Neuroacanthocytosis Syndromes – A Current Overview

Neuroacanthocytosis syndromes are characterized by the presence of “thorny” red blood cells and neurodegeneration of the basal ganglia, along with peripheral neuromuscular findings, seizures, and a variety of neuropsychiatric features. In recent years significant progress has been made in understanding the molecular pathophysiology of these disorders; cases are now identified as autosomal recessive chorea-acanthocytosis, X-linked McLeod syndrome, or more rarely, pantothenase kinase-associated neurodegeneration or Huntington’s disease-like 2. Molecular analysis of classic reports of neuroacanthocytosis will clarify nomenclature and improve understanding of genotype-phenotype correlations. In addition, there are issues of atypical inheritance patterns which remain to be elucidated. A relatively high incidence of chorea-acanthocytosis in Japan may indicate a genetic founder effect, and has led to significant developments from Japanese researchers. R.H. Walker Departments of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, NY and Mount Sinai School of Medicine, New York, NY, USA [email protected] 1 Advances in Neuroacanthocytosis ....................................................................................... 4 2 Neuroacanthocytosis in Japan .............................................................................................. 5 3 Levine–Critchley Syndrome ................................................................................................ 5 4 Subsequent Neuroacanthocytosis Reports ........................................................................... 9 5 Chorea-Acanthocytosis – Recent Developments ................................................................. 10 5.1 Molecular Studies ....................................................................................................... 10 5.2 Clinical Features ......................................................................................................... 10 6 Inheritance Patterns .............................................................................................................. 11 7 Treatment of Neuroacanthocytosis Syndromes.................................................................... 13 7.1 Pharmacological Therapy ........................................................................................... 13 7.2 Neurosurgery ............................................................................................................... 13 7.3 Other Therapeutic Issues............................................................................................. 13 8 Conclusions .......................................................................................................................... 14 References .................................................................................................................................. 14 R.H. Walker et al. (eds.), Neuroacanthocytosis Syndromes II. 3 © Springer-Verlag Berlin Heidelberg 2008 4 R.H. Walker et al. 1 Advances in Neuroacanthocytosis This volume follows up on “Neuroacanthocytosis syndromes” [2], which summarized the proceedings of a symposium which took place in Seeon, Bavaria, in May 2002. That meeting brought together a diverse group of researchers from around the world, including movement disorder neurologists, molecular biologists, hematologists, and neurogeneticists, and many others involved in studying this group of rare diseases. The group explored “New perspectives for the study of basal ganglia degeneration”, following the discovery by scientists in England and Japan of the genetic basis of the core neuroacanthocytosis (NA) syndromes, McLeod syndrome (MLS) and chorea-acanthocytosis (ChAc) [43, 100, 142]. The collaborations initiated at this meeting led to the second Neuroacanthocytosis Symposium (Montreal Neurological Institute, Montreal, Canada, April 2005) and the third symposium, a satellite meeting of the 10th International Congress of Parkinson’s disease and Movement Disorders, organised by the Movement Disorder Society, in Kyoto, Japan, October 2006 (Figs. 1 and 2 of the Foreword). An interim meeting was convened at the Third International Congress on Vascular Dementia in Prague, Czech Republic, October 2003 [27]. The present volume expands on the abstracts of the Kyoto [111] and Montreal [7] symposia. Major scientific developments since the first meeting in 2002 have included the publication of the reference method for acanthocyte detection [127], the description of XK mutations without full-blown MLS [54, 150], and the discovery of additional members, XPLAC and XTES, of the XK family [18]. The genes related to CHAC were found to belong to a conserved gene family involved in vacuolar protein sorting, thus leading to the renaming of CHAC as VPS13A [143]. The