Disease characteristics. McLeod neuroacanthocytosis syndrome (designated as MLS throughout this review) is a multisystem disorder with central nervous system (CNS), neuromuscular, and hematologic manifestations in males. CNS manifestations are a neurodegenerative basal ganglia disease including (1) movement disorder, (2) cognitive impairment, and (3) psychiatric symptoms. Neuromuscular manifestations include a (mostly subclinical) sensorimotor axonopathy and clinically relevant muscle weakness or atrophy. The hematologic manifestations are red blood cell acanthocytosis, compensated hemolysis, and the McLeod blood group phenotype resulting from absent expression of the Kx erythrocyte antigen and reduced expression of the Kell blood group antigens. The Kell blood group system can cause strong reactions to transfusions of incompatible blood and severe anemia in newborns of Kell-negative mothers. Heterozygous females have mosaicism for the Kell system blood group antigens and RBC acanthocytosis but lack CNS and neuromuscular manifestations.
Diagnosis/testing. The diagnosis of MLS is based on clinical and hematologic findings. XK is the only gene currently known to be associated with McLeod neuroacanthocytosis syndrome. Molecular genetic testing is available on a research basis only.
Management. Treatment of manifestations: dopamine antagonists (e.g., tiapride, clozapine, quetiapine, tetrabenazine) to ameliorate chorea; routine treatment of psychiatric problems, cardiac abnormalities, seizures; long-term and continuous multidisciplinary psychosocial support for affected individuals and their families. Prevention of secondary complications: Kx-negative blood or banked autologous blood for tranfusions when possible. Surveillance: Holter ECG and echocardiography every two to three years in those without known cardiac complications; monitor for seizures; monitor serum CK concentrations for evidence of rhabdomyolysis if excessive movement disorders are present or if neuroleptic medications are being used.
Genetic counseling. McLeod neuroacanthocytosis syndrome is inherited in an X-linked manner. If the mother of an affected male is a carrier, the chance of transmitting MLS in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will usually not be affected. Affected males pass the disease-causing mutation to all of their daughters and none of their sons. No laboratories offering molecular genetic testing for prenatal diagnosis of MLS are listed in the GeneTests Laboratory Directory; however, prenatal testing may be available through laboratories offering custom prenatal testing.
Diagnosis of McLeod neuroacanthocytosis syndrome (MLS) is established in individuals with the following combination of manifestations:
The McLeod blood group phenotype
A family history consistent with X-linked inheritance AND any combination of the following:
CNS manifestations
Progressive chorea syndrome similar to that seen in Huntington disease including the clinical triad of movement disorder, cognitive impairment, and psychiatric symptoms
Seizures, mostly generalized
Neuromuscular manifestations (often subclinical or mild)
Sensorimotor axonopathy
Myopathy
Dilated cardiomyopathy and arrhythmias
McLeod blood group phenotype. The diagnosis of the McLeod blood group phenotype is based on the immunohematologic determination of absent expression of the Kx erythrocyte antigen and reduced expression of the Kell blood group antigens using human anti-Kx and anti-Kell human alloantibodies, respectively [Allen et al 1961, Lee et al 2000b].
Mixed red blood cell populations, typical of female heterozygotes, may be identified with flow cytometric analysis of Kx and Kell RBC antigens [Oyen et al 1996; Kawakami et al 1999; Jung, Hergersberg et al 2001; Singleton et al 2003].
RBC acanthocytosis. RBC acanthocytosis is found in virtually all males with MLS, particularly if determinations are repeated. However, no data are available on the age at which acanthocytosis develops.
Accurate determination of RBC acanthocytosis is challenging. The best procedure for the detection of RBC acanthocytosis requires diluting whole blood samples 1:1 with heparinized saline followed by incubation for 60 minutes at room temperature; wet cell monolayers are then prepared for phase-contrast microscopy. When all RBCs with spicules (corresponding to type AI/AII acanthocytes and echinocytes are counted, normal controls show less than 6.3% acanthocytes/echinocytes [Storch et al 2005].
Note: Dry blood smears are often inadequate and underlie description of "late-appearing acanthocytes" [Sorrentino et al 1999] or "neuroacanthocytosis without acanthocytes" [Malandrini et al 1993].
Confirmation of erythrocyte morphology by scanning electron microscopy may be helpful if available.
