Neuroacanthocytosis

INTRODUCTION — Neuroacanthocytosis refers to a group of rare diseases that share the features of central nervous system degeneration, neuromuscular manifestations, and acanthocytosis on a peripheral blood smear.

An acanthocyte is a spiculated form of a red blood cell (RBC) (picture 1). The name is derived from the Greek word (acantha) for thorn. It should be differentiated from the echinocyte, which has more numerous, uniform, and finer spiny projections and is associated with severe renal and liver disease.

Acanthocytes may be seen in a variety of diseases, including severe liver disease. In neuroacanthocytosis, the degree of neurologic impairment does not correlate with the degree of acanthocytosis on the smear.

The general category of neuroacanthocytosis includes abetalipoproteinemia, chorea-acanthocytosis, and McLeod syndrome. Acanthocytes appear more variably in pantothenate kinase-associated neurodegeneration (PKAN) and in Huntington disease-like 2 (HDL2). These disorders are discussed here. Acanthocytosis in liver and other systemic disease are discussed separately. (See "Burr cells, acanthocytes, and target cells: Disorders of red blood cell membrane", section on 'Burr cells and acanthocytes'.)

ABETALIPOPROTEINEMIA — Abetalipoproteinemia, also known as Bassen-Kornzweig disease, is an autosomal recessive disorder caused by mutations in the microsomal triglyceride transfer protein (MTTP) gene [1-4]. The encoded protein is essential for the formation and eventual secretion of apolipoprotein B-containing lipoproteins, both from the intestine (chylomicrons) and liver (low-density lipoprotein [LDL] and very low-density lipoprotein [VLDL]). Chylomicron formation is necessary for absorption and initial transport of the fat-soluble vitamins.

The neurologic manifestations of abetalipoproteinemia result from the inability to absorb and transport vitamin E [5]. Vitamin A deficiency may also contribute to the retinal degeneration. Neuropathologic changes affect posterior columns and spinocerebellar tracts [4].

Clinical features — This disorder typically presents in early childhood with steatorrhea, abdominal distension, and failure to thrive [4,6,7].

Clumsiness may be the first neurologic manifestation. During childhood or adolescence, progressive ataxia, neuropathy, and vision impairment develop. Impaired visual acuity and visual field defects are common. Funduscopic examination reveals pigmentary degeneration of the retina (retinitis pigmentosa). Dysarthria is common. The sensory motor neuropathy manifests with weakness and distal muscle atrophy. Reflexes are diminished or absent, although extensor plantar responses may be present. There is truncal and limb ataxia. Proprioceptive sensory loss and possibly impaired pain and temperature sensation occur as well.

The clinical presentation is virtually indistinguishable from that associated with severe vitamin E deficiency. (See "Overview of vitamin E", section on 'Deficiency'.)

Laboratory and test findings — Characteristic laboratory findings include [7]:

●Triglyceride levels and total cholesterol levels are very low (less than 1.5 mmol/L). Lipoprotein electrophoresis will reveal the absence of beta-lipoproteins.

●Acanthocytes (picture 1) constitute 50 to 90 percent of the circulating red blood cell (RBC) population [8]. A mild, normocytic anemia is common.

●Sensory nerve conduction studies have shown absent sensory nerve action potentials (SNAPs) or SNAPs of reduced amplitudes. Conduction velocities are usually normal (despite features of peripheral nerve demyelination on pathology specimens) [9,10]. Motor nerve conduction studies may be normal.

●Vitamin E levels (alpha-tocopherol and gamma-tocopherol) are undetectable or very low.

●Some patients develop elevated transaminases due to hepatic steatosis [11].

●Homozygotes may have an impaired cortisol response to adrenocorticotrophic hormone (ACTH) [12].

Diagnosis — The diagnosis of abetalipoproteinemia is based on the clinical findings and the striking abnormalities on serum lipid analysis. Molecular genetic testing for mutations of the MTTP gene confirms the diagnosis.

