McLeod syndrome

McLeod Syndrome: A Rare Genetic Disorder

McLeod syndrome is a rare X-linked recessive genetic disorder that affects various parts of the body, including the blood, brain, peripheral nerves, muscle, and heart [1]. It is caused by mutations in the XK gene on the X chromosome, which leads to the absence or weak expression of the Kx antigen on red blood cells [7][13].

Symptoms and Characteristics

The disorder primarily affects males, with only about 150 cases reported worldwide [3]. McLeod syndrome is characterized by a range of symptoms, including:

• Chorea: involuntary jerking motions, particularly in the arms and legs
• Dystonia: muscle tensing in the face and throat, leading to grimacing and vocal tics
• Acanthocytosis: abnormal star-shaped red blood cells
• Muscle weakness or atrophy of different degrees
• Cardiac manifestations [6]

Neurological Manifestations

McLeod syndrome affects the central nervous system (CNS), causing progressive chorea, cognitive alterations, and psychiatric manifestations [9][11]. The disorder can also lead to a multisystemic progressive disorder with CNS, neuromuscular, cardiovascular, and hematologic manifestations in males [11].

Genetic Cause

The XK gene encoding for the McLeod protein is responsible for producing the Kx protein, which plays a crucial role in apoptosis regulation [14]. Mutations in this gene lead to the absence or weak expression of the Kx antigen on red blood cells.

In summary, McLeod syndrome is a rare X-linked recessive genetic disorder that affects various parts of the body, including the blood, brain, peripheral nerves, muscle, and heart. It is characterized by symptoms such as chorea, dystonia, acanthocytosis, muscle weakness or atrophy, and cardiac manifestations, primarily affecting males.

References:

[1] McLeod syndrome (/mə-ˈkloʊd/ mə-KLOWD) is an X-linked recessive genetic disorder that may affect the blood, brain, peripheral nerves, muscle, and heart. [3] McLeod neuroacanthocytosis syndrome is primarily a neurological disorder that occurs almost exclusively in males. Only about 150 cases have been reported worldwide. [7] McLeod syndrome is an X-linked disorder characterized by the absence or weak expression of the Kx antigen on red blood cells. [13] Hematologically, McLeod syndrome is characterized by the absence of red blood cell Kx antigen, weak expression of Kell red blood cell antigens, acanthocytosis, and compensated hemolysis. [14] McLeod syndrome is caused by mutations of the XK gene encoding the XK protein, which carries the Kx RBC antigen.

McLeod Syndrome: A Rare Neurological Disorder

McLeod syndrome is a rare X-linked recessive disorder that primarily affects males. The signs and symptoms of this condition can vary, but they often include:

• Movement Disorders: Chorea (involuntary movements), progressive chorea, and other movement-related issues are common in individuals with McLeod syndrome.
• Cognitive Impairment: Cognitive changes, such as memory loss, difficulty with problem-solving, and decreased cognitive function, may occur in some cases.
• Psychiatric Symptoms: Behavioral changes, including lack of self-restraint, anxiety, depression, and changes in personality, are frequent and may appear many years prior to the movement disorders.
• Cardiac Problems: Cardiac manifestations include dilated cardiomyopathy, atrial fibrillation, and tachyarrhythmia.
• Neuromuscular Manifestations: Sensorimotor axonopathy (a type of nerve damage) and muscle weakness or atrophy may also be present.

Additional Symptoms

Other symptoms that may occur in McLeod syndrome include:

• Enlarged liver and spleen (hepatosplenomegaly)
• Hemolytic anemia
• Behavioral changes, such as lack of self-restraint, the inability to take care of oneself, anxiety, depression, and changes in personality

Age of Onset

The signs and symptoms of McLeod neuroacanthocytosis syndrome usually begin in mid-adulthood, with individuals typically noticing symptoms in their 30s. The course is usually slowly progressive.

References

• [1] McLeod neuroacanthocytosis syndrome is inherited in an X-linked recessive fashion and is caused by genetic changes in the XK gene.
• [3] McLeod syndrome is a rare X-linked disorder similar to chorea-acanthocytosis.
• [5] Patients usually begin to notice symptoms in their 30s and the course is usually slowly progressive.
• [6] 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.
• [10] The signs and symptoms of McLeod neuroacanthocytosis syndrome usually begin in mid-adulthood.

McLeod syndrome can be diagnosed through various tests, including:

• Serological testing: This involves analyzing red blood cells (RBCs) to determine if they have weakened expression of Kell system antigens. This test is typically performed on males, as the condition is X-linked recessive.
• DNA analysis: Genetic testing can confirm a mutation in the XK gene, which is responsible for producing the Kx protein. This test can be performed on both males and females.
• Flow cytometry: This test measures the expression of Kell antigens on RBCs and can detect two populations of RBCs: one with normal expression and one with reduced expression.
• Molecular genetic testing: This test detects a heterozygous pathogenic variant in the XK gene, which is typically performed on females who are carriers of the condition.

These tests can be used to confirm a diagnosis of McLeod syndrome in males, while in females, the diagnosis is often established through DNA analysis or flow cytometry (see [2], [5], and [10]).