Compensated hemolysis. Compensated hemolysis (i.e., hemolysis without anemia) is found in virtually all males with MLS.
Muscle enzymes. All males with MLS examined so far have had elevated serum creatine phosphokinase (CK) concentrations reaching values up to 4000 U/L [Danek, Rubio et al 2001; Jung, Hergersberg et al 2001].
Serum concentrations of LDH, AST, and ALT may also be elevated [Danek, Rubio et al 2001; Jung, Hergersberg et al 2001].
Clinical electroneuromyography
Electromyography may demonstrate neurogenic and myopathic changes [Danek, Rubio et al 2001].
Electroneurography may demonstrate axonal damage of variable degree [Danek, Rubio et al 2001].
Muscle CT. Computed tomography (CT) scan of muscle may reveal a selective pattern of fatty degeneration of lower-leg muscles preferentially affecting the vastus lateralis, biceps femoris, and adductor magnus muscles and sparing the gracilis, semitendinosus, and lateral head of the gastrocnemius muscle [Ishikawa et al 2000].
Muscle biopsy. Except for one individual with a XK missense mutation who had normal histologic and immunohistochemical findings [Jung et al 2003], the following pathologic muscle findings have been identified in skeletal muscle examined to date:
Fiber type grouping, type 1 fiber predominance, type 2 fiber atrophy, increased variability in fiber size, and increased central nucleation [Swash et al 1983; Jung, Russo et al 2001]
A weak background signal on Kell and XK immunohistochemistry without a specific staining pattern, in contrast to control muscles in which a type 2 fiber-specific intracellular staining (most probably confined to the sarcoplasmic reticulum) is observed [Jung, Russo et al 2001]
Normal dystrophin staining [Oechsner et al 1996] (see Dystrophinopathies)
Sural nerve biopsy. Nerve biopsy may demonstrate a chronic axonal neuropathy with prominent regenerative activity and selective loss of large myelinated fibers [Dotti et al 2004].
Cardiac studies
Echocardiography may demonstrate congestive cardiomyopathy or dilated cardiomyopathy [Mohiddin & Fananapazzir 2004].
Electrocardiography (ECG) may demonstrate atrial fibrillation or tachyarrhythmia [Mohidden & Fananapazzir 2004].
Neuroimaging. CT and magnetic resonance imaging (MRI) of the brain may demonstrate atrophy of the caudate nucleus and putamen of variable degree [Danek, Rubio et al 2001; Jung, Hergersberg et al 2001]. In asymptomatic female carriers of MLS, and at the beginning of the disease in males, neuroimaging findings may be normal [Jung, Hergersberg et al 2001; Jung et al 2003]. Basal ganglia volumes are inversely correlated with disease duration [Jung, Hergersberg et al 2001]. In two males with MLS, cerebral MRI demonstrated extended T2-hyperintense white matter alterations [Danek, Rubio et al 2001; Nicholl et al 2004].
Magnetic resonance spectroscopy (MRS). 1H-MRS demonstrates pathologic NAA/(Cr+Cho) ratios in frontal, temporal, and insular areas with an individual pattern in persons with MLS with predominant psychiatric or neuropsychological manifestations [Dydak et al 2006].
Nuclear medicine. SPECT studies using 123I-IMP and 123I-IBZM, respectively, revealed reduction of striatal perfusion as well as striatal D2-receptor density in some individuals with MLS [Oechsner et al 2001].
Using [18F]-FDG (2-fluoro-2-deoxy-glucose) PET, bilaterally reduced striatal glucose uptake was found in all symptomatic individuals with MLS [Jung, Hergersberg et al 2001; Oechsner et al 2001]. Quantitative FDG-PET demonstrated reduced striatal glucose uptake also in asymptomatic males with the McLeod blood group phenotype and in female heterozygotes [Jung, Hergersberg et al 2001; Oechsner et al 2001]. In addition, the degree of reduction of striatal glucose uptake correlated with disease duration [Jung, Hergersberg et al 2001].
Brain pathology. Data from only two individuals with MLS (one male and one manifesting female carrier) are available [Hardie et al 1991, Brin et al 1993]. Marked striatal atrophy was observed macroscopically. Nonspecific loss of nerve cells and reactive astrocytic gliosis with predominant alterations in the head of the caudate nucleus were found microscopically. In one individual with MLS, slight white matter myelin pallor was noted. In contrast to chorea-acanthocytosis (ChAc), MLS did not demonstrate pathology in the thalamus or substantia nigra. In addition, neither Lewy bodies nor definite abnormalities in other brain areas such as the cortex were observed.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. XK is the only gene currently known to be associated with MLS.
