Neuroacanthocytosis by William Stamey MD (Dr

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Neuroacanthocytosis By William Stamey MD (Dr. Stamey of Mid Coast Hospital in Brunswick, Maine, has no relevant financial relationships to disclose.) Originally released May 13, 1994; last updated October 9, 2017; expires October 9, 2020

Introduction

This article includes discussion of neuroacanthocytosis, amyotrophic neuroacanthocytosis, Levine-Critchley syndrome, chorea-acanthocytosis, choreoacanthocytosis, McLeod syndrome, abetalipoproteinemia, Huntington disease-like 2, and pantothenate kinase-associated neurodegeneration. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Neuroacanthocytosis is a neurologic syndrome characterized by a broad spectrum of movement disorders that often share acanthocytes on the blood smear. In addition to a variety of hyperkinetic and hypokinetic movement disorders, behavioral and cognitive disturbances are common features. An autosomal recessive disorder, chorea-acanthocytosis overlaps clinically with McLeod syndrome, which is inherited as an X-linked disorder. Neuroacanthocytosis must be considered in the differential diagnosis of patients presenting with movement disorders and behavioral/cognitive findings. Treatments, including deep brain stimulation, are met with various levels of success.

Key points • Chorea-acanthocytosis is an autosomal recessive disorder due to mutations in the VPS13A gene (chromosome 9q21), and is among the disorders known to cause neuroacanthocytosis. • Neuroacanthocytosis should be considered in the differential diagnosis of patients with neuropsychiatric symptoms and chorea or in adult onset tourettism. • A tongue-protrusion “feeding dystonia” is highly suggestive of neuroacanthocytosis. • A peripheral smear revealing 3% acanthocytes is considered positive, though in early cases, the smear may appear normal. • A variety of other neurologic symptoms may accompany neuroacanthocytosis, including seizures, motor neuron disease, and dementia.

Historical note and terminology

Neuroacanthocytosis is an umbrella term for a rare multisystem neurodegenerative syndrome with several etiologies (Zhang et al 2013). Unifying these diverse conditions is the acanthocyte (acanth, “thorn,” Greek), an abnormal, contracted red blood cell, with several irregularly spaced thorny projections from the surface. Up to 3% acanthocytes in the peripheral blood smear may be considered normal; ranges beyond this are often associated with disease. Cases of neuroacanthocytosis typically are associated with striatal atrophy, subsequent movement disorders, behavioral changes, and a pattern of frontal subcortical dementia. Caudate atrophy, peripheral neuropathy, and myopathy are other core neuropathological features that arose in the literature early on (Bird et al 1978). With the advent of gene testing, the classification of neuroacanthocytosis has allowed investigators to distinguish various etiologies.

Acanthocytosis was initially used as a term to describe abnormal red blood cells in the Bassen-Kornzweig syndrome of fat malabsorption (Bassen 1950). This blood abnormality in the setting of neurologic dysfunction was first reported in a New England family (Rovito and Pirone 1963; Levine 1964). Levine described 21 members of a family with a dominantly inherited neurologic disorder and acanthocytes, though some were noted to have the histologically distinct Burr cells (echinocytes) as well, in the peripheral blood smear (Levine 1964). Most symptomatic individuals had acanthocytes on their smear, as did 3 asymptotic relatives. In the following years, other symptoms were described among these individuals, including muscle weakness, leg cramps, lack of coordination, epilepsy, chorea, distal sensory deficits, dementia, and gait disorder (Estes et al 1967). Critchley reported a second family with chorea, self-mutilation, areflexia, dementia, and a characteristic eating dystonia: "when he ate his tongue would involuntarily push his food out onto the plate" (Critchley et al 1968). Affected individuals were found in 2 generations. The disease was known for some period as Levine-Critchley syndrome, but it is often now reported varyingly as amyotrophic chorea-acanthocytosis or, more commonly, neuroacanthocytosis, a term coined originally by Jankovic and colleagues to draw attention to the heterogeneous presentation with a variety of hyperkinetic movement disorders (chorea, dystonia, tics) and hypokinetic movement disorders (parkinsonism) in addition to other neurologic deficits and abnormal laboratory findings (Jankovic et al 1985). Spitz and colleagues subsequently defined neuroacanthocytosis as a rare neurodegenerative disorder characterized by acanthocytes in the peripheral blood smear, motor neuron disease, and movement disorder; including such manifestations as chorea, tongue and lip biting, parkinsonism, orofacial dyskinesias, and vocal and facial tics (Spitz et al 1985).

