Clinical manifestations

Presentation and course

In a case series of 19 patients with neuroacanthocytosis, the mean age of onset was 32 years (range 8 to 62 years), and the clinical course was progressive but with marked phenotypic variation (26). There have been increasing numbers of studies revealing marked phenotypic variation (104). In a report with 2 siblings with neuroacanthocytosis, one presented with dystonia, lip biting, and eating difficulties, whereas the other had generalized seizures several years before developing choreatic movements (01). Clinical diagnostic criteria have been proposed including the following: adult onset, progressive orofacial dyskinesia and choreatic movements, tongue or lip biting, denervation, acanthocytosis of greater than 3%, and elevated creatine phosphokinase (81). Myopathy, including dilated cardiomyopathy, has been also reported to be part of the peripheral spectrum of manifestations associated with neuroacanthocytosis (35; 82). Cases have been reported in which acanthocytes did not appear until later in the course of the disease, well after the manifestation of the clinical syndrome (87). Likewise, the acanthocyte count does not predict disease severity (72).

Psychiatric. Behavioral, emotional, and psychiatric manifestations are common. In the original family there was a report of a schizophreniform disorder. Cases of psychosis, obsessive-compulsive disorder, depression, and paranoia have been reported (75; 47; 26; 57). Self-mutilative behavior is characteristic, and compulsive head-banging or biting of tongue, lips, and fingers can lead to severe injury. Some patients exhibit obsessive-compulsive behaviors when treated with agents such as citalopram (25). Obsessive-compulsive disorder may herald the development of chorea-acanthocytosis, as early as the age of 10 years (108). Antisocial behavior, though not common, is noted in some patients (11). Dysphoria, anxiety disorder, and marked emotional lability have been prominent in patients with self-mutilation behavior (21). These appear to be similar to the case reported by Wyszynski and colleagues:

Some patients progress through the stages of the disease without any behavioral or mood disorder. In a series of 19 cases, half were described as having behavior, personality, and cognitive impairment (26).

Cognition. Dementia is often reported, in many cases, with particular problems in psychometric tests of attention and planning, consistent with frontal-subcortical dysfunction (26; 37).

In one case, a 50-year-old man with McLeod syndrome presented with a progressive, “restlessness and impulsivity,” chorea, dysarthria, areflexia, and unsteady gait as an adult. At the age of 40, he began hoarding items including object from the neighbors’ trash. At 45 he lost his job as a chef due to disorganization. Cognitive testing revealed: difficulty switching tasks, with “preservation of intellectual capacity, with relative deficits in the areas of attention, verbal fluency and verbal memory…perseverative at times.” Testing repeated 4 years later suggested deterioration in planning and sequential thinking. Patients are reported with language, memory, and executive dysfunction (113).

Epilepsy. A considerable proportion of patients with neuroacanthocytosis have seizures (26). Rarely, epilepsy can be the presenting feature (84). Familial temporal lobe epilepsy was reported in kindreds with chorea-acanthocytosis (03). Further, the patients required multiple antiepileptic medications for control.

Involuntary movement disorder. Involuntary movements have been described by a variety of authors: "jerky movements of the limbs" (20); "sucking, chewing and smacking movements of the mouth" (07); "shoulder shrugs, flinging movements of the arms and legs and thrusting movements of the trunk and pelvis" (21); "wild lurching truncal and flinging proximal arm movements that occurred with minimal stimulation" (21). Oral-facial dyskinesias; tic-like, repetitive, and stereotyped movements; and involuntary vocalizations are common.

Occasional patients have primarily dystonia. A very rare syndrome is that of the autosomal dominant familial acanthocytosis with paroxysmal exertion-induced dyskinesias and epilepsy (90).

Shibasaki and colleagues compared the movements in patients with neuroacanthocytosis with those seen in patients with Huntington disease (86). Truncal movements were more prominent in neuroacanthocytosis. Mental effort and commands to suppress movements were effective in reducing the frequency of movements in patients with neuroacanthocytosis but not Huntington disease. Studies of EEG activity time-locked to choreic movements indicated that a negative potential change, resembling the Bereitshaft potential that precedes voluntary movement, was seen in patients with neuroacanthocytosis but not in patients with Huntington disease.

Disordered voluntary movement. Lack of oral facial coordination is prominent in patients with neuroacanthocytosis. Dysarthria and dysphagia occur in most cases. We saw one patient who continued to speak as he inhaled and exhaled (paradoxical speech). Many patients have a characteristic eating disorder in which food is propelled out of the mouth by the tongue, the so-called “feeding dystonia.” Patients may learn to swallow with their head tipped back "facing the ceiling" or place a spoon over the mouth to prevent the food from escaping (21; 05). Bradykinesia in concert with chorea is common, as in Huntington disease, and may become more prominent in the later stages of the illness (88). Gait is disordered and features a combination of involuntary movements and poor postural reflexes. The combination of chorea, dystonia, and exaggerated extensor posturing can result in a bizarre ambulation that may mimic a functional disorder, referred to as “rubber man” gait (95).