Research testing. The vast majority of XK mutations comprise deletions, nonsense mutations, or splice-site mutations predicting absent or truncated XK protein devoid of the Kell protein binding site [Ho et al 1994; Ho et al 1996; Hanaoka et al 1999; Dotti et al 2000; Ueyama et al 2000; Danek, Rubio et al 2001; Jung, Hergersberg et al 2001; Supple et al 2001; Russo et al 2002; Jung et al 2003; Singleton et al 2003].
To date, only three XK missense mutations have been described [Danek, Rubio et al 2001; Russo et al 2002; Jung et al 2003].
Table 1 summarizes molecular genetic testing for this disorder.
Test Method | Mutations Detected | Mutation Detection Frequency 1 | Test Availability |
---|---|---|---|
Direct DNA 2 | XK mutations | Unknown | Research only |
1. Proportion of affected individuals with a mutation(s) as classified by gene/locus, phenotype, population group, genetic mechanism, and/or test method
2. Direct DNA methods may include mutation analysis, mutation scanning, sequence analysis, or other means of molecular genetic testing to detect a genetic alteration associated with a specific disorder.
No other phenotypes are associated with XK mutations.
Larger X-chromosomal deletions including the XK gene may result in a contiguous gene syndrome, comprising X-linked chronic granulomatous disease (CGD; OMIM 306400), Duchenne muscular dystrophy (DMD; OMIM 310200), and X-linked retinitis pigmentosa (RP3; OMIM 300389) [Brown et al 1996, El Nemer et al 2000].
McLeod neuroacanthocytosis syndrome (MLS) is a multisystem disorder with central nervous system (CNS), neuromuscular, and hematologic manifestations in males. CNS manifestations of MLS resemble Huntington disease. Symptoms comprise the prototypic triad of a progressive neurodegenerative basal ganglia disease including (1) movement disorder, (2) cognitive impairment, and (3) psychiatric symptoms [Danek, Rubio et al 2001]. It should be noted that each sign and symptom may develop in isolation or in variable combinations.
Choreiform movements are the presenting symptom in about 30% of individuals with MLS, and develop in up to 95% of individuals over time [Danek, Tison et al 2001; Jung, Hergersberg et al 2001].
Cognitive impairment is not a major presenting symptom of MLS; however, "subcortical" cognitive deficits are eventually found in at least 50% of individuals [Danek, Rubio et al 2001; Jung, Hergersberg et al 2001; Danek et al 2004].
About 20% of individuals manifest psychiatric abnormalities including personality disorder, anxiety, depression, obsessive-compulsive disorder, bipolar disorder, or schizo-affective disorder. Psychopathology develops in about 80% of individuals over time [Danek, Rubio et al 2001; Jung, Hergersberg et al 2001; Jung & Haker 2004].
Seizures may be the presenting symptom in about 20% of individuals. Up to 40% of individuals with MLS eventually have seizures, usually described as generalized seizures.
Neuromuscular manifestations are not a common presenting symptom of MLS. However, almost all individuals with MLS have absent deep tendon reflexes as a sign of a (mostly subclinical) sensorimotor axonopathy [Danek, Rubio et al 2001; Jung, Hergersberg et al 2001]. About 50% of individuals develop clinically relevant muscle weakness or atrophy during the disease course. The deterioration rate of the myopathy is slow, and only a few individuals develop severe weakness [Kawakami et al 1999; Danek, Rubio et al 2001; Jung, Hergersberg et al 2001].
Cardiac manifestations including dilated cardiomyopathy, atrial fibrillation, and tachyarrhythmia are rarely presenting signs and symptoms of MLS. About 60% of individuals develop cardiac manifestations over time [Danek, Rubio et al 2001].
Hepatosplenomegaly occurs in about one third of males with MLS [Danek, Rubio et al 2001].