Neuroacanthocytosis is currently classified as follows (Thomas and Jankovic 2003): (1) neuroacanthocytosis with normal serum lipoproteins, (2) neuroacanthocytosis with hypobetalipoproteinemia, (3) neuroacanthocytosis with abetalipoproteinemia, and (4) X-linked neuroacanthocytosis (McLeod syndrome). “Core neuroacanthocytosis syndromes” included in this spectrum are the autosomal-recessive chorea-acanthocytosis, the X-linked McLeod syndrome, Huntington disease-like 2, and pantothenate kinase-associated neurodegeneration (Danek et al 2005).

Bassen Kornzweig disease, in which acanthocytes are present in concert with ataxia, retinitis pigmentosa, proprioceptive sensory loss, and areflexia, is included as a less common cause of neuroacanthocytosis. However, there is usually no deficiency of beta-lipoprotein in other etiologies. Other reported neurologic syndromes with associated acanthocytosis include neurodegeneration with brain iron accumulation, Huntington disease-like 2 (Walker et al 2003b), and 2 cases of mitochondrial encephalopathy.

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 (Hardie et al 1991). There have been increasing numbers of studies revealing marked phenotypic variation (Walker et al 2007). In a report with 2 siblings with neuroacanthocytosis, 1 presented with dystonia, lip biting, and eating difficulties, whereas the other had generalized seizures several years before developing choreatic movements (Aasly et al 1999). 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 (Sakai 1981). Myopathy, including dilated cardiomyopathy, has been also reported to be part of the peripheral spectrum of manifestations associated with neuroacanthocytosis (Kageyama et al 2007; Saiki et al 2007). 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 (Sorrentino 1999). Likewise, the acanthocyte count does not predict disease severity (Rampoldi 2002).

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 (Rovito and Pirone 1963; Levine et al 1968; Hardie et al 1991; Miranda et al 2007). 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 (Habermeyer and Fuhr 2007). Obsessive-compulsive disorder may herald the development of chorea-acanthocytosis, as early as the age of 10 years (Walterfang et al 2008). Antisocial behavior, though not common, is noted in some patients (Danek et al 2007). Dysphoria, anxiety disorder, and marked emotional lability have been prominent in patients with self-mutilation behavior (Feinberg et al 1991). These appear to be similar to the case reported by Wyszynski and colleagues: The patient. . . appeared needy, anxious, and restless. . .There was perseveration of word elements and phrases and an almost continuous humming and sighing vocalization. . . capacity for sustained attention was limited. . . exhibited continual neediness, provocativeness. . . head banging and lip and tongue biting appeared to exhibit a voluntary component (Wyszynski et al 1989).

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 (Hardie et al 1991). Cognition. Dementia is often reported, in many cases, with particular problems in psychometric tests of attention and planning, consistent with frontal-subcortical dysfunction (Hardie et al 1991; Kartsounis and Hardie 1996).

In 1 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 (Zeman 2005).

Epilepsy. A considerable proportion of patients with neuroacanthocytosis have seizures (Hardie et al 1991). Rarely, epilepsy can be the presenting feature (Schwartz et al 1992). Familial temporal lobe epilepsy was reported in kindreds with chorea-acanthocytosis (Al-Asmi et al 2005). 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" (Estes et al 1967); "sucking, chewing and smacking movements of the mouth" (Bird et al 1978); "shoulder shrugs, flinging movements of the arms and legs and thrusting movements of the trunk and pelvis" (Feinberg et al 1991); "wild lurching truncal and flinging proximal arm movements that occurred with minimal stimulation" (Feinberg et al 1991). Oral-facial dyskinesias; tic-like, repetitive, and stereotyped movements; and involuntary vocalizations are common.{embed="pagecomponents/media_embed" entry_id="10066"} Occasional patients have primarily dystonia. A very rare syndrome is that of the autosomal dominant familial acanthocytosis with paroxysmal exertion-induced dyskinesias and epilepsy (Storch et al 2004).