Differential diagnosis — The neurologic findings in abetalipoproteinemia are similar to those found in a number of the dominantly inherited spinocerebellar atrophy syndromes, including Machado-Joseph disease and Friedreich ataxia [13] (see "Autosomal dominant spinocerebellar ataxias" and "Friedreich ataxia"). The autosomal recessive inheritance, presence of acanthocytes, and abnormal lipid studies of abetalipoproteinemia are important distinguishing features.

Abetalipoproteinemia is distinguished from severe vitamin E deficiency by the absence of apolipoprotein B-containing lipoproteins. The lipid profile also helps distinguish it from a rare autosomal recessive ataxia (ataxia with vitamin E deficiency [AVED]) associated with low or absent vitamin E levels and normal lipids; this entity is associated with mutations of the alpha-tocopherol transfer protein [13-15]. Vitamin E supplementation slows progression and may improve ataxia in these conditions. (See "Overview of vitamin E", section on 'Deficiency'.)

Mutations in the apolipoprotein B gene cause hypobetalipoproteinemia [4,16-19]. Individuals homozygous for these mutations may present with clinical findings indistinguishable from abetalipoproteinemia. Heterozygotes typically have milder phenotypes and low but detectable VLDL and LDL levels. As in abetalipoproteinemia, triglyceride and cholesterol levels are very low. Diagnosis is based on the autosomal codominant pattern of inheritance, clinical features, and lipid/lipoprotein analysis. Commercial molecular genetic testing for mutations in the apolipoprotein B gene is not currently available. Patients are treated with vitamin E supplementation.

A similar disorder characterized by hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (called the HARP syndrome) is caused by mutations of the PANK2 gene [20-22]. The HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration (PKAN). (See 'Pantothenate kinase-associated neurodegeneration' below.)

Treatment — The neurologic manifestations of abetalipoproteinemia can be prevented and at least partially reversed with the administration of vitamin E, 150 mg/kg per day [7,23-27]. Analysis of vitamin E levels in adipose tissue biopsies can be used to assess adequacy of vitamin E dosing [28].

The other fat-soluble vitamins (A, K, and D) should also be supplemented. Vitamin A 100 to 400 international units/kg/day has been a suggested dose; serum carotene concentrations can help guide titration and avoid toxicity [7]. Vitamin K 5 to 35 mg/week and vitamin D 800 to 1200 international units/day are also recommended [29].

A longitudinal study of patients with abetalipoproteinemia and hypobetalipoproteinemia showed that mild retinal degeneration may occur despite supplementation with both vitamins E and A [30].

Dietary modification to limit fat intake ameliorates the gastrointestinal symptoms.

CHOREA-ACANTHOCYTOSIS — Chorea-acanthocytosis has also been called choreoacanthocytosis, familial amyotrophic chorea with acanthocytosis, familial amyotrophic choreoacanthocytosis, and Levine-Critchley syndrome.

This is an autosomal recessive disorder caused by mutations in the VPS13A (previously called CHAC) gene, which encodes a large protein called chorein [31-33]. The function of chorein is not known. This protein is expressed in many body tissues, including erythrocyte membranes [34].

The disorder is very rare, with an estimated 1000 cases worldwide [35]. Clusters of disease have been described in Japan and in French Canada.

Clinical features — Clinically, this disorder is characterized by the onset in young adulthood of chorea and/or parkinsonism, oro-lingual-facial dystonias, tics, social disinhibition, seizures, areflexia, and distal muscle wasting.

The mean age of onset is 35 years with a broad range from the first to the seventh decade. Initial clinical symptoms can vary [35]:

●The movement disorder is often the most prominent clinical feature. Chorea is the typical manifestation, although some patients may present with parkinsonism (bradykinesia and rigidity) [36,37]. Flinging arm and leg movements, shoulder shrugs, and pelvic thrusts are common [38]. Ambulation is usually severely affected with an odd lurching type of gait. Postural reflexes are impaired and falls are very common. Violent trunk spasms with head banging may occur [39].

Dystonias affecting the mouth region and pharynx are characteristic. Repetitive tongue protrusions, so-called "feeding dystonia," combined with impaired swallowing can lead to cachexia [40,41]. Tongue and lip biting are characteristic features [42]; patients may learn to put a handkerchief or towel in the mouth to prevent such self-mutilation [43]. Limb dystonias may also be present.