About 30% of males with the McLeod blood group phenotype do not have neuromuscular or CNS symptoms at the time of initial diagnosis of the blood group abnormalities and are only recognized during routine workup in blood banks or in the course of family evaluations [Danek, Rubio et al 2001; Jung, Hergersberg et al 2001]. However, most males with the McLeod blood group phenotype developed neurologic manifestations during long term follow-up [Danek, Rubio et al 2001].
The age of onset of neurologic manifestations is between 18 and 61 years; the majority of individuals become symptomatic before age 40. Almost all clinical observations indicate a slowly progressive disease course [Danek, Rubio et al 2001; Jung, Hergersberg et al 2001]. Because of difficulty in determining the exact onset of disease, little reliable data regarding disease duration are available. Activities of daily living may become impaired as a result of the movement disorder, psychiatric symptoms, cognitive impairment, or cardiomyopathy.
The interval between reported disease onset and death ranges from seven to 51 years [Danek, Rubio et al 2001; Jung, Hergersberg et al 2001]. Mean age of death is 53 years, ranging from 31 to 69 years [Danek, Rubio et al 2001; Jung, Hergersberg et al 2001]. Cardiac problems, in particular tachyarrhythmia, appear to be a major cause of premature death in MLS. Cardiovascular events, epileptic seizures, and aspiration pneumonia may be the major causes of death in older individuals [Danek, Rubio et al 2001; Jung, Hergersberg et al 2001].
Females. Females who are heterozygous for an XK mutation have mosaicism for the Kell system blood group and RBC acanthocytosis by virtue of X-chromosome inactivation [Oyen et al 1996; Kawakami et al 1999; Jung, Hergersberg et al 2001; Singleton et al 2003].
The most probable reason for the following clinical manifestations observed in female heterozygotes is skewed X-chromosome inactivation, in which the X chromosome with the normal XK allele is inactivated by chance in a disproportionately large number of cells [Ho et al 1996].
One female heterozygote developed the typical MLS phenotype [Hardie et al 1991].
A female heterozygote had acanthocytosis, a bimodal pattern of Kell blood group antigens on flow cytometry, elevated serum creatine kinase concentrations, and a tic-like movement disorder [Kawakami et al 1999].
In one family, female heterozygotes had slight cognitive deficits and reduced striatal glucose uptake in the absence of an obvious movement disorder [Jung, Hergersberg et al 2001].
Data presently available are insufficient to draw conclusions about genotype-phenotype correlations in McLeod neuroacanthocytosis syndrome [Danek, Rubio et al 2001]. MLS shows considerable phenotypic variability, even between family members with identical XK mutations [Danek, Tison et al 2001; Walker et al 2006].
Only three XK missense mutations have been reported so far. Although rare, they are potentially useful in the elucidation of structural and functional relationships.
The 1061G>A mutation (resulting in E327K) was associated with an isolated immunohematologic phenotype without evidence for muscular, central, and peripheral nervous system involvement [Jung et al 2003]. Similarly, an individual with the 746C>G mutation (resulting in R222G) did not show significant neurologic or systemic abnormalities.
In contrast, the individual bearing the XK 962T>C mutation (resulting in C294R) manifested the full McLeod neuroacanthocytosis syndrome.
All three of the missense mutations occurred in the transmembrane domains and on highly conserved amino-acid residues in the proteins that are evolutionarily related to XK, suggesting possible important roles in structure or function. E327 and R222 residues may be involved in the basic structure of XK rather than in its function, and the C294 residue, which is conserved specifically in the XK family, may be critical for normal function [Walker et al 2007].
One additional McLeod mutation, a single base substitution in an intron near a splice junction (IVS2+5G>A, resulting in alternative splicing and some degree of normal splicing) does not appear to lead to any significant neurologic abnormalities [Walker et al 2007].
In males, the penetrance of neurologic and neuromuscular manifestations of MLS is high after age 50 years.
The term "neuroacanthocytosis" refers to several genetically and phenotypically distinct disorders [Danek et al 2004, Danek et al 2005]; see Differential Diagnosis.
The term "McLeod blood group phenotype" describes the immunohematologic abnormalities consisting of absent expression of Kx RBC antigen and reduced expression of Kell RBC antigens in the index case originally described by Allen et al (1961).
The terms "Kell blood group precursor" and "Kell blood group precursor substance" for the XK protein or the Kx RBC antigen, respectively, are incorrect and no longer in use.
