Progress in the Diagnosis and Management of Chorea-acanthocytosis

Yang Liu, Ziyuan Liu, Xinhua Wan, Yi Guo＊

1Department of Neurosurgery,

2Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

CHOREA-ACANTHOCYTOSIS (ChAc) is an autosomal recessive hereditary disorder caused by the mutation of gene VPS13A.It is the most common subtype of neuroacanthocytosis (NA) syndromes. NA syndromes refer to group of syndromes characterized by the presence of acanthocytes and neurological dysfunctions, which can be further classified into two major groups. First,the “core” NA syndromes present with basal ganglia degeneration, movement disorders, cognitive impairment and psychological symptoms. Based on various etiologies, there are four subtypes: ChAc, McLeod syndrome, Pantothenate kinase-associated neurodegeneration and Huntington’s disease-like 2. The second major group of NA syndromes include abetalipoproteinemia (Bassen-Kornzweig syndrome) and familial hypobetalipoproteinemia, with peripheral neuropathy and sensory ataxia, but without movement disorders.In addition, several sporadic systemic diseases are also associated with acanthocytosis.1Despite that ChAc is the most common NA subtype, its prevalence is still exceedingly low, making comprehensive understanding of ChAc less feasible. Considering ChAc has a long clinical course with protean clinical manifestations, it is likely to be misdiagnosed at early phase. The management of ChAc, especially from a surgical perspective,has made substantial progress recently. This review focused on the epidemiology, clinical manifestations,diagnosis and treatment strategies of ChAc, aiming to improve physicians’ understanding of this disorder.

ETIOLOGY AND PATHOGENESIS

The exact mechanism underlying ChAc remains elusive. Currently ChAc is thought to be caused by mutations on gene VPS13A (also called CHAC).2-3VPS13A, located on chromosome 9q21, has 73 exons throughout the whole length. Its protein product,vacuolar protein sorting-associated protein 13A (VPS13A, also called chorein), is a member of VPS13 protein family. VPS13A mutations can result in either complete absence of4or functionally-compromised5VPS13A. Mammalian VPS13 protein family consists of VPS13A-VPS13D, each playing specific roles, and VPS13B-VPS13D cannot compensate the absence of VPS13A.6Several researches have already unraveled some functions of VPS13A, while the exact pathophysiology of how VPS13A dysfunction can lead to the phenotype of ChAc remains unknown. A study of yeast VPS13p protein (homologue of mammalian VPS13)has demonstrated its role in maintaining normal mitochondrial function,7and another report showed that VPS13A was involved in polymerization of actin and in lipid synthesis.8Therefore, it was postulated that the abnormal spiky shape of erythrocytes in ChAc might be attributed to not only oxidative damage of membrane lipid secondary to mitochondrial dysfunction but also defected cell scaffold formation secondary to actin dysfunction. Besides, VPS13A was also involved in intracellular trafficking of vesicles.9However, how these dysfunctions could translate into phenotypes still remains to be clarified. Moreover, considering ChAc has high phenotypic variation, patients could have quite different symptoms even in one family, suggesting possible epigenetic or environmental influence to be unraveled.10

EPIDEMIOLOGY

ChAc was a rare disease with only scattered reports. Currently its actual prevalence was unknown. A relatively higher prevalence in Japan and some ethic groups (such as French-Canadians11) was reported,possibly due to founder effect.

CLINICAL FEATURES

ChAc generally has an onset in the age of twenties.1The key features of movement disorders in ChAc is choreiform movements affecting both trunk and extremities. Especially, prominent orolingual dyskinesia is thought to be pathognomonic in ChAc, which can cause self-mutilation such as lip- or tongue-biting.12Trunk instability with spasms (often called “rubber-man gait”)can also be seen in patients with ChAc, while falls are uncommon (balance generally preserved).13Rarely,patients can develop Parkinsonism in the late stage,which may be related with involvement of nigrostriatal pathways as disease progresses.14

Besides, behavioral, cognitive and psychiatric disturbances can also be seen in patients with ChAc, such as depression,15schizophrenia-like behaviors16and compulsive behaviors.17Remarkably, psychiatric manifestations often precede movement disorders, leading to high risk of misdiagnosis sans thorough examination and continuous follow-up.