Vocal tics consisting of gasping, sighing, clicking, whistling, blowing, sucking, grunting, and humming occur in two-thirds of patients [39,44].

●A "frontal lobe syndrome" has been described in these patients, which may include social and sexual disinhibition, impaired decision-making capacity, impaired insight, obsessive compulsive tendencies, and self-neglect [45,46]. Anxiety, paranoia, aggression, and even frank psychosis have also been described. Suicidal behavior may also occur. The neuropsychiatric symptoms may precede the movement disorder, particularly in retrospect [35,46]. In such cases, the later appearance of a movement disorder may be wrongly attributed to neuroleptic drug administration and delay diagnosis.

Impaired memory and executive functioning are common but not invariable.

●Dysarthria is common and may be a presenting symptom [47]. Some patients become mute.

●Generalized tonic-clonic or partial complex seizures occur in half of patients; some patients develop epilepsy as their initial clinical manifestation [48]. In many patients, seizures are found to emanate from one or both temporal lobes [49-51].

●Neuropathy is mild and often subclinical, manifesting with distal muscle wasting, depressed distal deep tendon reflexes, and mild sensory abnormalities, particularly impaired vibration sense. At least one patient has been described with a motor neuron disease-like presentation [52].

●Subtle eye movement abnormalities may occur, such as impaired upgaze [53,54].

Once symptoms develop, significant disability may accrue in just a few years [42]. Death occurs between the ages of 28 to 61 years.

Laboratory and test findings — Typical laboratory and test findings include [35]:

●Acanthocytes usually constitute 5 to 50 percent of the circulating red blood cell (RBC) population. Acanthocytes may appear late in the course of the disease [55] and may be absent altogether [43]. To improve the yield of finding acanthocytes in this disease, one recommended technique is to dilute the sample 1:1 with heparinized normal saline, incubate the specimen for 5 to 30 minutes, fix it with Karnofsky solution, and view the cells under Nomarski optics [56].

●Most patients have elevated serum creatine kinase (CK) levels (300 to 3000 units/L). Less commonly, lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) serum levels may be increased. The cause of the CK elevations is not clear.

●Magnetic resonance imaging (MRI) may show atrophy of the caudate head and dilatation of the anterior horns of the lateral ventricles [57-60]. In one patient, susceptibility-weighted MRI demonstrated attenuation in the caudates bilaterally, consistent with iron deposition [61]. Functional neuroimaging studies also support the striatum as an area of primary dysfunction [62]. Computed tomography (CT) imaging may only show mild cerebral atrophy [53].

●The interictal electroencephalography (EEG) typically shows nonspecific findings [63].

●Nerve conduction studies reveal features suggestive of a sensory axonal neuropathy with low sensory nerve action potential (SNAP) amplitudes but normal conduction velocities [53]. Motor nerve conduction studies may be entirely normal. Electromyography reveals evidence of chronic denervation with reinnervation.

The muscle biopsy shows predominantly neurogenic features including small angulated fibers and grouped atrophy [64]. An increase of central nuclei and split fibers has also been described [65]. Peripheral nerve biopsies have shown a loss of predominantly large-diameter fibers with features of nerve regeneration [53]. Biopsies of the muscle or nerve are not required for diagnosis.

Differential diagnosis — Chorea-acanthocytosis and McLeod syndrome are clinically indistinguishable, but the McLeod blood group phenotype differentiates McLeod syndrome from chorea-acanthocytosis. (See 'Mcleod syndrome' below.)

Huntington disease and Huntington disease-like 2 (HDL2) can also present with chorea or parkinsonism, along with cognitive and behavioral changes [66,67]. Atrophy of the caudate nucleus is shared by these entities. Prominent orofacial dyskinesias causing dysarthria and dysphagia suggest chorea-acanthocytosis. The autosomal pattern of inheritance, the phenomenon of anticipation (earlier disease onset in successive generations), lack of serum CK enzyme elevations and distal muscle wasting, and significant cortical atrophy help distinguish Huntington disease and HDL2 from chorea-acanthocytosis. Finally, these two disorders may be diagnosed by molecular genetic analysis. (See "Huntington disease: Clinical features and diagnosis" and 'Huntington disease-like 2' below.)