use of chorein antibodies for diagnosis of ChAc using Western blot assay [30] was a major clinical advance, obviating the need for molecular analysis of the large VPS13A gene for diagnosis in most cases. Major developments from Japan included the observation of cellular inclusions in ChAc muscle [133] and the first animal model for ChAc [137], mice with the VPS13A deletion-mutation found in the Ehime province [71, 87]. The nosology of NA syndromes has evolved since the Seeon meeting. A family reported there with autosomal dominant NA [148] was identified as having Huntington’s disease-like 2 [144, 146, 147, 149] (see chapter by Margolis). The fourth “core” NA syndrome, pantothenate-kinase associated neurodegeneration (PKAN), has been better delineated with the availability of genetic testing for PANK2 mutations. The so-called HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, pallidal degeneration), of which only two cases have been reported, was proven to be allelic with PKAN [26, 46, 95]. The occurrence of acanthocytes as a feature of PKAN – in at least 8% of patients – has lately become more appreciated [39, 97]. Here we discuss the history of NA in Japan and in the English medical literature, including the appropriateness of the use of the “Levine–Critchley” eponym and the confusion in diagnosis of NA syndromes prior to the molecular era. We discuss recent developments in ChAc and issues related to the genetics of this disorder Neuroacanthocytosis Syndromes – A Current Overview 5 (advances in MLS are discussed in the chapter by Jung). Therapy for NA syndromes is at present in its infancy and is limited to symptom management, however patients with these debilitating disorders may nevertheless derive significant benefit from medical and non-medical interventions, which are summarised below. 2 Neuroacanthocytosis in Japan A historical perspective of NA (probable ChAc, but never confirmed using current methods) reveals the large number case reports in Japanese, starting with Shimizu’s report of 1974 [122] and continuing into the 1990s, most of which were initially presented at local meetings of the Japanese Society of Neurology [9, 13, 35, 45, 48, 50–53, 55, 57–59, 63, 65, 66, 68, 81, 91, 92, 106, 114, 119, 120, 123, 128–130, 132, 136, 151]. According to a personal communication by Prof. Hirose (and see his chapter in this volume), the topic of NA syndromes was selected for a symposium at the 1980 Annual Meeting by the then president (Prof. Kameyama, Kyoto) of the Japanese Society of Neurology [1]. Much of what was presented there [10, 41, 64, 67, 88, 107, 112, 116, 118, 153] had already been reported locally and, since funds had been devoted to the study of NA by the Ministry of Health and Welfare of Japan to Prof. Toyokura of Tokyo University, these cases were also collected as brief reports for a government record of these activities [138]. All relevant studies were reported in more detail in journals with English abstracts such as “Rinsho Shinkeigaku” (Clinical Neurology), “Shinkeinaika” (Neurological Medicine), “No To Shinkei” (Brain and Nerve), or in international journals [12, 42, 60, 62, 72, 89, 93, 94, 96, 113, 115, 117, 121, 124, 126, 131, 134, 135, 140, 141, 152]. An exact count of case numbers in Japan is difficult because of inaccessibility of material to English speakers and duplicate publications, but the number of 71 patients mentioned by Prof. Hirose in his chapter appears to be a conservative estimate. Thus Japan, in contrast to the few reports from other parts of Asia [5, 15, 17, 28, 37, 61, 69, 83, 84, 104, 139] and the approximately 150–200 cases from the rest of the world [25], appears to have the highest diagnosis rate in the world. 3 Levine–Critchley Syndrome To date, confirmation of the identity of the patients with the original NA “Levine– Critchley syndrome” has not been possible. Attempts to trace the New England family described since 1960 by Irving M. Levine (Fig. 1) and others [33, 34, 70, 74–76, 103] have not yet been rewarding. The description of the proband is consistent with ChAc or MLS, particularly the descriptions that “his gait was lurching in character with long strides and somewhat ataxic because of quick involuntary knee buckling movements. ... Speech was moderately inarticulate because it was interrupted by involuntary tongue and facial movements.” [75] However, the clinical features of other family members and the pedigree diverge to some extent from the 6 R.H. Walker et al. features of patients with molecularly identified ChAc. There was consanguinity five generations previous to the affected family members. Examination of the pedigree shows that chorea was present in one of the proband’s siblings, a maternal aunt, and a cousin who had chorea gravidarum [75]. All of these subjects had acanthocytosis. The neurological findings in many of the