Finally, several clinical features are thought to be pathognomonic in ChAc. Seizures can present early in disease course, even before motor deficits.18-19Other findings, such as peripheral neuropathy,20cardiac involvements21(arrhythmia, cardiomyopathy), although more commonly seen in McLeod syndrome, can suggest a diagnosis of NA syndromes and be distinguished from other hyperkinetic disorders such as Huntington’s disease.

ChAc is a highly disabling disease which slowly progresses for as long as 15 to 30 years. Orolingual dyskinesia and walking difficulty can be highly disturbing and debilitating. Swallowing problems can cause malnutrition and aspiration. Sudden death can result from choke, seizure attack or cardiac arrhythmia.

LABORATORY WORKUPS AND NEUROIMAGING

Several laboratory workups can assist the diagnosis of ChAc. Elevated serum creatine kinase can be seen in most patients with ChAc or McLeod syndrome.22Acanthocytosis in peripheral blood smear suggests ChAc, while it’s very insensitive (positive rates as low as 5%-50%) and a number of patients need additional saline enhancing experiments or electron microscope scan after glutaraldehyde treatment to validate increased acanthocyte counts. Acanthocytosis can appear at late stage,23therefore a clear blood smear cannot rule out ChAc,24and a close monitoring is suggested when suspecting ChAc. Acanthocytes can also be found in people with heterozygous mutations of VPS13A (asymptomatic).25

In neuroimaging, atrophy of heads of caudate nuclei and dilation of the anterior horn of the lateral ventricles in magnetic resonance imaging are typical signs of ChAc.26FDG-PET/CT also demonstrates impaired glucose metabolism in the basal ganglia.27-28Besides,there were reports of striatal and pallidal iron accumulation.29

DIAGNOSIS AND DIFFERENTIALS

To make a solid diagnosis, either VPS13A mutation confirmed by gene sequencing,3or chorein deletion in red blood cells proven by Western blotting is required. However, only a small portion of ChAc patients reported in China were diagnosed at a gene/protein level.30Most diagnosis are made according to typical clinical manifestations, peripheral blood cells and radiological features.

Differential diagnosis includes: (1) Huntington disease (HD), an autosomal dominant inherited disorder associated with gene IT15 mutation.31HD has a common onset age of 35 to 45 years. Epileptic seizure and peripheral nerve impairments are rarely seen. Myopathy is not common and serum creatine kinase level is usually normal. Chorea symptoms of the limbs are more prominent in HD patients. Peripheral acanthocyte level is normal in most cases.27,32(2) Other types of NA syndromes such as McLeod syndrome. It is another extremely rare disease, which is X-linked recessive associated with gene XK. Most are male patients, with abnormal blood group antigen Kell. McLeod syndrome has an onset of 20 to 60 years of age. The symptoms of central nervous system and radiological features of ChAc and McLeod syndrome are not easy to distinguish. The latter has longer clinical course and higher prevalence of cardiac arrhythmia and dilated cardiomyopathy.1

Due to the complexity of symptoms and the drastic changes throughout the whole course, there is currently no single uniform rating scale for ChAc. Rating scales for different types of movement disorders are applied, including Marsden-Schachter Chorea Rating Scale (MSCRS),33Unified Parkinson Disease Rating Scale (UPDRS), Unified Huntington Disease Rating Scale (UHDRS)34and Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), as well as other scales for cognitive, behavioral and psychological evaluations. It is still challenging to set up a unified evaluation system for ChAc.