Wilson disease is an autosomal recessive disease that may present with hepatic, neurologic, or psychiatric symptoms almost always before age 50 years. Patients with Wilson disease may present with a variety of abnormal movements, including tremors, chorea, choreoathetosis, or parkinsonian features. An important feature that distinguishes chorea-acanthocytosis from Wilson disease is the absence of liver disease. Low serum copper and ceruloplasmin levels along with increased urinary copper excretion are specific to Wilson disease. Testing for mutations in the gene responsible for Wilson disease (ATP7B) is commercially available. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history".)

Pantothenate kinase-associated neurodegeneration (PKAN; also known as Hallervorden-Spatz syndrome) is an autosomal recessive disease characterized by progressive dystonia and pigmentary retinopathy before the age of 10 years. Atypical forms of the disease may present at a later age. The MRI finding "eye of the tiger" may be diagnostic in some patients. (See 'Pantothenate kinase-associated neurodegeneration' below and "Bradykinetic movement disorders in children", section on 'Neurodegeneration with brain iron accumulation'.)

Diagnosis — The diagnosis of chorea-acanthocytosis is based on recognizing the characteristic clinical features, along with peripheral acanthocytosis and normal lipid studies [34]. Particularly in male patients, testing for the McLeod blood phenotype should be done concomitantly because McLeod syndrome may present indistinguishably from chorea-acanthocytosis.

Detection of biallelic mutations in VPS13A confirms the diagnosis.

Management — No curative disease-modifying treatment for chorea-acanthocytosis currently exists. Treatment is aimed at symptom management [68]. A multidisciplinary approach to disease management is recommended [35].

●The movement disorder symptoms are most challenging to manage. Physical and occupational therapy can provide assistance. Strategies employed in other conditions may be tried in patients with chorea-acanthocytosis (see "Treatment of dystonia in children and adults" and "Huntington disease: Management", section on 'Management of chorea' and "Initial pharmacologic treatment of Parkinson disease" and "Device-assisted and lesioning procedures for Parkinson disease", section on 'Deep brain stimulation'). As examples:

•Orofacial dystonias may be ameliorated by botulinum toxin injections into overactive muscles [42,69].

•In a single case report, the atypical antipsychotic clozapine dramatically, but temporarily, ameliorated chorea [70].

•Deep brain stimulation and other neurosurgical procedures have improved the motor status of patients in some cases [71]. In one individual, bilateral thalamic brain stimulation did significantly reduce trunk spasms, and the benefit lasted for one year [72]. Bilateral stimulation of the globus pallidus interna has been helpful in some cases [73-77] but not in others [70].

●Patients should have regular evaluations by speech and language pathology. Swallowing function should be monitored; feeding assistance and gastrostomy may become necessary. When speech communication becomes difficult, an augmentative communications specialist can assist with devising a computer-controlled speech system [42].

●Seizures are typically controlled with standard antiseizure medication regimens. (See "Overview of the management of epilepsy in adults" and "Initial treatment of epilepsy in adults".)

●While uncommon, cardiomyopathy has been described in chorea-acanthocytosis [78,79]. An electrocardiogram (ECG) and screening transthoracic echocardiogram are recommended in these patients during the initial evaluation. Early consultation with cardiology is recommended if evidence of a cardiomyopathy is found.

Genetic testing may be useful, but because the disease presents later in adulthood, parents of affected individuals are relatively unlikely to have more children. Siblings have a one in four chance of inheriting the disease, but children of affected individuals do not manifest the disease [35].

MCLEOD SYNDROME — McLeod syndrome is an X-linked disorder that is caused by mutations in the XK gene [80-83].

The function of the XK protein is not known, but it shares homologies with the ced-8 protein in C. elegans. Ced-8 has an important role in caspase-mediated cell death (apoptosis). The XK protein is expressed in many tissues, including erythroid tissues, the brain, and muscle. In red blood cells (RBCs), the XK protein is linked to the Kell glycoprotein via a single disulfide bond. The two proteins are thought to form a functional complex. The cellular functions of this complex are not well understood. In instances when the XK protein is not expressed (as in McLeod syndrome), the Kell glycoprotein is absent or very reduced.