Confusion in terminology has arisen because, in the past, many reports of males with the McLeod blood group phenotype, including the index case, described only hematologic findings, and no neurologic or neuroimaging work-up was performed in these individuals [Allen et al 1961, Symmans et al 1979, Bertelson et al 1988, Lee et al 2000a]. In some of these individuals, however, neurologic manifestations were noted during long term follow-up [Bertelson et al 1988; Danek, Rubio et al 2001]. Available data indicate that most males with the "McLeod blood group phenotype" will develop clinical symptoms of McLeod neuroacanthocytosis syndrome [Bertelson et al 1988; Hardie et al 1991; Danek, Rubio et al 2001; Jung et al 2001]. However, even after long-term follow-up neurologic and neuromuscular symptoms may be absent or only minor in some males with the "McLeod blood group phenotype" [Jung et al 2003, Walker et al 2007].
The prevalence of MLS cannot be determined based on the data available from the approximately 150 cases known worldwide.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Hutington disease (HD). HD is the prototypic hereditary chorea syndrome and manifests with progressive movement disorder and cognitive and psychiatric disturbances. The mean age of onset of HD ranges from 35 to 44 years, and the median survival is 15 to 18 years after onset. The symptoms of HD and MLS may be indistinguishable. However, autosomal dominant inheritance and anticipation in HD and the presence of seizures, elevated serum CK concentrations, and manifest myopathy in MLS may help distinguish the two conditions. Diagnosis of HD rests on the detection of an expansion of the CAG trinucleotide repeat in the HD gene.
Other neuroacanthocytosis syndromes. Neurologic disorders associated with RBC acanthocytosis have been summarized as neuroacanthocytosis syndromes [Danek et al 2004, Danek et al 2005].
One group of neuroacanthocytosis syndromes is associated with lipid malabsorption and primarily affects the spinal cord, cerebellum, and peripheral nervous system. The neurologic findings include: (1) a progressive spinocerebellar degeneration with gait ataxia, dysmetria, and dysarthria; (2) a demyelinating sensorimotor and axonal peripheral neuropathy with hyporeflexia and diminished vibration and position sense; (3) rarely, pyramidal tract signs; and (4) rarely, cranial nerve involvement [Kane & Havel 1995]. These disorders include the following:
Hypobetalipoproteinemia type 1 (FHBL1)
Hypobetalipoproteinemia type 2 (FHBL2)
Abetalipoproteinemia (ABL, Bassen-Kornzweig disease)
FHBL1, FHBL2, ABL, and MLS share the findings of acanthocytosis, dysarthria, neuropathy, and areflexia but differ in that ABL and HBL have pigmentary retinopathy and do not have basal ganglia involvement. ABL and HBL are caused by mutations affecting the microsomal triglyceride transfer protein causing vitamin E deficiency. ABL is inherited in an autosomal recessive manner. HBL has clinical manifestations in both the homozygous and heterozygous states.
A second group of neuroacanthocytosis syndromes predominantly affects the central nervous system, in particular the basal ganglia, resulting in a chorea syndrome resembling Huntington disease (Table 2). These disorders include the following:
Chorea-acanthocytosis (ChAc) is characterized by a progressive movement disorder and an often subclinical myopathy. The movement disorder is mostly chorea. In contrast to MLS, some individuals present with a Parkinsonian syndrome. In addition, dystonia is common and affects the trunk and in particular the oral region and the tongue, causing dysarthria and serious dysphagia with resultant weight loss. Habitual tongue and lip biting are characteristic. Progressive cognitive and behavioral changes resemble a frontal lobe syndrome. Seizures are observed in almost half of affected individuals and can be the initial manifestation. Myopathy results in progressive distal muscle wasting and weakness. Mean age of onset is about 35 years, although ChAc can develop as early as the first decade or as late as the seventh decade. ChAc runs a chronic progressive course and may lead to major disability within a few years; life expectancy is reduced. Diagnosis of ChAc rests on presence of typical clinical and MRI findings. Molecular genetic testing of VPS13A is performed on a research basis only. Testing for RBC expression of chorein, the VPS13A product, is a useful alternative [Dobson-Stone et al 2004]. Inheritance is autosomal recessive.