MEDICAL MANAGEMENT

Botulinum toxin injection is a possible treatment for the typical orofacial dystonia of ChAc patients.However, there is not yet a uniform standard regarding the injection sites, dosage or methods. Botulinum toxin injections into the genioglossus muscle (125 units35)relieve tongue protrusion dystonia. Paucar et al36performed ultrasound-guided botulinum toxin injection (10 units) into genioglossus, which significantly improved eating and speaking. Ortega et al37carried out electromyography-guided botulinum toxin application to the inferior head of the lateral pterygoid muscles (35 units) and masseters (15 units) of one ChAc patient,and managed to reduce severe teeth clenching and grinding. Concerning about the risk of suppression of other adjacent muscles associated with swallowing,physicians must be cautious about the application of local botulinum toxin injections. Tetrabenazine inhibits the synthesis and promotes the consumption of dopamine. It was reported to be effective in treating the tongue protrusion symptoms of ChAc patients,38but may exacerbate dysphagia.39Some patients choose to remove all their teeth in order to reduce tongue and cheek biting, or use an oral protective stick or towel to passively reduce injury.38Truncal and limb chorea and dystonia can be treated with classic anti-dystonia medications, including anticholinergics, benzodiazepines and baclofen.38Amantadine (200 mg/d) is also reported to be effective in treating chorea symptoms.40Parkinsonism is less commonly seen. Amantadine improves the gait of ChAc patients but levodopa was found to be weak.39

SURGICAL MANAGEMENT

In 1997, Fujimoto reported a patient with ChAc undergoing bilateral pallidotomy, which was the ear-liest attempt of managing ChAc surgically.41Later on,with the introduction of deep brain stimulation (DBS)technique, more and more reports emerged regarding this novel treatment modality. Here we present a review of literature of ChAc treated by DBS (Table 1).

All of the present reports (Table 1) chose globes pallidus internus (GPi) as the target except for one who selected ventral oral posterior nucleus.51There are movement disorders which share some of the manifestations with ChAc can also be managed by stimulation of GPi, such as Huntington’s disease52and Gille de la Tourette syndrome,53indicating a mutual neuromodulating effect on the pathophysiological basis.Considering that the number of the cases was limited,no agreement was achieved regarding the stimulation parameters. For patients receiving high-frequency stimulation,45-46,48some had evident improvements of symptoms especially orofacial and axial dystonia,chorea was also improved, but the symptoms of dysarthria didn’t seem to respond well. For patients receiving low-frequency stimulation,47,5improvements were mainly in chorea and dystonia, some of which even had symptoms exacerbation (such as chorea and dysarthria) under high-frequency stimulation.Generally, it seems that patients with dystonia as a major manifestation will benefit more from high-frequency stimulation and those with major findings of chorea and dysarthria are suitable for low-frequency stimulation. However, as present cases were all very limited in number and highly heterogeneous in surgery and protocols for motor function evaluation,a single-center or multi-center protocol-guided perspective study is strongly warranted for evidences of higher level.

Table 1. Cases reporting deep brain stimulation in treating chorea-acanthocytosis

Currently, there are only limited literature assessing the short-term and long-term outcomes for ChAc treated with GPi-DBS. Miquel et al34retrospectively analyzed 15 cases of ChAc from multiple centers treated with bilateral GPi-DBS. As for symptoms, there were major improvements in chorea, and also improvements of varied degrees regarding dystonia and gait disturbance, but dysarthria didn’t seem to respond to the treatment well. As for motor function, a mean improvement of UHDRS reached 54.3% from 1 month to 5 months postoperatively, and reaching 44.1% 6 months postoperatively. Some patients had symptoms recurred after 6 months postoperatively, which indicates that a maximum benefit might be achieved around 6 months after the surgery, after which close follow-ups should be carried out for evaluation of symptoms and adjustment of stimulation parameters in order to optimize the effect.

There are still many questions to answer in the diagnosis and management of ChAc. As an orphan disease, the number of patients with ChAc is highly limited. To make things worse, the long disease courses and high heterogeneity of manifestations further adds to the problem of misdiagnosis. Both limited patient number and the issue of misdiagnosis make it a challenge to maintain a constantly functional database for patient data collection and follow-ups, and furthermore, to establish a unified rating scale for evaluation. Current there are no agreements for the selection of treatment regimen of ChAc, and surgical interventions (such as DBS) is primarily for patients refractory to medications. It remains unexplored whether an early DBS will help to improve the total outcome. Finally, the initial programming and adjustment of stimulation parameters for ChAc are also to be studied.

Conflicts of interest statement

The authors have no conflicts of interest to disclose.

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