In addition to these tests, blood samples may also be taken for further analysis, including:

• Blood typing: This involves analyzing RBCs to determine their Kell antigen expression.
• Extracted DNA testing: This test analyzes DNA extracted from a blood sample or other tissue to confirm the presence of a mutation in the XK gene.

It's worth noting that diagnosis may also involve clinical evaluation and neuroimaging studies (see [3], [8], and [9]).

References:

[2] - Absence of Kx antigen on RBCs is a key diagnostic feature of McLeod syndrome. [5] - DNA analysis confirms a mutation in the XK gene, which is responsible for producing the Kx protein. [10] - Flow cytometry can detect two populations of RBCs: one with normal expression and one with reduced expression. [3], [8], and [9] - Clinical evaluation and neuroimaging studies may also be used to support a diagnosis of McLeod syndrome.

Treatment Options for McLeod Syndrome

McLeod syndrome, a rare multisystem disorder, requires symptomatic and supportive treatment to manage its various symptoms. While there is no cure for the condition, medication can provide temporary relief from certain symptoms.

• Antipsychotic drugs: Medications like haloperidol can help alleviate tics and chorea (involuntary movements) by blocking dopamine receptors in the brain [3][8].
• Botulinum toxin injections: These injections have been shown to improve involuntary movements, particularly those affecting chewing and swallowing (feeding dystonia) [12].
• Levetiracetam: This antiepileptic medication has been reported to reduce tics in some patients with McLeod syndrome [15].
• Benztropine, quetiapine, and lorazepam: These medications have also been used in combination to manage symptoms of McLeod syndrome, although their effectiveness can vary from person to person [15].

Important Considerations

It's essential to note that treatment for McLeod syndrome is highly individualized and may involve a multidisciplinary approach. Patients with the condition often require ongoing medical care to manage their various symptoms.

• Avoiding certain medications: Antiepileptic drugs like carbamazepine and lamotrigine should be avoided in patients with McLeod syndrome, as they can worsen involuntary movements [5].
• Multivitamin and vitamin E supplements: These may be recommended for patients with mild swallowing difficulties or lipid disorders [6].

Current Research and Future Directions

While these treatment options are available, further research is needed to better understand the underlying mechanisms of McLeod syndrome and to develop more effective treatments.

Differential Diagnosis of McLeod Syndrome

McLeod syndrome, also known as McLeod neuroacanthocytosis syndrome (MLS), is a rare X-linked disorder that can be challenging to diagnose due to its similarity with other neurological conditions. The differential diagnosis of McLeod syndrome involves considering several disorders that may present with similar symptoms.

Key Differential Diagnoses:

• Chorea-acanthocytosis: This condition is characterized by movement disorders, peripheral neuropathy, seizures, and cognitive changes, which are similar to the full syndrome of McLeod syndrome. However, chorea-acanthocytosis can be distinguished from McLeod syndrome by the absence of self-mutilating lip and tongue biting [2].
• Huntington disease: This neurodegenerative disorder presents with movement disorders, cognitive alterations, and psychiatric symptoms, which are similar to the CNS manifestations of McLeod syndrome. However, Huntington disease is typically inherited in an autosomal dominant pattern, whereas McLeod syndrome is X-linked [9][10].
• Huntington disease-like syndromes: These conditions present with progressive hyperkinetic movement disorders and may be considered in the differential diagnosis of McLeod syndrome [11].

Other Differential Diagnoses:

• Autosomal recessive chorea-acanthocytosis (ChAc): This condition presents with a similar full syndrome to McLeod syndrome, but can be distinguished by the absence of self-mutilating lip and tongue biting [2].
• Progressive distal muscle wasting & weakness: This condition is characterized by progressive muscle wasting and weakness, which may be considered in the differential diagnosis of McLeod syndrome [4].

Clinical Characteristics:

McLeod neuroacanthocytosis syndrome (MLS) is a multisystem disorder with central nervous system (CNS), neuromuscular, cardiovascular, and hematologic manifestations in males. The CNS manifestations include movement disorders, cognitive alterations, and psychiatric symptoms [13][14][15].

References:

[1] Review XK-Associated McLeod Syndrome: Nonhematological Manifestations and Relation to VPS13A Disease. [Transfus Med Hemother. 2022] [2] The differential diagnosis of McLeod syndrome depends upon the presentation. [3] The differential diagnoses depend on the presenting symptoms and include chorea-acanthocytosis, Huntington disease, Huntington disease-like disorders, and ... [4] Table 2. [5] Apr 1, 2015 — This condition is one of a group of disorders called neuroacanthocytoses that involve neurological problems and abnormal red blood cells. McLeod ... [6] McLeod syndrome is a rare X-linked disorder similar to chorea-acanthocytosis. Clinically it manifests as chorea, axonal peripheral neuropathy, myopathy, cardiomyopathy, and hematologic abnormalities. [7] Specific genetic testing is possible in all NA syndromes. Differential diagnoses include Huntington disease and other causes of progressive hyperkinetic movement disorders. [8] Clinical characteristics: 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. [9] 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. [10] 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. [11] McLeod syndrome is named after a Harvard medical student, Hugh McLeod, who did not express the Kell antigen on erythrocytes, as all affected male subjects with this condition.