other reported family members from four generations are challenging to interpret, and consist predominantly of various combinations of hyporeflexia, mild weakness and muscle atrophy. Acanthocytosis was found mostly in family members with these findings, but did not necessarily cosegregate with the neurological abnormalities. There is apparent male–male transmission excluding the diagnosis of MLS and the inheritance pattern in general appears to be autosomal dominant. However, the variability of the neurological findings, and the presence of acanthocytes in a girl with epilepsy on the father’s side of the family, which was otherwise not felt to be affected, make it difficult to draw a conclusion as to the nature of the disorder being described. The patients reported by Edmund Critchley from two families, one from East Kentucky, USA [22, 23], the other from Lancashire, UK [16, 21], however, display the typical clinical features of genetically confirmed cases [25]. Edmund Critchley (Fig. 2) nicely has summarized his findings [20], most recently in an enjoyable “Neurologist’s Tale” [19]. Fig. 1 Irving M. Levine (right) with Mitchell F. Brin, circa 1985. Photograph courtesy of Dr Mitchell F. Brin Neuroacanthocytosis Syndromes – A Current Overview 7 While working at the Department of Neurology of David Barrett Clark in Lexington, Kentucky, it was his task to provide neurologic care in the small towns of the hinterland: “I went about weekly to a regional clinic. We would hire a State limousine, seating at least six people and holding an EEG set, and travel down a state highway at about 90 mph (looking out for helicopters) to a National Park, where we stay the night before an early start treating epilepsy, genetic diseases and other neurological disorders referred to us.” [19] In these isolated regions he discovered his “prize patient”, for whom he uses the alias Terry. “The poor were white, the Scots-Irish, the inbred white people living along the ‘creeks’ or narrow river valleys, the Appalachian poor. ... Forced to work on the plantations of Virginia to pay their passage to America, many chose to escape and live rough as frontiersmen. They found a creek with a bit of land, safe from other feuding wild men ... married and produced offspring. The progeny moved further along the creek to poorer and poorer land, intermarrying with their own kith and kin” [19]. Fig. 2 Edmund Critchley. Photograph courtesy of Dr E.M.R. Critchley 8 R.H. Walker et al. “Terry had presented to Abe Wikler, Professor of Psychiatry, Neurology and Pharmacy, who had attempted to try to control his movement disorder to no avail. Dave Clark was determined that he should be thoroughly investigated and I was the man to do so .... Terry was a 29-year-old white male. When first seen at the age of 26, he exhibited involuntary movements and had a grossly swollen, raw, bitten tongue. He had had 15–20 similar episodes of tongue, lip and cheek biting, which often occurred at night. The episodes started 6 years earlier on a background of increased generalized weakness, nervousness, ‘fits and jerks’, and had increased in frequency and severity. The involuntary movements included finger-snapping, grimacing, dystonic and choreiform movements, hyperextension of the trunk, twisting movements of his shoulders, sucking noises, plosive sounds and drooling. ... There had been times when he could not speak plainly: ‘the inside of his mouth would draw’, he would ‘snap at his lips, and his stomach would stick’. When he ate, his tongue would involuntarily push food out on to his plate. For 4 years he had preferred to retire to a separate room to eat. “He showed no psychotic or hallucinatory behaviour, but on his later admissions, appeared somewhat disinhibited sexually. Over 2 years, he had two episodes of ‘passing out’ preceded by abnormal noises and shaking or tremor of the abdomen and outstretched extremities, ‘drawing up of the legs’. These episodes, which lasted for 30 min, were followed by confusion and a ‘wild look’ which persisted for approximately 1 h. On admission in 1967, his involuntary movements were so intense that he could not walk without assistance. He was alert, well-orientated, had no gross memory defects, and was disturbed by his own repulsive appearance. He slurred and stuttered when talking, was often indistinct and had occasional inappropriate laughter. Despite the involuntary movements, there was no ataxia and co-ordination tests were intact. He had generalized hypotonia, flexor plantar responses, and loss of deep tendon reflexes. There was a suspicion of thinning with coarse twitching of his calves. His IQ was 72 (WAIS), verbal 81, and performance 61. ... He was the 10th child. “The eldest died of seizures, bit her tongue and had involuntary limb movements. She became forgetful, emaciated and bedfast with violent shaking of her