Cases have been described with opisthotonic posturing and concurrent blepharospasm. (53). Authors have proposed that a new gait type, referred to as “stutter-step,” may be shared between neuroacanthocytosis and Huntington disease (93). Stutter-step gait is defined by “reduced stride length and cadence, hesitation (especially during heel‐off terminal stance phase), hyperflexion of the knee during mid‐stance phase, and asymmetric weight bearing on the foot during foot‐flat or loading response phase.”

Remarkably, severely disabled patients with neuroacanthocytosis can sometimes suppress their movements to perform a coordinated act such as writing or speaking clearly for short periods.

Ocular findings. These include impaired saccades, pursuit abnormalities, limited upgaze, apraxia of gaze, convergence difficulties, blepharospasm, and voluntary vertical gaze paresis (88; 26). Gradstein and colleagues evaluated eye movements by neuro-ophthalmologic exam and the magnetic search coil technique in 3 patients with genetically confirmed chorea-acanthocytosis (23). Testing revealed saccades (vertical more than horizontal), pursuit deficits, and fixation instability defined by 35 or more square wave jerks per minute, or continuous square wave oscillations. Square wave jerks are presumed to occur when there is a loss of inhibition at the level of saccadic burst neurons in the brainstem.

Neuromuscular weakness. Peripheral neuropathy with distal sensory loss and hypo- or areflexia is common in neuroacanthocytosis. Electrophysiological studies show increased duration and amplitude of motor unit potentials indicative of chronic denervation. Nerve conduction velocities are normal; sensory potentials reduced. Posterior column neuropathy is seen in abetalipoproteinemia (112). On muscle biopsy fiber type grouping is present, suggestive of neurogenic atrophy (07), or central nucleation, and fiber splitting suggestive of myopathic changes (49). One case report showed slight volumetric variations in the mitochondria, dilatation of the T tubules, and vesicular sarcoplasmic reticulum with axonal degeneration by electron microscopy (01). Loss of large myelinated fibers and unmyelinated fibers is seen on nerve biopsy (26). The findings are consistent with an axonal, sensorimotor neuropathy. In some cases, a motor neuron disorder has been suggested. Depletion of anterior horn cells was reported in 2 patients (65), but no obvious abnormality was seen in another case (26). Primary skeletal muscle involvement has been reported in chorea-acanthocytosis, wherein chorein is unevenly distributed along the sarcolemma of type 1 fibers, a finding not present in Huntington disease, McLeod syndrome and normal controls (82). Two brothers, the product of consanguineous parents, with the combination of Tourette syndrome, acanthocytosis, motor neuron disease, and progressive parkinsonism were reported (88). EMG was performed on one of the brothers and revealed diffuse fasciculations and denervation. Nerve conduction velocity studies were normal. Neuromuscular involvement is commonly associated with McLeod syndrome and autosomal-recessive chorea-acanthocytosis (55). Chorea-acanthocytosis muscle biopsy may reveal variation in size of muscle fibers, small angular fibers, and fibers with internal nuclei by light microscopy and nemaline rods by electron microscopy (92). There is a report of overlapping phenotype with LGMD2A (89). In this Caucasian family from Brazil, 6 members had concurrent calpainopathy (CAPN3 mutation confirmed), as well as XK gene mutations consistent with McLeod syndrome. A novel mutation in the XK gene is reported in a Japanese family with overlap between neuroacanthocytosis and neuromuscular disease characterized by proximal weakness, hyporeflexia, and hyperCKemia, as well as muscle biopsy revealing increased variability in fiber diameter with small rounded fibers and a mild increase of internal nuclei (98). Interestingly, the McLeod locus is localized on chromosome Xp21, adjacent to the dystrophin gene locus for Duchenne muscular dystrophy, although staining for dystrophin in both of these reports was normal.

Cardiac findings. About half of patients with McLeod syndrome may develop cardiomyopathy, and sudden cardiac death may result (63). There are reports of cardiomyopathy in patients with autosomal-recessive chorea-acanthocytosis as well (35).

Prognosis and complications

The disease is invariably progressive, leading to a state of complete dependence for activities of daily living and eventual death. Communication becomes difficult, and self-mutilative behavior may lead to infectious complications. Swallowing disorder becomes severe and usually leads to aspiration pneumonia. Isolated cases of cardiomyopathy have been reported.