Huntington disease-like 2 (HDL2) manifests in the third to fourth decade and has a progressive course over 10 to 15 years [Margolis et al 2001]. Phenotypic variation is marked. Dystonia is a frequent finding, and presentation with chorea or Parkinsonism may change with evolution of the disease. With the exception of one Mexican pedigree, all affected individuals reported to date have been of African ancestry [Margolis et al 2001, Stevanin et al 2002, Walker et al 2003]. Some individuals with HDL2 have RBC acanthocytosis. Diagnosis of HDL2 rests on detection of an expansion of the CTG trinucleotide repeat in the JPH3 gene. Inheritance is autosomal dominant.
Pantothenate kinase-associated neurodegeneration (PKAN) [neurodegeneration with brain iron accumulation (NBIA), formerly Hallervorden-Spatz syndrome] is characterized by progressive dystonia and basal ganglia iron deposition with onset usually occurring before age ten years. Dysarthria, rigidity, and pigmentary retinopathy are common. About 25% of individuals have an "atypical" presentation with onset after age ten years, prominent speech defects, psychiatric disturbance, and more gradual progression of disease [Swaiman 2001, Zhou et al 2001]. Acanthocytosis is observed in at least 8% of individuals. The so-called 'eye of the tiger' sign on MRI is characteristic [Hayflick et al 2003]. Diagnosis of PKAN rests on the presence of typical clinical and MRI findings. About 50% of affected individuals have identifiable mutations in the PANK2 gene. Inheritance is autosomal recessive.
HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) is allelic with PKAN [Ching et al 2002, Houlden et al 2003]. The continued use of this term is discouraged particularly since "hypoprebetalipoproteinemia" is not a meaningful entity.
Table 2 summarizes the diseases in the differential diagnosis of MLS.
Disease | Gene Symbol | Chromosomal Locus | Protein Name | OMIM |
---|---|---|---|---|
Autosomal Dominant | ||||
Huntington disease | HD | 4p16.3 | Huntingtin | 143100 |
HDL1 (Huntington disease-like 1) | PRNP | 20pter-p12 | Major prion protein | 603218 |
HDL2 | JPH3 | 16q24.3 | Junctophilin-3 | 606438 |
Dentatorubral-pallidoluysian atrophy | ATN1 | 12p13.31 | Atrophin-1 | 125370 |
Neuroferritinopathy | FTL | 19q13.3-q13.4 | Ferritin light chain | 606159 |
Spinocerebellar ataxia type 3 | ATXN3 | 14q24.3-q31 | Ataxin-3 | 109150 |
Spinocerebellar ataxia type 17 | TBP | 6q27 | TATA box-binding protein | 600075 |
Benign hereditary chorea (BHC) | TITF-1 | 14q-13.1 | Thyroid transcription factor 1 | 118700 |
Autosomal Recessive | ||||
Chorea-Acanthocytosis | VPS13A | 9q21 | Chorein | 200150 |
HDL3 | HDL3 | 4p15.3 | Protein not identified | 604802 |
Wilson disease | ATP7B | 13q14.3-q21.1 | Copper transporting ATPase 2 | 277900 |
Aceruloplasminemia | CP | 3q23-q24 | Ceruloplasmin | 604290 |
Pantothenate kinase-associated neurodegeneration, including HARP | PANK2 | 20p13-p12.3 | Pantothenate kinase 2 | 234200 |
Infantile neuroaxonal dystrophy (Karak syndrome) | PLA2G6 | 2q13.1 | 85-kd calcium-independent phospholipase A2 | 256600 (608395) |
X-Linked | ||||
X-linked dystonia-parkinsonism syndrome (Lubag) | DYT3 | Xq13.1 | Multiple transcript system DYT3 | 314250 |
Lesch-Nyhan syndrome | HPRT1 | Xq26-q27.2 | Hypoxanthine guanine phosphoribosyl-transferase 1 | 300322 |
To establish the extent of disease in an individual diagnosed with McLeod neuroacanthocytosis syndrome (MLS):
Neurologic and neuropsychological examination
Serum CK concentration and liver function tests
Cardiac examination, including ECG, Holter ECG, and echocardiography
Cerebral MRI and electroencephalography
Dopamine antagonists such as tiapride, clozapine, or quetiapine, as well as tetrabenazine to ameliorate the choreatic movement disorder
Treatment of psychiatric problems according to the clinical presentation
Treatment of cardiac abnormalities according to the clinical and/or ECG presentation
Anti-epileptic drugs (AEDs) for treatment of seizures
Extended and continuous multidisciplinary psychosocial support for affected individuals and their families
The Kell blood group system can cause strong reactions to transfusions of incompatible blood and severe anemia in newborns of Kell-negative mothers [Lee et al 2000b].