Shibasaki and colleagues compared the movements in patients with neuroacanthocytosis with those seen in patients with Huntington disease (Shibasaki et al 1982). 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 1 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 (Feinberg et al 1991; Bader et al 2010). Bradykinesia in concert with chorea is common, as in Huntington disease, and may become more prominent in the later stages of the illness (Spitz et al 1985). 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 (Thomas and Jankovic 2003).{embed="pagecomponents/media_embed" entry_id="10067"} 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 (Spitz 1985; Hardie et al 1991). Gradstein and colleagues evaluated eye movements by neuro-ophthalmologic exam and the magnetic search coil technique in 3 patients with genetically confirmed chorea-acanthocytosis (Gradstein et al 2005). 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 (Zamel et al 2008). On muscle biopsy fiber type grouping is present, suggestive of neurogenic atrophy (Bird et al 1978), or central nucleation, and fiber splitting suggestive of myopathic changes (Limos et al 1982). 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 (Aasly et al 1999). Loss of large myelinated fibers and unmyelinated fibers is seen on nerve biopsy (Hardie et al 1991). 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 (Ohnishi et al 1981), but no obvious abnormality was seen in another case (Hardie et al 1991). 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's disease, McLeod syndrome and normal controls (Saiki et al 2007). Two brothers, the product of consanguineous parents, with the combination of Tourette syndrome, acanthocytosis, motor neuron disease, and progressive parkinsonism were reported (Spitz 1985). EMG was performed on 1 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 (Miki et al 2010). 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 (Tamura 2005). There is a report of overlapping phenotype with LGMD2A (Starling 2005). 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 (Ueyama 2000). 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 (Oechslin et al 2009). There are reports of cardiomyopathy in patients with autosomal-recessive chorea-acanthocytosis as well (Kageyama 2007).

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 (Rubio et al 1997). 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 (Rampoldi et al 2001). 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 (Dobson-Stone 2004). 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. More recent data show that chorein is involved in the exocytosis of dopamine containing dense core vesicles of neuronal cells (Hyashi et al 2012). Among patients with chorea-acanthocytosis, cortical inhibitory networks are disrupted (Dubbioso et al 2017).

In some cases the disorder is inherited in an autosomal dominant fashion (Estes et al 1967). One Japanese family with Alzheimer disease had typical autosomal-recessive chorea-acanthocytosis phenotype (Sakai et al 2003). 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 (Ishida et al 2009).

Rare sporadic cases have been reported (Hardie 1991).

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 (Honisch et al 2015). 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 (Ueno et al 2001), a mouse model of the chorea-acanthocytosis form of neuroacanthocytosis has been developed (Tomemori 2005). 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 (Hardie 1991). 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 (De Yebenes et al 1988). Investigation of 6 chorea-acanthocytosis patients with confirmed mutations in the VPS13A gene revealed symmetric atrophy of the caudate nuclei (Henkel et al 2006). 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.

McLeod syndrome. In this X-linked clinical syndrome, there is a lack of a common red blood cell antigen, Kx (Redman et al 1988). 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 (Calenda 2006; Lee 2006). 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 (Miranda et al 2012). The gene defect has been mapped to a region of a few hundred kilobases on Xp21 (Ho et al 1992). A case of McLeod syndrome affecting a female has been reported (Hardie et al 1991).

Neurodegeneration with brain iron accumulation. Acanthocytes may be seen in variants of neurodegeneration with brain iron accumulation, a progressive movement disorder (Dusek et al 2012) 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 1 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 (Zhou et al 2001). 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 (Hayflick 2003). 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 (Kotzbauer 2005).

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 (Feinberg et al 1991). 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 (Walker et al 2002). 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) (Walker et al 2003a). The JPH3 gene is present on chromosome 16q24.3 (Holmes et al 2001). The repeat size ranges from 6 to 27 in normal individuals, with those affected having between 41 to 58 repeats (Margolis 2001). Of note, not all patients with clinical neuroacanthocytosis and genetically proven Huntington disease-like 2 will have acanthocytosis, whereas clinically unaffected siblings may (Walker 2003b). 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 (Nishi 2002).

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 (Sheetz et al 1976). 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 (Oshima et al 1985; Sakai et al 1991).

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 (Lee 1997). 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 (Asano et al 1985). Kay and colleagues have reported that there is an abnormal flux of chloride through the red cell membrane in neuroacanthocytosis (Kay et al 1990). 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 (Kay et al 1990).

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 (De Franceschi et al 2012).

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 (Levine 1964). 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 (Estes et al 1967; O'Brien et al 1990). 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 (Feinberg et al 1991). Dilution of the patients' blood cells caused a greater percentage to change shape (Estes et al 1967). 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 (Feinberg et al 1991).

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 (Oechsner et al 2001). 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 (Peppard et al 1990). 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 (Cui et al 2015).

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 (Bird et al 1978). Neuronal loss is seen in the caudate, putamen, globus pallidus, and substantia nigra (Hardie et al 1991). 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 (Katsube et al 2009).