Clinical vignette

A 30-year-old male police officer of French Canadian origin with a negative family history for neuroacanthocytosis presented to our clinic for evaluation of his abnormal movements. At age 25 he developed a “dance-like” gait and very sloppy handwriting. Due to concerns by his superiors, he was taken off patrol and given a desk job. Over the next several months he began to “chatter” and hum most of the time and exhibited echo- and palilalia. A psychological evaluation, including the Minnesota Multiphasic Personality Inventory, was interpreted as normal and the symptoms were attributed to stress. However, the patient continued to worsen and by the age of 27 he developed abnormal movements, particularly of the arms. While walking he would adduct the shoulders and flex the elbows and wrists. His stride included side-to-side movements with frequent “turning-in” of the left foot, resulting in falls. By age 28 he frequently produced clucking noises with his tongue, smacking of the lips, and had irregular respirations. Haldol initially improved his gait and his left foot “straightened out.” However, 6 weeks after initiation of therapy, he suddenly deteriorated for no apparent reason, with increased clicking, smacking, and the new symptom of biting the buccal mucosa and tongue to the point of bleeding. Bruxism began, causing him to break his fillings and necessitating multiple dentist visits. During this time he also noted a loss of dexterity with fine motor movements as well as a complex tic of pinching. At the age of 29 neuropsychological testing revealed a performance IQ of 82, verbal IQ of 97, and memory quotient of 105. Peripheral smear revealed marked acanthocytes. Bone marrow, serum lipoprotein electrophoresis, alpha-tocopherol, ceruloplasmin, and copper were normal. Creatine phosphokinase was elevated at 313. MRI of the brain was interpreted as a “30%” reduction of the caudate.” Haloperidol was discontinued and multiple medications were attempted and discarded due to intolerable side effects. These included: thioridazine, clonazepam, reserpine, clonidine, and fluphenazine.

At the age of 30, he presented to our clinic for initial consultation with his wife, who noted a 35-pound weight loss over the preceding 7 months, weakness climbing stairs, forgetfulness, inappropriate behavior, and the use of a specific 4-letter word multiple times per hour. Neurologic exam revealed a somewhat asthenic man who was in obvious distress due to his constant involuntary movements. Behavior was childish and speech markedly impaired, with stuttering and palilalia. He would complete every phrase with repetition of the last word, “yes, yes, yes,” humming, or other involuntary vocalizations. Frequent facial grimacing and involuntary irregular frontalis contraction with retraction of the corners of the mouth, lip smacking, tongue protrusion, and flexion of the neck were noted. Marked atrophy of the hands and feet was present. Gait was choreatic, dance-like, and with frequent side-to-side trunk extension, superimposed with continuous, non-patterned jerk-like movements of the arms and legs. Dystonic circumduction of the left leg was present, with inversion of the left foot, and eversion of the right foot. Our lab evaluation revealed a creatine phosphokinase over 5000, elevated LFTs, and 13% acanthocytes. He was treated with tetrabenazine with initial success in reducing his abnormal movements.

Biological basis

Etiology and pathogenesis

The various illnesses that cause the syndrome of neuroacanthocytosis are most often genetically based, frequently involving red blood cell structural or membrane problems, though a complete understanding of the gene products is often lacking.

Chorea-acanthocytosis. In 11 families from 6 different countries, autosomal-recessive chorea-acanthocytosis (OMIM #200150) has been mapped on chromosome 9q21 (76). Formerly known as “CHAC,” the VPS13A gene exists on human chromosome 9q21 (OMIM *8605978), is composed of 73 exons, and encodes a 3174 amino acid protein termed chorein (73). The protein in man shares a great degree of similarity with the protein Vps13 of S. cerevisiae, which has been found to take part in protein sorting at the level of the trans-Golgi network. Investigators have shown that human chorein is expressed in a variety of cell lines, including primary skin fibroblasts and erythrocytes (16). VPS13A mutations lead to absence or marked reduction of chorein expression, and chorein can be detected in association with the erythrocyte membrane. In McLeod syndrome and Huntington disease, patient samples showed normal chorein expression levels. This study demonstrated the efficacy of Western blotting of the chorein protein as a screening method for autosomal-recessive chorea-acanthocytosis. In most cases in which consanguinity is present, and in all cases that occur in a single generation, autosomal recessive inheritance is likely. Data show that chorein is involved in the exocytosis of dopamine containing dense core vesicles of neuronal cells (32). Among patients with chorea-acanthocytosis, cortical inhibitory networks are disrupted (18). Three Irish siblings have been reported with genetically confirmed ChAc, and 2 of the siblings had a coexisting Huntington disease allele with a 37 repeat CAG expansion that is considered abnormal with reduced penetrance (59).