limbs. Two others also died about the age of 26. The fourth child had an illness of 2 years duration, with passing out spells and rejection of food from the mouth. The fifth gave birth to an unaffected child and soon afterwards became bedfast and emaciated. The ninth remained healthy till aged 31, before developing choreic movements and grand mal fits. She has always refused admission to hospital but did permit an examination on herself and her normal 17-month child. I witnessed what appeared to be an attack of hystero-epilepsy with partial loss of consciousness, opisthotonus (bending the back in hyperextension) and drawing and grasping movements of all four limbs. Speech and swallowing were normal but she showed facial grimacing sans distal choreic movements. The deep tendon reflexes were absent and the diagnosis of acanthocytosis confirmed” [19]. Critchley provides us with the vivid picture of a severe and progressive neurological condition starting in the third decade in possibly seven male and female siblings (out of ten) from a genetically isolated background favoring interNeuroacanthocytosis Syndromes – A Current Overview 9 marriage and manifestation of autosomal recessive traits. He clearly describes severe orofacial dyskinesia with a tongue that would involuntarily push food out on to the plate, generalized chorea severely interfering with gait, sudden trunk flexion and hyperextension, some neuropsychiatric and cognitive impairment and possible epileptic seizures. Critchley also noted the resemblance to the tics of the Gilles de la Tourette syndrome [20]. It is commonly said that “chance favors the prepared mind” and this was certainly true for Edmund Critchley when he happened to see a single patient with an almost identical movement disorder, her parents unrelated, coming from different counties [20]. “Within a year of my return to England, a 30-year old patient was referred to me ... her husband had noticed ... that her walk was ungainly and had avoided drinking with her in company because of her tendency to slobber ... increasingly irritated by grunting noises, of which at first she was unaware. ... She started to lose weight ... complaining of intermittent difficulty in swallowing and a tightness in the throat. ... Most disturbing were the wide variety of oro-facial tics ... continually present during waking hours, though fluctuating in severity from day to day ... Her speech was dysarthric, partly broken by involuntary movements. She would also grunt, suck, make repetitive sounds, bite her tongue and lower lip, or struggle to control the pooling of saliva. The involuntary limb movements were sometimes dystonic and choreiform with hyperextension and flexion of her trunk and throwing out of an arm or leg ... she took her own life ... A coroner’s post-mortem was cursorily performed ...” [19]. All of Critchley’s cases appear to have had a phenotype identical to that seen in patients with a molecular diagnosis of ChAc [25]. However, in the absence of genetic testing, we may never know whether Levine–Critchley syndrome truly was ChAc or some other related neurodegenerative disease, making use of the eponym rather imprecise. 4 Subsequent Neuroacanthocytosis Reports The question of diagnosis is illustrated by the paper of Hardie and collaborators from Queen Square [38]. This often-cited NA case series has become problematic since its group of 19 patients has since been shown to be genetically heterogeneous (see chapter by Gandhi et al.). Cases 1–4 (family H) were found to be compound heterozygotes for mutations in the VPS13A gene (family CHAC 01 [105]). Cases 5–10 (family L) carry a McLeod mutation [44]. This family, which was originally reported as having a benign condition [79], is unique because of the severe disease expression in a female mutation carrier. Her neuropathological findings are described in chapters by Danek et al. and Geser et al. Cases 11–12 (family B) were only found to have one VPS13A mutation (family CHAC 09 [100]). A few of Hardie’s cases have not yet been diagnosed using molecular methods. Another report in which the diagnosis remains to be clarified is that of two Russian-Jewish brothers who presented in their 50’s with proximal muscle 10 R.H. Walker et al. weakness and sensory neuropathy in addition to chorea and orofacial dyskinesia [4]. Based on an observation from Israel, where homozygous deletions of VPS13A (6059delC) had been found in two unrelated patients, it was postulated that these cases provide support for a founder effect of ChAc in Ashkenazi Jews [78]. However, gender, age at onset and clinical manifestations are more consistent with a diagnosis of MLS than of ChAc, as is the pedigree structure of the two brothers [4]. Motor restlessness, seizures and neuropathy in the mother would not be expected in the autosomal recessive condition of ChAc and could be better explained if she were a manifesting MLS mutation carrier. 