Individuals with MLS who receive multiple transfusions are at risk for transfusion hazards caused by allogenic antibody production. If possible, Kx-negative blood or banked autologous blood should be used for tranfusions.
Early recognition and treatment of cardiac problems and seizures is important, as these potential complications may be severe and can even cause premature death [Danek, Rubio et al 2001].
If no pathologic findings are identified at initial evaluation, cardiac examinations (Holter ECG and echocardiography) should be repeated every two to three years.
In the case of suspected epilepsy, EEG should be performed. If treatment with AEDs is necessary, surveillance of laboratory parameters and serum concentrations should be done according to the substance used.
Since one individual with MLS developed life-threatening rhabdomyolysis, serum CK concentrations should be carefully monitored, in particular if excessive movement disorders are present or if neuroleptic medications are being used [Jung & Brandner 2002].
Blood transfusions with elective surgery should be autologous when possible to avoid sensitization.
Treatment with neuroleptics, in particular clozapine, should be carefully monitored.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
McLeod neuroacanthocytosis syndrome (MLS) is inherited in an X-linked manner.
This section is written from the perspective that molecular genetic testing for this disorder is available on a research basis only and results should not be used for clinical purposes. This perspective may not apply to families using custom mutation analysis. —ED.
Parents of the proband
The father of an affected male will not have the disease nor will he be a carrier of the mutation.
In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the affected male may have a de novo gene mutation and thus the mother is not a carrier. One de novo mutation in MLS has been described [Supple et al 2001].
If a woman has more than one affected son and the disease-causing mutation cannot be detected in DNA extracted from her leukocytes, she may have germline mosaicism. However, no data regarding germline mosaicism in MLS are available to date.
When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:
The affected male has a de novo disease-causing mutation in the XK gene and his mother is not a carrier.
His mother has a de novo disease-causing mutation in the XK gene, either (a) as a germline mutation (i.e., occurring at the time of her conception and thus present in every cell of her body); or (b) as germline mosaicism (i.e., present in some of her germ cells only).
His mother has a disease-causing mutation that she inherited from a maternal female ancestor.
Sibs of the proband
The risk to sibs depends upon the carrier status of the mother.
If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually not be affected.
If the disease-causing mutation has not been identified in the mother's DNA, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
Offspring of the proband. Affected males will pass the disease-causing mutation to all of their daughters and none of their sons.
Other family members of the proband. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending upon their gender, may be at risk of being carriers or of being affected.
Carrier testing using molecular genetic techniques is currently not offered because it is not clinically available.
Carrier testing using immunohematologic techniques is available in specialized immunohematology laboratories.
Family planning. The optimal time for determination of genetic risk is before pregnancy.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which molecular genetic testing is available on a research basis only. See DNA Banking for a list of laboratories offering this service.
No laboratories offering molecular genetic testing for prenatal diagnosis of MLS are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering custom prenatal testing, see .
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see .
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Gene Symbol | Chromosomal Locus | Protein Name |
---|---|---|
XK | Xp21.2-p21.1 | Membrane transport protein XK |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot
314850 | KELL BLOOD GROUP PRECURSOR; XK |
Gene Symbol | Locus Specific | Entrez Gene | HGMD |
---|---|---|---|
XK | XK | 314850 | XK |
For a description of the genomic databases listed, click here.
Note: The terms "Kell blood group precursor" for the XK protein or the Kx RBC antigen, respectively, are incorrect and should no longer be used.
The XK protein is predicted to have ten transmembrane domains and the structural characteristics of prokaryotic and eukaryotic membrane transport proteins [Ho et al 1994]. The XK protein is linked to the Kell glycoprotein by a single disulfide bond (XK Cys347- Kell Cys72) when they are co-expressed, and the two proteins most probably form a functional complex [Russo et al 1998]. XK and Kell are predominantly expressed in erythroid tissues, but the expression in non-erythroid tissues differs. XK is ubiquitously expressed in many other tissues, especially in high amounts in skeletal muscle and brain. On the other hand, Kell is expressed in very small amounts in different tissues including human brain and skeletal muscle. XK and Kell are both expressed in testis [Russo et al 2000; Camara-Clayette et al 2001; Jung, Russo et al 2001]. However, recent studies by in situ hybridization histochemistry (ISHH) and RT-PCR of mouse tissues indicated that Kell is not present in brain and skeletal muscle. XK is expressed in various cerebral regions with high amounts in pontine region, olfactory lobe, and cerebellum [Lee et al 2006]. It is speculated that isolated XK may have a different function than when it is complexed with Kell.