In some cases the disorder is inherited in an autosomal dominant fashion (20). One Japanese family with Alzheimer disease had typical autosomal-recessive chorea-acanthocytosis phenotype (79). A single heterozygous mutation in the last nucleotide of exon 57 of the CHAC gene of the affected members was found, which the authors predict induces skipping of exon 57 and causes a frameshift. This mutation then may lead to premature termination of translation of chorein mRNA. One other autopsy and genetically proven case has been reported to be associated with an autosomal dominant heterozygous mutation (G-A) at nucleotide position 8,295 in exon 57 of VPS13A (33). Two novel heterozygous mutations in the VPS13A gene have recently been described (100).

Rare sporadic cases have been reported (26).

Over 70 mutations are known in the VPS13A gene. The protein product, chorein, is found in tissues related to the clinical findings of the disease: erythroid precursors, brain, and skeletal muscle. Chorein is a regulator of actin cytoskeleton in several cell lines and is associated with structural disorganization of cytoskeletal structures (31). Mutations are evenly dispersed along the length of the gene without clustering. Thus, no single genetic lesion seems to predominate, and the majority of mutations are unique to the proband or familial group. A variety of deletions, insertions, frameshift, and nonsense mutations are reported, possibly resulting in truncated protein products or abnormal mRNA.

Patterned after a common mutation found in Japanese patients, deletion in exons 60 and 61, Ehime mutation (97), a mouse model of the chorea-acanthocytosis form of neuroacanthocytosis has been developed (96). The deletion is present in the coding region of the gene, producing a truncated chorein protein. The mutant mice are viable and able to reproduce. However, once aged, the mutants gradually manifest morphological changes and abnormal movement, in a pattern similar to that seen in human patients. Brain pathology reveals apoptotic cells and marked gliosis in the striatum and substantia nigra pars reticulata, findings that correlate with human autopsy cases (26). Acanthocytes are present and neurochemical evaluation is consistent with a decrease in the dopamine metabolite, homovanillic acid, in the striatum and midbrain of the mutant mice, similar as well to findings in autopsy studies of human brain monoamines, which reflect depletion of homovanillic acid, as well as substance P (14). Investigation of 6 chorea-acanthocytosis patients with confirmed mutations in the VPS13A gene revealed symmetric atrophy of the caudate nuclei (28). In particular, the head of the caudate was showed the most significant atrophy, potentially damaging cortical-subcortical loops that could mediate cognitive and neuropsychiatric disorders found in the disease.

ELAC2 mutation. Biallelic mutation of the elaC ribonuclease Z 2 (ELAC2) gene results in an uncommon mitochondrial disease typified by hypertrophic cardiomyopathy, delayed psychomotor development, and death during childhood. Survival into adulthood is exceedingly rare. One case report described a 69-year-old hyperkinetic patient with chorea, progressive dementia, psychosis, and acanthocytosis (68).

McLeod syndrome. In this X-linked clinical syndrome, there is a lack of a common red blood cell antigen, Kx (74). Etiology is mutations in the XK gene (MIM 314850) encoding the Kx protein, a putative membrane transport protein of yet unknown function. In erythroid tissues, Kx forms a functional complex with the Kell glycoprotein. Red cells have decreased in vivo survival, and many are acanthocytes. Multiple members of the XK/Kell complex exist and researchers continue to identify new genes and their products (08; 45). McLeod syndrome is characterized by hemolysis, myopathy, cardiomyopathy, areflexia, elevated creatine phosphokinase, liver disease, and chorea, and there may be a progression after several years to a parkinsonian, hypokinetic phenotype (58). The gene defect has been mapped to a region of a few hundred kilobases on Xp21 (29). A case of McLeod syndrome affecting a female has been reported (26). Several novel mutations in the XK gene were described in 2019, including a case in a Vietnamese patient (40; 109; 111).

Neurodegeneration with brain iron accumulation. Acanthocytes may be seen in variants of neurodegeneration with brain iron accumulation, a progressive movement disorder (19) previously referred to as Hallervorden-Spatz syndrome. A genetic analysis of patients with typical and atypical neurodegeneration with brain iron accumulation found a common mutation in the pantothenate kinase gene (PANK2) (MIM 234200), on chromosome 20p13, and described as pantothenate kinase-associated neurodegeneration (PKAN), an autosomal recessive disorder. This cohort included one consanguineous family with pigmentary retinopathy and late onset dystonia consistent with the HARP syndrome (hyperprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration), with a homozygous missense mutation in PANK2 (115). HARP, NBIA1, and PKAN are now synonymous terms. The PANK2 gene is expressed ubiquitously, especially in the retina and the basal ganglia, correlating to the clinical features of the syndrome. In a large series of patients with a clinical presentation of neurodegeneration with brain iron accumulation and confirmed PANK2 mutations, 8% were found to have acanthocytosis (27). However, the true prevalence of acanthocytosis among patients with neurodegeneration with brain iron accumulation may be underestimated, as blood smear is often not included in the workup and labs may not stress the sample properly in order to detect this finding.