5 Chorea-Acanthocytosis – Recent Developments 5.1 Molecular Studies Autosomal recessive chorea-acanthocytosis (ChAc) is due to mutations of the large gene VPS13A [100, 25, 29, 142] which encodes for the protein chorein that appears to be fairly widely expressed in brain [11, 14, 71] (see chapter by Bader et al.). The function of its protein product, chorein, is not known, apart from that it is likely to be a sorting protein, and may be involved in intracellular protein trafficking (see chapter by Velayos-Baeza et al.). A large number of different mutations, including frameshifts (small deletions or insertions), nonsense, splice-site, deletions, and missense mutations, and deletions of whole exons have been found throughout the entire gene, making screening a challenge [29, 100, 142]. 5.2 Clinical Features The typical onset of ChAc is in young adulthood, but may occur at younger ages. Initial presentation with a variety of neuropsychological syndromes is being increasingly recognized, including depression, psychosis, obsessive-compulsive symptoms, trichotillomania [78], tourettism [90, 108], anxiety and agitation (see chapter by Sano). Self-mutilation due to lipand tongue-biting may be due to apparent obsessive behaviors or to involuntary movements [145]. Behavioral changes suggesting a frontal lobe-type syndrome, including disinhibition and selfneglect, may present prior to development of the movement disorder. Dementia is frequently seen, with deficits primarily in memory and executive skills. The use of psychiatric medications may obscure the diagnosis for several years, as the involuntary movements are attributed to tardive dyskinesia. The involuntary movements of ChAc are usually chorea and dystonia, but occasionally Parkinsonism. Orofacial and lingual dyskinesias are typically prominent and troublesome, and may result in marked difficulty with eating [99]. Neuroacanthocytosis Syndromes – A Current Overview 11 Seizures are seen in approximately 40% of patients [99], but were more common in a cluster of French-Canadian families (70–80%; discussed in more detail below). Most attacks are described as generalized, probably of temporal origin, although mesial temporal sclerosis is not documented [3]. The presence of cortical abnormalities, either structural or functional [11, 32, 98], is under discussion (see chapter by Leenders and Jung). Neuromuscular signs comprise peripheral neuropathy and myopathy [99]. Serum creatine kinase (CK) elevation may be detected before the appearance of neurologic signs or symptoms [78]. Muscle atrophy and weakness, as well as CK elevation, may be regarded as secondary to chronic denervation. However, a primary myopathic process is suggested by nemaline rods [133] or accumulations of tissue transglutaminase [85] on muscle biopsy, and a predisposition to rhabdomyolysis [102]. In symptomatic carriers of apparently a single mutation of chorein, accumulations of chorein may be seen along the muscle cell membrane [110] (see chapter by Saiki and Tamura). Involvement of the autonomic nervous system is occasionally noted in ChAc (see chapter by Kihara et al.). Non-neurologic findings such as hepatosplenomegaly are sometimes, but not invariably, observed [99]. Hepatosplenomegaly does not seem to be a significant cause of morbidity, as long as its etiology is recognized, and it does not prompt invasive investigations. Neuroimaging in ChAc is typically reported as strongly resembling that in HD [73], although quantitative studies [40] indicate that the head of the caudate nucleus is particularly vulnerable (see chapter by Henkel et al.). Polysomnographic studies in several ChAc patients reveal sleep fragmentation, poor sleep efficiency, short total sleep time and a high rate of wakefulness after sleep onset [125] (see chapter by Ghorayeb et al.). These findings likely explain the daytime somnolence in these patients. The observations resemble those in HD and thus may be due to a common pathophysiological mechanism. 6 Inheritance Patterns Although the inheritance of ChAc is generally accepted as being autosomal recessive, and that of MLS as being X-linked, there are reports of apparent NA families in which the inheritance pattern does not conform to either of these. As discussed above, inheritance has been suggested as being autosomal dominant in Levine’s cases [75] and the same has been speculated about in Critchley’s Kentucky family [23]. The daughter of the eldest sibling (who was similarly affected to her brother “Terry”) also had severe neurological abnormalities, however, her syndrome was quite dissimilar (with a Friedreich’s ataxia-like phenotype and developmental delay) and Critchley himself doubted a relation of the two conditions [19]. A French-Canadian case cluster, centered around Saguenay-Lac