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, 1 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 (Dobson-Stone et al 2005). Unrelated Ashkenazi Jewish patients have been reported with the same mutation as well, also raising speculation for founder effect (Lossos et al 2005).

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

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 (Walker et al 2003b). 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 (Walker 2003b).

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 (Mejia and Jankovic 2005). 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 (Henkel et al 2006). Progressive striatal atrophy may be seen in serial images (Valko et al 2010). 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 (Walterfang et al 2011). In pantothenate kinase associated neurodegeneration, the so-called “eye of the tiger” may be present (Hayflick 2003). 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 (Feinberg et al 1991). A screening test including normal values and test specificity/sensitivity using a prospective reader-blinded study was proposed to increase sensitivity for detecting acanthocytes (Storch 2005). 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 (Sorrentino 1999). 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 (Danek et al 2005).

(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 (Ueno 2001; Dobson-Stone 2002). Protein assay for chorein via Western blotting has been developed as an alternative to gene testing (Dobson-Stone 2004). McLeod syndrome genetic testing is more widely available, and a directory for labs that offer this test may be found at GeneTests.

(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 (Walker 2015). 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 1 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. 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 (Fontenelle and Leite 2008; Thapa et al 2016).

Antidopaminergic drugs such as tetrabenazine and quetiapine have been used to treat self-mutilation (Ak et al 2015).

Anticonvulsants are indicated for those patients exhibiting seizure disorders. Investigators have reported benefit with deep brain stimulation (Guehl et al 2007; Lim et al 2013; Miquel et al 2013). 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 (Nakano et al 2015). Some authors suggest that botulinum toxin is beneficial in tongue protrusion dystonia of other etiologies, and thus, may be helpful in neuroacanthocytosis (Schneider et al 2006). Electroconvulsive therapy has reportedly been useful (Vazquez and Martinez 2009; Rutherford 2012).

Special considerations

Pregnancy

Postpartum deterioration with the development of additional chorea-acanthocytosis symptoms has been reported (Lossos et al 2005).

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**References especially recommended by the author or editor for general reading.

Former authors

Walter Koroshetz MD (original author), Hubert H Fernandez MD, Joseph H Friedman MD, and Ramon Rodriguez MD

ICD and OMIM codes

OMIM numbers

Choreoacanthocytosis: #200150

Profile

Age range of presentation

8-62 years with mean age of 32 (Hardie 1991; Kuroiwa 1984)

Sex preponderance male>female,3:1 in Japan (Kuroiwa 1984) male=female,1:1 in UK (Hardie 1991) male>female,2:1, other European (Quinn 1998)

Family history

Family history may be obtained.

Heredity

Consanguinity is a factor, especially among autosomal recessive cases. Chorea-acanthocytosis (ChAc): AR ChAc variant: sporadic (rare) (Hardie 1991) ChAc variant: AD (rare) (Sakai et al 2003) McLeod syndrome: X-linked Bassen-Kornzwieg: AR Huntington disease-like 2: AD, CTG/CAG trinucleotide repeat expansion Pantothenate kinase-associated neurodegeneration: AR HARP: AR

Population groups selectively affected none selectively affected

Occupation groups selectively affected none selectively affected

Differential diagnosis list

Neuroacanthocytosis syndromes with normal serum lipoproteins • Chorea-acanthocytosis • Huntington's disease-like 2 • Neurodegeneration with brain iron accumulation variants, including pantothenate kinase-associated neurodegeneration (most commonly the PKAN2 mutation)

Neuroacanthocytosis syndromes with abnormal serum lipoproteins • Abetalipoproteinemia (Bassen-Kornzweig syndrome) • Familial hypobetalipoproteinemia • Hyperprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP), a subtype of neurodegeneration with brain iron accumulation • Anderson disease • Atypical Wolman disease

X-Linked Neuroacanthocytosis • McLeod syndrome

Systemic causes of Neuroacanthocytosis • Vitamin deficiency states • Liver disease • Malnutrition

Similar phenotype without acanthocytosis • Huntington disease • Wilson disease • Tourette syndrome and primary tic disorder(s) • Tardive dyskinesia • Lesch Nyhan syndrome • Pallidal degeneration

Associated disorders

Chorea Epilepsy HARP syndrome (hyperprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) Hallervorden Spatz syndrome Neurodegeneration with brain iron accumulation (formerly known as Hallervorden Spatz syndrome) Wilson disease Tourette syndrome