Female carriers may manifest subtle signs of McLeod syndrome [35]. Skewed inactivation of the X chromosome not harboring the mutation is probably responsible for disease manifestations in these carriers.

McLeod syndrome is quite rare, with an estimated few hundred cases worldwide [35].

Clinical features — This disorder usually presents in young adulthood with choreiform movements, cognitive impairment, psychiatric symptoms, (often subclinical) neuromuscular findings, and acanthocytosis. Cardiomyopathy is an important systemic manifestation of the disorder.

The age of onset is usually around 40 years but varies from 18 to 61 years [83]. The symptoms tend to progress over decades [35,84]:

●Approximately one-third of patients present with chorea. Restlessness and small-amplitude involuntary movements of the ankles and fingers may be seen in early stages of the disease [85]. Later, choreiform movements of the limbs appear in up to 95 percent of the patients. Involuntary tic-like facial movements are also common, but orofacial dystonias are atypical [86].

●Up to 80 percent of patients develop psychopathology over time [87-91]. Anxiety and depression and "emotional lability" are common; some patients develop obsessive compulsive disorder or psychosis. Psychometric tests have revealed problems with memory and executive function.

●Almost all patients have absent ankle tendon reflexes, and generalized areflexia is common. It is uncommon for patients to have complaints about sensation. Slowly progressive muscle weakness and atrophy are common, but only approximately half of patients will ultimately develop weakness that is clinically significant.

●Two-thirds of patients have evidence of cardiac disease [92]. Cardiomyopathy and cardiac arrhythmias (atrial fibrillation and atrial flutter) have been described.

●Seizures occur in approximately half of patients.

●McLeod syndrome may be part of a contiguous gene syndrome on the X chromosome including chronic granulomatous disease, Duchenne muscular dystrophy, or X-linked retinitis pigmentosa [93,94]. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis" and "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis" and "Retinitis pigmentosa: Clinical presentation and diagnosis".)

The age of death ranges from 31 to 69 years, with a mean age of 53 years [53,87,88]. Tachyarrhythmias related to the cardiomyopathy are thought to be a common cause of premature death [92].

Laboratory and test findings — McLeod blood phenotype is sometimes identified in asymptomatic patients or carriers before the development of neurologic symptoms [95,96]. A weak reaction to Kell antisera and no reaction to XK antisera establish the diagnosis of the McLeod blood phenotype.

In addition to the McLeod blood phenotype, laboratory and test findings include [35]:

●Acanthocytes constitute 3 to 40 percent of the RBC population. A compensated hemolysis is present.

●Elevated serum creatine kinase (CK) levels (up to 4000 units/L) have been described in every patient to date. Patients are susceptible to rhabdomyolysis, particularly in the setting of other risk factors, such as neuroleptic medication use [97]. (See "Rhabdomyolysis: Epidemiology and etiology".)

●Progressive atrophy of the caudate nucleus is the most common finding on MRI [88,98]. Abnormalities on T2-weighted images have been described in the basal ganglia, specifically increased T2 signal in the lateral putamen [85].

●Nerve conduction studies may show low amplitudes for motor and sensory responses but normal conduction velocities, suggesting an axonal neuropathy [99]. Electromyography shows predominantly neurogenic features, although myopathic findings have also been described [53].

Muscle biopsy specimens may show neurogenic (fiber-type grouping) and myopathic (increased central nuclei, increased fiber size variation, and rare degenerating fibers) features. Type 1 fiber predominance and type 2 fiber atrophy also have been described [100,101].

Differential diagnosis — Chorea-acanthocytosis and McLeod syndrome patients present with similar clinical findings. Parkinsonism occurs in some patients with chorea-acanthocytosis but is rare in McLeod syndrome. The prominent orofacial dystonias of the former disease are also not usual in McLeod syndrome. (See 'Chorea-acanthocytosis' above.)