The etiology of the acanthocytosis that occurs in this disorder, and more importantly the relation of acanthocytosis to the neurodegeneration, has not yet been uncovered. However, the product of the PANK2 gene, PanK2 protein, was found to be localized to mitochondria of neurons in human brain, a point distinct from other pantothenate kinases (41).

PanK2 protein was further found to be sequentially cleaved at 2 sites by the mitochondrial processing peptidase. This produces a 48 kDa protein that catalyzes the initial step in coenzyme A (CoA) synthesis and utilizes feedback inhibition in response to acyl CoA. Some disease-associated point mutations cause marked reduction in catalytic activity. G521R, the most common mutation, results in profound instability of the intermediate PanK2 isoform and reduced production of the mature isoform. Kotzbauer suggests that this result implies that neurodegeneration with brain iron accumulation is caused by altered neuronal mitochondrial lipid metabolism caused by mutations disrupting PanK2 protein levels and catalytic activity. Note that over 100 mutations in the PANK2 gene have been detected.

Huntington disease-like 2. In some cases no family history of a similar disorder can be uncovered (21). The Huntington disease mutation has not been found in patients with clinical neuroacanthocytosis who have been tested. Interestingly, in a kindred with phenotypic presentation of neuroacanthocytosis and an autosomal dominant mode of inheritance, all 3 members had acanthocytes in peripheral smear. Neuropathological examination of the proband revealed intranuclear inclusion bodies in the cerebral cortex that were immunoreactive for polyglutamine repeats (105). The inclusion bodies were also immunoreactive for ubiquitin and torsin A, and affected members demonstrated an abnormality in the membrane protein, band 3, of the red blood cell membranes. The affected family members had variable features of chorea or parkinsonism and marked cognitive decline, but had no seizures, increased creatine kinase levels, or peripheral neuropathy commonly seen in the autosomal recessive forms. On further testing, this family was found to have an expansion of the CTG/CAG repeat within the junctophilin-3 gene (JPH3), consistent with the diagnosis of Huntington disease-like 2 (OMIM #606438) (103). The JPH3 gene is present on chromosome 16q24.3 (30). The repeat size ranges from 6 to 27 in normal individuals, with those affected having between 41 to 58 repeats (52). Of note, not all patients with clinical neuroacanthocytosis and genetically proven Huntington disease-like 2 will have acanthocytosis, whereas clinically unaffected siblings may (106). Junctophillin-3, the protein product of JPH3, is speculated to be associated with junctional membrane structures and likely is involved in calcium regulation. Predominantly found in the brain, the protein is further speculated to be involved in neural signaling. Knockout mice have impaired performance in motor coordination tasks (61).

Acanthocytosis is seen in disorders of membrane lipid as occur in abetalipoproteinemia and cirrhosis. The red cell membrane exhibits decreased deformity, and there is a decreased red cell survival. An expansion of lipid in the outer leaflet of the bilayer is considered a cause of red cell membrane buckling (85). Sakai and colleagues have reported that the red cells of patients with neuroacanthocytosis have altered phospholipid content, increased amounts of palmitic acid, and decreased amounts of stearic acid (67; 80).

Red cell shape is also dynamically determined by physical properties of the cell's cytoskeletal proteins.

In the McLeod syndrome red cell lipid analysis is normal, but the Kx antigen is lacking. Kx is a member of the Kell blood group family, which consists of 25 antigens, resulting from single-nucleotide polymorphisms (43). These molecules are important in transfusion medicine due to their highly immunogenic properties.

Cytoskeletal proteins have been reported to undergo self-digestion faster than the normal rate (04). Kay and colleagues have reported that there is an abnormal flux of chloride through the red cell membrane in neuroacanthocytosis (38). This may be due to an abnormality in the major anion transporter in erythrocytes, Band III. The group has reported circulating antibodies to Band III in patients with neuroacanthocytosis that react against brain Band III (38).

Many of the red cell cytoskeletal proteins are homologous to neuronal cytoskeletal or synaptic proteins. The functional alterations in the physical properties of the red cell cytoskeleton caused by phosphorylation events, and alterations in intracellular calcium have features in common with neuronal membrane-protein interactions. Altered cell kinases are likely involved in the generation of acanthocytosis as demonstrated via tyrosine-phosphoproteomic analysis (13).

