Background: Neuroacanthocytosis (NA) syndromes are a group of rare diseases characterized by the presence of acanthocytes and neuronal multisystem pathology, including chorea-acanthocytosis (ChAc), McLeod syndrome (MLS), Huntington’s disease-like 2 (HDL-2), and pantothenate kinase-associated neurodegeneration (PKAN). China has the largest population in the world, which makes it a good location for investigating rare diseases like NA.
Methods: We searched Medline, ISI Proceedings, China National Knowledge Infrastructure, and Wanfang Data for literature published through December 31, 2013 for all the published Chinese NA case reports and extracted the clinical and laboratory findings.
Results: A total of 42 studies describing 66 cases were found to be eligible for inclusion. Age of symptom onset ranged from 5 to 74 years. The most common findings included hyperkinetic movements (88%), orofacial dyskinesia (80%), dystonia (67%), and dysarthria (68%), as well as caudate atrophy or enlarged lateral ventricles on neuroimaging (64%), and elevated creatine kinase (52%). Most cases were not confirmed by any specific molecular tests. Only two cases were genetically studied and diagnosed as ChAc or MLS.
Discussion: In view of the prevalence of NA syndromes in other countries, the number of patients in China appears to be underestimated. Chinese NA patients may benefit from the establishment of networks that offer specific diagnoses and care for rare diseases.
Neuroacanthocytosis (NA), an umbrella term for a group of rare diseases characterized by misshapen erythrocytes (acanthocytes) and neuronal multisystem pathology, includes diseases such as autosomal recessive chorea-acanthocytosis (ChAc), X-linked McLeod syndrome (MLS), Huntington's disease-like 2 (HDL-2), and pantothenate kinase-associated neurodegeneration (PKAN).1 NA was first described as Levine-Critchley syndrome on the basis of reports by Levine and Critchley in two families from North America in the 1960s.2,3 Although the clinical manifestations of NA resemble Huntington's disease (HD), there are clear differences in the mode of inheritance and neuropathological changes. In the last decade, molecular and protein methods have rapidly developed for the diagnosis of different NA subtypes.
China has the largest population in the world (1.35 billion), making it a suitable location for investigating rare diseases like NA. The first Chinese NA literature is a translation of the paper by Sakai et al in 1981.4,5 Over the last 30 years, few Chinese NA case reports have been published.6–53 Moreover, communication with foreign scholars was limited because most of the reports were published in Chinese. ChAc has been reported in many different ethnic groups, and the relatively high prevalence in Japan appears to be due to a founder mutation.54 In light of the similar East Asian backgrounds in the two countries, we suspect that in China NA syndromes are underdiagnosed, leading to a significant underestimation of the prevalence.
In the current study, we systematically reviewed Chinese NA epidemiology by searching for published NA cases. We aimed to summarize the features of Chinese NA cases in comparison with other countries and identify potential reasons for underestimation.
We searched Medline (from January 1, 1949 to December 31, 2013), ISI Proceedings (January 1, 1990 to December 31, 2013), China National Knowledge Infrastructure (http://www.cnki.net, from January 1, 1979 to December 31, 2013) and Wanfang Data (http://www.wanfangdata.com.cn, from January 1, 1984 to December 31, 2013). The search terms in English and their Chinese equivalents included “neuroacanthocytosis,” “chorea-acanthocytosis,” “McLeod syndrome,” “choreoacanthocytosis,” “hereditary acanthocytosis syndrome,” and “Levine-Critchley syndrome.” We also tried to identify cases from cross-references between papers. We only included those case reports where an explicit diagnosis of NA had been made by the original authors. For inclusion, patients had to be of Chinese origin and diagnosed in China. We extracted information on geographical origin, sex, age of onset, and clinical and laboratory findings from each case.
We identified a total of 48 publications with 66 cases reported (37 males and 29 females) (Table 1). All of these patients had been diagnosed with NA, ChAc, or MLS by the reporting physicians. Only one ChAc case was confirmed by a genetic test (VPS13A gene), and no cases were confirmed by Western blot for the protein chorein that is affected in ChAc.55 An elevated proportion of acanthocytes in blood samples was regarded as the most important diagnostic clue by Chinese physicians. However, heterogeneous methods for detecting acanthocytosis were used in the different reports, thus affecting the accuracy of the test. Only one MLS case, from Hong Kong, was reported with a corresponding XK gene mutation.