The differential diagnosis of McLeod syndrome overlaps substantively with chorea-acanthocytosis and includes Huntington disease, Huntington disease-like 2 (HDL2), pantothenate kinase-associated neurodegeneration (PKAN; also called Hallervorden-Spatz syndrome), and Wilson disease. (See 'Differential diagnosis' above.)

The McLeod blood phenotype separates McLeod syndrome from other disorders. (See 'Laboratory and test findings' above.)

Diagnosis — The diagnosis rests on the combination of clinical findings, acanthocytosis, and the McLeod blood phenotype. A weak reaction to Kell antisera and no reaction to XK antisera establish the diagnosis of the McLeod blood phenotype. The percentage of individuals with the McLeod blood phenotype who never present with neurologic manifestations is unknown. Molecular genetic testing for mutations of the XK gene confirms the diagnosis.

Management — There is no curative treatment or disease-modifying therapy for McLeod syndrome. Current treatment is aimed at symptom management [68].

●A screening ECG and echocardiogram should be obtained during the initial work-up. Many of these patients will need to be followed by cardiology. Patients at risk for cardiogenic embolism should be anticoagulated. Some suggest that asymptomatic carriers of the McLeod blood phenotype should also be screened for cardiac disease.

●Medications used to treat chorea in other syndromes can be tried. In single cases, hyperkinetic movements have responded to tiapride and sulpiride but not tetrabenazine or buspirone [88]. (See "Huntington disease: Management", section on 'Management of chorea'.)

●Seizures can be well controlled with a variety of antiseizure medications. Specifically, carbamazepine, phenytoin, and lamotrigine have been used with success in these patients [88]. (See "Initial treatment of epilepsy in adults".)

●Symptom-appropriate psychotropic drugs should be used as needed; however, psychiatric symptoms may be resistant to standard pharmacotherapy. One such patient responded to electroconvulsive therapy [90].

●Genetic counseling is appropriate. Affected males will pass on the mutation to all of their daughters, whose sons will have a one in two chance of developing the syndrome and whose daughters will have a one in two chance of being carriers [35]. Female carrier heterozygotes rarely develop a neurologic syndrome.

PANTOTHENATE KINASE-ASSOCIATED NEURODEGENERATION — Pantothenate kinase-associated neurodegeneration (PKAN), formerly known as Hallervorden-Spatz disease, is an autosomal recessive disorder; most cases are caused by mutations in the gene encoding pantothenate kinase 2 (PANK2) [102-104]. PANK2 catalyzes the rate limiting step in the synthesis of coenzyme A from vitamin B5. PKAN is included in a group of disorders known as neurodegeneration with brain iron accumulation. (See "Bradykinetic movement disorders in children", section on 'Neurodegeneration with brain iron accumulation'.)

Classic PKAN present in the first decade of life with extrapyramidal signs including orofacial and limb dystonia, dysarthria, rigidity, and choreoathetosis. Retinopathy, spasticity, and cognitive decline are common [104]. Acanthocytosis occurs in just 8 to 10 percent. Less commonly, patients may present later in life (in the second decade) with more prominent rigidity and a slower progression. In such patients, the clinical syndrome overlaps with juvenile-onset Huntington disease, Huntington disease-like 2 (HDL2), and chorea-acanthocytosis.

On brain MRI, iron deposition in the globus pallidus creates a hallmark "eye of the tiger" sign in these patients, which can be diagnostic [104]. Sequence analysis of the PANK2 gene is commercially available to confirm the diagnosis.

This disorder is discussed in more detail separately. (See "Bradykinetic movement disorders in children", section on 'Neurodegeneration with brain iron accumulation'.)

HUNTINGTON DISEASE-LIKE 2 — Huntington disease-like 2 (HDL2) is a rare autosomal dominant disorder caused by cytosine-thymine-guanine (CTG) trinucleotide repeat mutations in the junctophilin-3 gene (JPH3) [105-107]. Apparently unaffected individuals with repeats in the JPH3 gene may develop the disease later. HDL2 has been reported mainly in patients of African ancestry [108], although it has also been reported in a patient of apparent European ancestry [109]. It is a rare disorder with approximately 25 pedigrees and 40 affected individuals reported as of a 2012 publication [106].