Normal red cells undergo shape change from the normal biconcave disc shape to the crenated echinocyte (Burr cell) in the absence of ATP, dilution of serum proteins, increased intracellular calcium, or interaction with glass. In Levine's first report, an excess of Burr cells (echinocytes) in affected patients was mentioned (46). Some patients with the clinical syndrome of neuroacanthocytosis were found not to have acanthocytes on their peripheral smears but are siblings of patients with the same syndrome and acanthocytes (20; 62). Red cells from these patients can be more susceptible to developing echinocytic or true acanthocytic shapes when stressed by aging in the test tube, ATP depletion, interaction with glass, or dilution of serum proteins (21). Dilution of the patients' blood cells caused a greater percentage to change shape (20). Furthermore, this same metabolic insufficiency is assumed to also occur in the nervous system as well as in the red cell, leading eventually to neuronal death (21).

An immunohistochemistry study comparing skeletal muscle of normal controls with that of a McLeod patient has shown a strong type 2 fiber-specific staining of the Kx protein in the sarcoplasmic reticulum of normal muscles but not in the McLeod muscle. This suggests that the Kx protein (which is not detectable in McLeod syndrome) may have a crucial role in the maintenance of normal muscle structure and function and also provides a potential explanation to the type 2 fiber atrophy commonly seen in McLeod myopathy.

PET scans using 18-fluoro-deoxyglucose in McLeod syndrome have shown reductions in striatal FDG uptake (64). This is similar to PET studies using 18-fluoro-labeled dopa in patients with autosomal recessive neuroacanthocytosis showing reduced posterior putamen uptake. Unfortunately, this finding is nonspecific but suggests selective involvement of dopaminergic projections between the substantia nigra pars compacta and the posterior putamen in the pathogenesis of neuroacanthocytosis (70). FDG-PET in a patient with chorea-acanthocytosis has demonstrated hypometabolism in the bilateral caudate and putamina, with a mildly increased uptake in the pituitary gland (10).

The basis of the symptoms experienced by patients with neuroacanthocytosis can be explained by the pathology that demonstrates degeneration of peripheral nerve, muscle, and basal ganglia (07). Neuronal loss is seen in the caudate, putamen, globus pallidus, and substantia nigra (26). Like Parkinson disease, patients with akinetic-rigid features have severe neuronal loss in the ventrolateral region of the substantia nigra. Cerebellar atrophy in the presence of striatal atrophy has been reported as well (36).

Serum neurofilament light chain (sNfL) has been found to be significantly higher than controls in a case cohort of patients with chorea-acanthocytosis and in another cohort with the McLeod syndrome (69). Elevations of serum neurofilament light chain are thought to result from neuroaxonal damage in both the peripheral and the central nervous syndrome.

Epidemiology

Although rare, familial cases are reported in Europe, North America, Scandinavia, and Japan. Founder effect mutations are reported in some forms of the disease. For example, one study of 5 apparently unrelated French Canadian families with autosomal-recessive chorea-acanthocytosis describes the identification of the same deletion of VPS13A exons 70-73 (17). Unrelated Ashkenazi Jewish patients have been reported with the same mutation as well, also raising speculation for founder effect (51).

Prevention

There are no known preventive measures, and no known risk factors except positive family history of a similar disorder. Associated conditions include cardiomyopathy (usually in the McLeod phenotype) and hemolytic anemia in a subset of patients.

Differential diagnosis

Confusing conditions

Huntington disease is the major disorder that is misdiagnosed in patients with neuroacanthocytosis. Peripheral neuropathy, elevated creatine phosphokinase, self-mutilation, and acanthocytes are not seen in Huntington disease. Emotional disorder, cognitive dysfunction, chorea, dystonia, and bradykinesia are seen in both disorders. The caudate atrophy appears similar in the 2 conditions. However, the cortical, cerebellar, subthalamic, and brainstem involvement of Huntington disease is not typically seen in neuroacanthocytosis. The description of the unusual eating disorder of neuroacanthocytosis in which food is propelled out of the mouth by the tongue is also not usually seen in Huntington disease.

Huntington disease-like 2 (MIM 60526), a trinucleotide repeat expansion disease, is another disorder that shares many of the clinical manifestations of neuroacanthocytosis. In a family previously diagnosed with autosomal dominant chorea-acanthocytosis, Walker and colleagues reported finding a mutation in the junctophilin-3 (JHP3) in all family members. Acanthocytes were also found in a member of a family diagnosed as Huntington disease-like 2 (106). Acanthocytosis is not found in all patients with Huntington disease-like 2, and no correlation has been found between the size of the triplet expansion and the presence of acanthocytes (106).