St. Jean, Quebec, a farming region with a small founding population, was initially thought 12 R.H. Walker et al. to show dominant inheritance [6]. Most cases originally presented with epilepsy as mentioned above [3]. Molecular analysis permitted clarification of the rather complex pattern of inheritance in four French Canadian pedigrees with eleven affected patients [31]. Three out of the four pedigrees were homozygous for a deletion of the four terminal exons of VPS13A. Two females in the fourth family were homozygous for a splicing mutation (4242 + 1 G > T). The affected males in this highly consanguineous pedigree were compound heterozygotes for the two mutations just mentioned. Identification of a common haplotype associated with the terminal deletion in four apparently unrelated families implied a founder effect for ChAc in French Canadians. Thus, the recessive transmission of VPS13A mutations was obscured by the high degree of consanguinity in the Saguenay-Lac St. Jean population, with the misleading impression of dominant inheritance [6]. Autosomal dominant inheritance of NA was suggested for an Italian family, although consanguinity of the parents suggests the possibility of pseudo-dominance [80]. Acanthocytes were also observed in members otherwise unaffected by NA symptoms from a further family [86]. Molecular analysis of these cases has not been reported. Some of the descriptions of Japanese families with autosomal dominant transmission of NA syndromes could be due to isolation of the population and intermarriage. A founder effect has been shown for ChAc in Japan, in the form of the deletion mutation of VPS13A from the Ehime province [142]. One family has been reported with possibly autosomal dominant inheritance of ChAc, prior to the advent of genetic testing, although MLS or HDL2 (the latter unlikely in this population) was not excluded [62]. In two Japanese families apparent autosomal dominant effects of VPS13A mutations have been described. In one family of an affected woman with a homozygous point mutation (3889C > T causing R1297X), several relatives who carried a single copy of the diseased gene were said to display symptoms and signs characteristic for ChAc [47]. However, it is not completely clear that the neurological findings in the family could not have resulted from alternative causes. In another family a single mutation was found of one allele of the gene, a heterozygous G > A transversion at the last nucleotide of VPS13A exon 57 in a brother and sister [49, 108, 109]. Their unaffected mother, not consanguineous with the father, showed a homozygous wild type sequence at that site. The father and grandfather were not available for examination, but it was presumed that the mutation had been introduced from the paternal side. Although genetic analysis was not performed, ChAc was also felt to be present in three subjects with acanthocytosis and chorea from successive generations in side branches of the pedigree, fitting a pattern of autosomal dominant inheritance. It is possible that, comparable to initial findings in the French-Canadians, additional mutations were present in this pedigree. A second mutation of the index siblings may have been missed due to technical reasons, as was not felt to be unusual in our analyses of ChAc, where the second mutation had remained undetected in altogether 12 patients from 66 pedigrees [25]. Assay of chorein levels and further genetic analysis will help clarify this issue. Neuroacanthocytosis Syndromes – A Current Overview 13 7 Treatment of Neuroacanthocytosis Syndromes 7.1 Pharmacological Therapy To date treatment for the NA syndromes is purely symptomatic. As in other choreiform disorders, reduction of involuntary movements may be achieved in principle by reducing dopaminergic neurotransmission, using atypical antipsychotic agents or tetrabenazine. However, as in HD, this may not necessarily result in functional improvement. Anticonvulsants such as levetiracetam [24, 101] and topiramate [36] can be beneficial in secondary choreas, and may be considered in NA. Levetiracetam has been reported as providing specific benefit to truncal tics in ChAc [77], yet anecdotal experience in a single case has not confirmed this effect. Carbamazepine and lamotrigine may worsen involuntary movements [8]. Neuropsychiatric issues are often a major cause of morbidity and mortality, as suicide is not infrequent (see chapter by Sano). Depression should be aggressively treated. Selective serotonin-reuptake inhibitors and tricyclic antidepressants may be useful for depression, in addition to mood-stabilizing medications such as anticonvulsants. The second-generation neuroleptics, especially clozapine and quetiapine, may improve both mood disorders and chorea. Classical neuroleptics should be avoided in order to avoid potential induction of tardive movement disorders.