|Ref.||Place of Diagnosis||Year of Publication||No. Cases||Sex||AOO||Initial Symptoms||Acanthocytes (%)||Reported Diagnosis||Our Diagnostic Hypothesis|
|6||Anhui||1984||2||2M||19, 27||Orof. (1), MD/Orof. (1)||23%, 3%||ChAc|
|7||Anhui||1987||2||2M||26, 32||DYA (1), MD/Orof. (1)||10%||ChAc|
|8||Anhui||2000||2||2F||45, 46||MD (1), PSY (1)||35%, 17%||ChAc|
|11–14||Beijing||2005, 2012||8||2M, 6F||10–35||Orof. (4), MD (3), PN (1)||>10%||NA|
|15||Beijing||2007||2||2M||27, 37||MD (1), EPI (1)||15–25%||ChAc|
|19||Beijing||2013||3||3M||16–43||MD, Orof. (2), BP (1)||>30%||NA|
|24||Helongjiang||1989||2||1M, 1F||9, 11||Orof.||56%, 28%||ChAc||NBIA|
|29||He’nan||2011||2||1M, 1F||30, 31||MD (1), Orof. (1)||35%, 25%||ChAc|
|43||Shandong||2013||3||2M, 1F||26–50||MD/Orof. (1), PSY (2)||>30%||ChAc|
|47||Shanghai||2012||3||2M, 1F||31–74||MD (1), GD (2)||10–28%||NA|
|49, 50||Shanxi||2004||3||2M, 1F||26–30||EPI (2), Orof. (1)||12–30%||ChAc|
|51||Sichuan||2012||2||2M||17, 18||Orof. (2)||6%, 6%||ChAc|
In the most recent decade (2004 to 2013) the number of reported cases increased dramatically, being about five times the number documented from 1984 to 1993, and seven times the number documented between 1994 and 2003 (Figure 1). No video recordings were published with the publications reviewed in this study. With respect to the geographic distribution, all cases originated from 19 Chinese provinces, with 16 cases reported in Beijing, 7 cases from Anhui, and 7 cases from Shangdong as the top 3 provinces. The ages of onset ranged from 5 to 74 years and were concentrated in the third and fourth decades (n = 37, 56%) (Figure 2). Common initial symptoms were orofacial dyskinesia (n = 27, 41%) and hyperkinetic limb or trunk movements (n = 27, 41%). Dysarthria, epilepsy, gait disturbance, parkinsonism, and psychiatric symptoms were also reported as the initial symptoms. Diagnoses were mainly made based on the presence of a hyperkinetic movement disorder, elevated acanthocytes in the blood, the pattern of inheritance (recessive), and the exclusion of other possible diseases, such as HD.
Figure 3 summarizes the clinical and laboratory findings reported in Chinese NA cases. The most frequent findings were hyperkinetic movements (n = 58, 88%). Orofacial dyskinesia was reported in 53 patients (80%). In addition, dystonia (n = 44, 67%) and dysarthria (n = 45, 68%) were also common. 10 patients (15%) suffered from epilepsy, and 22 patients (33%) exhibited psychiatric symptoms.
With respect to clinical investigations, caudate atrophy or enlarged lateral ventricles on neuroimaging (n = 42, 64%) and elevated CK (n = 34, 52%) were the most frequently reported.
Hyperkinetic movements and orofacial dyskinesia were the most common symptoms in this series of Chinese NA cases, reported in 88% and 80% of patients, respectively. This is consistent with the literature in that orofacial dyskinesia appears to be a relatively specific NA symptom, characterized by tongue protrusion and feeding dystonia. Chorea was typical in the early stages and tended to progress to parkinsonism. Parkinsonism has occasionally been reported to be the initial symptom.56,57
In our study, 52% of Chinese NA cases had elevated CK levels, while only 11% of cases exhibited liver enzyme elevation, suggesting that CK is probably a more useful biomarker for NA than acanthocytes or liver enzymes, as is consistent with the literature. However, values within normal ranges are likely to have been omitted in many publications, thus, we could not accurately calculate the proportion of patients with normal CK or liver enzyme levels.58
The number of cases reported for 1994–2003 is relatively low in comparison to the numbers for 1984–1993 and 2004–2013. It is possible that some cases were not reported because they were not recognized or were not thought to be of interest after awareness was originally raised regarding the syndrome. It is important to determine whether these low rates of reported cases are due to publication bias and incomplete documentation, or whether these discrepancies are due to ethnic differences.
The clinical diagnosis of NA in China is mainly based on clinical manifestations and an elevated proportion of acanthocytes in the blood, as well as the exclusion of other possible diseases. Previously this was the standard diagnostic evaluation worldwide (e.g., a Chinese patient diagnosed with ChAc in Singapore in the 1980s).60 Recently, however, there have been clear NA cases without acanthocyte elevation.61
The other forms of NA, such as HDL-2 and PKAN, have not yet been reported in China. However, as some of the NA cases reported had an early age of onset (Table 1), it is likely that PKAN was the correct diagnosis.
With regard to MLS, only one Chinese case has been identified, indicating that it is probably underdiagnosed. Without specific molecular testing, an accurate diagnosis for presumed NA cases is impossible. As an alternative to DNA analyses, chorein detection by Western blot is an inexpensive method for diagnosing ChAc, and Kell antigen phenotyping can be performed to diagnose MLS.55,62
In view of the prevalence of NA syndromes in countries such as the United Kingdom and Germany (approximately 3 in 10 million), the number of NA patients in China should be at least 400 and appears to be underestimated. In addition to raising awareness among Chinese neurologists, the absence of specific molecular tests is the main diagnostic flaw that needs to be addressed. A Chinese network of NA collaboration may improve the diagnosis and treatment for patients affected by this group of incapacitating hyperkinetic movements.
1 Funding: None.
2 Financial Disclosures: None.
3 Conflict of Interests: The authors report no conflict of interest.
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