Wilson disease or primary tic disorders are often considered in patients with early stage neuroacanthocytosis. Although vocalizations are common, coprolalia is not. Neuroacanthocytosis should always be considered in the differential of adult-onset symptoms consistent with tourettism. In a study of 155 patients presenting to the Baylor Movement Disorders Clinic, 2 patients (1.2%), were found to chorea-acanthocytosis (54). Because of the prominent orofacial dyskinesias and the common treatment of the psychiatric disorder with neuroleptics, tardive dyskinesia is often considered in the initial differential diagnosis.

Tongue protrusion dystonia, which is common in the neuroacanthocytosis syndromes, may also be seen in tardive dystonia, posthypoxic dystonia, and Lesch-Nyhan syndrome (78).

Associated or underlying disorders

Huntington disease is the major disorder that is misdiagnosed in patients with neuroacanthocytosis. Peripheral neuropathy, elevated creatine phosphokinase, self-mutilation, and acanthocytes are not seen in Huntington disease. Emotional disorder, cognitive dysfunction, chorea, dystonia, and bradykinesia are seen in both disorders. The caudate atrophy appears similar in the 2 conditions. However, the cortical, cerebellar, subthalamic, and brainstem involvement of Huntington disease is not typically seen in neuroacanthocytosis. The description of the unusual eating disorder of neuroacanthocytosis in which food is propelled out of the mouth by the tongue is also not usually seen in Huntington disease.

Huntington disease-like 2 (MIM 60526), a trinucleotide repeat expansion disease, is another disorder that shares many of the clinical manifestations of neuroacanthocytosis. In a family previously diagnosed with autosomal dominant chorea-acanthocytosis, Walker and colleagues reported finding a mutation in the junctophilin-3 (JHP3) in all family members. Acanthocytes were also found in a member of a family diagnosed as Huntington disease-like 2 (106). Acanthocytosis is not found in all patients with Huntington disease-like 2, and no correlation has been found between the size of the triplet expansion and the presence of acanthocytes (106).

Wilson disease or primary tic disorders are often considered in patients with early stage neuroacanthocytosis. Although vocalizations are common, coprolalia is not. Neuroacanthocytosis should always be considered in the differential of adult-onset symptoms consistent with tourettism. In a study of 155 patients presenting to the Baylor Movement Disorders Clinic, 2 patients (1.2%), were found to chorea-acanthocytosis (54). Because of the prominent orofacial dyskinesias and the common treatment of the psychiatric disorder with neuroleptics, tardive dyskinesia is often considered in the initial differential diagnosis.

Diagnostic workup

The diagnosis in persons with the appropriate clinical syndrome includes:

(1) The demonstration of caudate atrophy or signal intensity changes in the basal ganglia, by CT scan or MRI (28; 111). Progressive striatal atrophy may be seen in serial images (99). Morphometric change of the caudate has been tracked in 13 patients with genetically or biochemically confirmed ChAc versus 25 matched controls, revealing not only reduction in size but abnormality of shape of the head of caudate (107). In pantothenate kinase associated neurodegeneration, the so-called “eye of the tiger” may be present (27). PET in a few cases has provided in vivo evidence of reduced glucose metabolism and dopamine function affecting the striatum.

(2) The demonstration of acanthocytes (greater than 3%) on the peripheral blood smear. If acanthocytes are not present but clinical suspicion remains high, then a dilution test of the patient's blood, 1:1 with normal saline along with a control, is warranted. The development of greater than 15% echinocytes on a wet preparation within 5 minutes (after which time cells are placed in fixative) or significant percentage of true acanthocytes on scanning electron microscopy should be considered confirmatory for the disorder (21). A screening test including normal values and test specificity/sensitivity using a prospective reader-blinded study was proposed to increase sensitivity for detecting acanthocytes (91). This study indicated that isotonic dilution of the blood sample and the wet preparation of the blood smear between 2 glass slides are superior to all other techniques with respect to the test sensitivity. Red cells from patients with Huntington disease do not have this same propensity for shape change with aging or dilution of serum proteins.

Note that acanthocytes are not always present early in the clinical disease (87). Also note that acanthocytes can be seen in a variety of other conditions such as hepatic failure, severe renal disease, hypothyroidism, anemia, postsplenectomy, vitamin E deficiency, and anorexia nervosa, or with exposure to certain medications such as prostaglandins or those that alter lipid physiology.

(3) For every patient with suspected neuroacanthocytosis, an adequate Kell blood group typing should be undertaken. Routine testing many not be sufficient. This test should utilize specific antibodies to rule out or confirm the weak expression of Kell antigens, which are common to McLeod syndrome erythrocyte phenotype (12).

(4) Elevated creatine phosphokinase.

