, Pahnke J, Treyer V, Röthlisberger B, Kollias SS, Russo D, Frey BM
Transfusion 2003 Jul;43(7):928-38. doi: 10.1046/j.1537-2995.2003.t01-1-00434.x. PMID: 12823753

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