The Kell protein is a member of M13 family of zinc endopeptidases and is an endothelin-3 converting enzyme generating the bioactive endothelin-3 [Lee et al 1999, Lee et al 2000b]. Experimental studies demonstrated that endothelin is a neurotrophic factor at low concentrations and a cytotoxic factor at high concentrations, suggesting that endothelin-related mechanisms could be implicated in neurodegeneration [Ehrenreich et al 2000]. However, no acanthocytosis or cerebral or neuromuscular signs and symptoms have been described in individuals with absent Kell membrane glycoproteins caused by the so-called KEL null (K0)-phenotype [Lee et al 2000a].
XK dysfunction may cause apoptosis dysregulation and should be considered as a major cause of myopathy and striatal neurodegeneration in McLeod neuroacanthocytosis syndrome. The XK protein is a member of XK family that comprises XK, XPLAC, and XTES. Phylogenetic analysis has shown that XK and XPLAC are present in vertebrate fish while XTES is found only in primate testis [Calenda et al 2006]. In addition to the XK family, the phylogram contained five gene clusters distantly related to the XK and ced-8 gene clusters which are present in the nematode C. elegans. The ced-8 domain (FLxxxPQL[x]nWxxxxxxxR[x]nHP) is a typical signature sequence found in all members of the XK-related gene clusters. The ced-8 protein of the nematode C. elegans shares a low homology with XK protein but the topological structure is similar to XK. The ced-8 protein is reported to play a role as a cell death effector downstream of the caspase ced-3 [Stanfield & Horvitz 2000]. The human homologue of ced-3, caspase-8, plays a crucial role in the striatal neurodegeneration of Huntington disease [Hackam et al 2000, Gervais et al 2002].
Normal allelic variants: The XK gene is organized in three exons. Only one splicing variant is known [Walker et al 2007].
Pathologic allelic variants: Table 3 (pdf) summarizes the mutations identified in the XK gene. See also Genomic Databases or Walker et al (2007), table.
Normal gene product: XK is a 444-amino acid protein. The exact function of the XK protein is not known, but its predicted structure suggests that it is a membrane transport protein [Ho et al 1994].
Abnormal gene product: Most XK mutations predict an absent or truncated XK protein devoid of the Kell protein-binding site, suggesting a loss of function. For missense mutations, see Genotype-Phenotype Correlations.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select for the most up-to-date Resources information.—ED.
Advocacy for Neuroacanthocytosis Patients
32 Launceston Place
London W8 5RN United Kingdom
Phone: (+44) 20 7409 0092
Fax: (+44) 20 7495 4245
Email: glenn@naadvocacy.org
www.naadvocacy.org
Cardiomyopathy Association
40 The Metro Centre
Tolpits Lane
Watford Herts WD18 9SB
United Kingdom
Phone: (+44) 1923 249 977
Fax: (+ 44) 1923 249 987
Email: info@cardiomyopathy.org
www.cardiomyopathy.org
Huntington's Disease Society of America (HDSA)
HDSA has material on their site to assist in caretaking issues for adult onset progressive neurologic diseases.
www.hdsa.org
WE MOVE (Worldwide Education and Awareness for Movement Disorders)
204 West 84th Street
New York NY 10024
Phone: 800-437-MOV2 (800-437-6683)
Fax: 212-875-8389
Email: wemove@wemove.org
www.wemove.org
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
Adrian Danek, MD (2004-present)
Carol Dobson-Stone, DPhil (2004-present)
Hans H Jung, MD (2004-present)
Sohee Lee, PhD (2007-present)
Colvin M Redman, PhD; New York Blood Center (2004-2007)
26 March 2007 (me) Comprehensive update posted to live Web site
3 December 2004 (ca) Review posted to live Web site
8 April 2004 (hj, ad) Original submission