(5) Electrophysiological confirmation of denervation and axonal sensorimotor neuropathy.

(6) EEG for evidence of epileptiform activity.

(7) Genetic testing for the Huntington disease, Huntington disease-like 2, and Dentatorubral-pallidoluysian atrophy mutation. Many of the gene tests for etiologies of neuroacanthocytosis are not easily obtained. The VPS13A gene, for example, is very large, with at least 71 mutations known. Testing is costly and only found at research facilities in Oxford and Japan (97; 15). Protein assay for chorein via Western blotting has been developed as an alternative to gene testing (16). McLeod syndrome genetic testing is more widely available, and a directory for labs that offer this test may be found at GeneTests. ELAC2 gene testing might be considered for rare individuals, though whole exome sequencing may be required (68).

(8) Measurement of ceruloplasmin and serum copper to exclude Wilson disease.

(9) Measurement of serum lead levels to rule out lead intoxication.

(10) Vitamin E deficiency may be present in the lipid disorders.

(11) In patients with a suspected disorder of lipids, lipoprotein electrophoresis is indicated.

(12) Pigmentary retinopathy may be found in pantothenate kinase associated neurodegeneration, lipoprotein disorders, and in some McLeod syndrome patients. Kayser-Fleischer rings should be considered as well, if Wilson disease remains in the differential.

(13) Cardiomyopathy should not be missed in patients with McLeod syndrome or autosomal-recessive chorea-acanthocytosis.

Management

No treatment is known to slow down progression of this syndrome and, therefore, only symptomatic therapies are available (102). Insufficient experience has accumulated to judge pharmacologic response in patients with neuroacanthocytosis. Many patient problems resemble those seen in Huntington disease, so similar strategies may prove helpful in individual cases. Neuroleptic agents, tetrabenazine, and reserpine are treatment options for chorea. We have used amantadine in one patient with minimal improvement. Dopaminomimetic therapy may alleviate parkinsonian symptoms. Judicious use of antidepressants may be used for dysthymic disorder; fluoxetine, carbamazepine, propranolol, or neuroleptic may be tried for emotional dyscontrol. Antipsychotics such as tiapride may relieve hyperkinetic symptoms (116). Patients with neuroacanthocytosis, in particular those with McLeod syndrome, should be evaluated by a cardiologist to rule-out and potentially treat cardiomyopathy. Those with lipid metabolism disorders should receive vitamin E supplementation if necessary. Those patients with dysphagia should undergo evaluation and treatment by a speech pathologist in order to avoid aspiration.

Protective actions need to be taken to prevent severe self-injury in patients with self-mutilative behavior. Protective head gear has been necessary in patients with head banging behavior. Although seemingly extreme, removal of teeth has been necessary to prevent dangerous tongue and lip biting, which may lead to chronic bleeding and dangerous infection. The use of a mouth guard has been reported to be effective in the treatment of oral self-mutilation associated with neuroacanthocytosis (22; 94).

Antidopaminergic drugs such as tetrabenazine and quetiapine have been used to treat self-mutilation (02).

Anticonvulsants are indicated for those patients exhibiting seizure disorders

Investigators have reported benefit with deep brain stimulation (24; 48; 56). A few case reports indicate that these patients required simultaneous stimulation of both GPi to control chorea and thalamic Vo complex to control trunk spasm (60). Other authors have reported that stimulation of the ventro-postero-lateral region of the globus pallidus pars interna (GPi) may reduce chorea and dystonia (44). Six patients with chorea-acanthocytosis with GPi deep brain stimulation responded most favorably to frequency stimulation ranging from 130 to 175 Hz, a mean current range of 2.08 to 3.06 mA, and a mean pulse width range of 75 to 98 μsec (50).

Some authors suggest that botulinum toxin is beneficial in tongue protrusion dystonia of other etiologies, and thus, may be helpful in neuroacanthocytosis for tongue protrusion. One author suggested 125 units of botulinum injections into the genioglossus muscle (83). Electroconvulsive therapy has reportedly been useful (101; 77). Other forms of dystonia may be treated with botulinum toxin or oral agents, with varying degrees of success. Bruxism and tongue biting may improve with 35 units of onabotulinum toxin injected into the inferior head of the lateral pterygoid muscles, with 15 units into each masseter (66). Benserazide/levodopa 25/100 mg 3 times daily reportedly improved dystonia in 2 patients (39). Anticholinergics such as trihexyphenidyl, benzodiazepines such as clonazepam, and antispasmodics such as baclofen, or the dopamine deplete tetrabenazine can all be considered for dystonia (102).

Special considerations

Pregnancy

Postpartum deterioration with the development of additional chorea-acanthocytosis symptoms has been reported (51).