This disease presents in midlife (age 29 to 41 years) with a progressive movement disorder, along with dementia and psychiatric disturbances (depression, apathy, irritability) [106,110]. The movement disorder may be one of predominant parkinsonism accompanied by rigidity, or chorea with abnormal eye movements. Neither seizures nor peripheral nerve or muscle problems have been reported in HDL2 [35]. Death occurs 10 to 20 years after presentation.

Acanthocytosis has been reported in some affected individuals, but this is not universal [111]. Brain MRI findings are similar to those of Huntington disease with prominent atrophy of the caudate and cerebral cortex.

The clinical presentation of HDL2 is similar to juvenile-onset Huntington disease and also overlaps with chorea-acanthocytosis [67,112] (see 'Differential diagnosis' above). The diagnosis is made by molecular genetic testing.

Treatment is symptomatic and is similar to that of Huntington disease. (See "Huntington disease: Management".)

Genetic counseling is appropriate, as siblings will have a 50 percent risk of developing the disease.

SUMMARY

●Disease spectrum – Neuroacanthocytosis refers to a group of rare diseases that share central nervous system degeneration, neuromuscular manifestations, and acanthocytosis (picture 1) on a peripheral blood smear. (See 'Introduction' above.)

●Abetalipoproteinemia – Abetalipoproteinemia is an autosomal recessive disorder caused by mutations in the microsomal triglyceride transfer protein (MTTP) gene. The neurologic manifestations result from the inability to absorb and transport vitamin E and include progressive ataxia, sensory-motor neuropathy, and vision impairment with retinitis pigmentosa. (See 'Clinical features' above.)

The diagnosis is made in the setting of the typical clinical findings accompanied by laboratory findings of acanthocytosis, very low triglyceride and total cholesterol levels, and absent beta-lipoproteins. (See 'Laboratory and test findings' above and 'Diagnosis' above.)

Neurologic manifestations can be prevented and partially reversed with the administration of vitamin E, 150 mg/kg per day along with other fat-soluble vitamins. (See 'Treatment' above.)

●Chorea-acanthocytosis – Chorea-acanthocytosis is a rare autosomal recessive disorder characterized by the onset in young adulthood of chorea and/or parkinsonism, oro-lingual-facial dystonias, tics, social disinhibition, seizures, areflexia, and distal muscle wasting. (See 'Clinical features' above.)

No formal diagnostic criteria for chorea-acanthocytosis exist; the disorder is suspected on the basis of the clinical symptoms and the presence of acanthocytosis. Genetic testing confirms the diagnosis, but is not widely available. (See 'Laboratory and test findings' above and 'Diagnosis' above.)

No curative or disease-modifying treatment for chorea-acanthocytosis currently exists. Treatment is aimed at symptom management. (See 'Management' above.)

●McLeod syndrome – McLeod syndrome is an X-linked recessive disorder that has a similar clinical presentation to chorea-acanthocytosis. Cardiomyopathy is an important systemic manifestation of the disorder. A specific test finding is the McLeod blood phenotype. Management includes symptomatic treatments, cardiologic screening and follow-up, and genetic counseling. (See 'Mcleod syndrome' above.)

●Pantothenate kinase-associated neurodegeneration (PKAN) – PKAN is an autosomal recessive disorder caused by mutations in the gene encoding pantothenate kinase 2 (PANK2). It typically presents in childhood with orofacial and limb dystonia, choreoathetosis, and spasticity. Retinopathy and cognitive decline are also common but not invariable. (See 'Pantothenate kinase-associated neurodegeneration' above.)

●Huntington disease-like 2 (HDL2) – HDL2 is an autosomal dominant disorder caused by a trinucleotide repeat expansion in JPH3. It mimics juvenile-onset Huntington disease with onset in midlife of parkinsonism and dystonia or chorea, accompanied by progressive dementia. It is diagnosed by molecular genetic testing. Similar to Huntington disease, management focuses on symptoms. (See 'Huntington disease-like 2' above.)