A Systematic Review of the Huntington Disease-Like 2 Phenotype

Abstract

Background: Huntington Disease-like 2 (HDL2) is a neurodegenerative disorder similar to Huntington Disease (HD) in its clinical phenotype, genetic characteristics, neuropathology and longitudinal progression. Proposed specific differences include an exclusive African ancestry, lack of eye movement abnormalities, increased Parkinsonism, and acanthocytes in HDL2.

Objective: The objective was to determine the similarities and differences between HD and HDL2 by establishing the clinical phenotype of HDL2 with the published cases.

Methods: A literature review of all clinically described cases of HDL2 until the end of 2016 was performed and a descriptive analysis was carried out.

Results: Sixty-nine new cases were described between 2001 and 2016. All cases had likely African ancestry, and most were found in South Africa and the USA. Many features were found to be similar to HD, including a strong negative correlation between repeat length and age of onset. Chorea was noted in 48/57 cases (84%). Dementia was reported in 74% patients, and Parkinsonism in 37%. Psychiatric features were reported in 44 out of 47 cases. Patients with chorea had lower expanded repeat lengths compared to patients without chorea. Eye movements were described in 19 cases, 8 were abnormal. Acanthocytes were detected in 4 of the 13 patients tested. Nineteen out of 20 MRIs were reported as abnormal with findings similar to HD.

Conclusion: This review clarifies some aspects of the HDL2 phenotype and highlights others which require further investigation. Features that are unique to HDL2 have been documented in a minority of subjects and require prospective validation.

Keywords

Acanthocytosis chorea HDL2 Huntington disease-like 2 Huntington’s disease junctophilin-3

INTRODUCTION

Huntington Disease like 2 (HDL2) is the Huntington Disease (HD) genocopy1 that most strongly resembles HD clinically and radiologically [1, 2]. Both are trinucleotide repeat disorders. HD is caused by a CAG repeat expansion occurring in exon 1 of the huntingtin gene on chromosome 4p16.3, while HDL2 is due to a CTG/CAG expansion mutation in exon 2A of the junctophilin-3 (JPH3) gene on chromosome 16q24.3 [3]. Since the discovery of the disease, there have been significant advances in the understanding of the genetics of HDL2, including data generated on the length of the repeat expansion and the haplotype associated with the mutation [4]. However, the clinical description so far derives from reports of small case series, scattered families, or isolated individuals. The phenotype has not been systematically or objectively reviewed.

Historical overview/background

The first eight cases of HDL2 were described in an African-American pedigree from the southeastern USA in 2001 [1]. The initial cases were found to have symptoms starting in the fourth decade of life with a movement disorder, psychiatric symptoms, weight loss, dementia, and a progressive and fatal course that was very similar to that of HD. The same authors identified the causative mutation in JPH3 [3]. The gene encodes a junctional membrane protein (junctophilin-3) that binds the plasma membrane to endoplasmic reticulum in neurons. JPH3 is expressed predominantly in the brain and testes [5].

In 2002, a family with three cases was published and described as “autosomal dominant chorea–acanthocytosis” [6]. These cases showed dementia, chorea, and Parkinsonism but lacked the orolingual dystonia and other typical features commonly seen in chorea–acanthocytosis. The first patient in this family was initially clinically diagnosed with HD. The clinical phenotype, autosomal dominant inheritance pattern and presence of acanthocytes in all three cases, suggested that the disorder was a novel variant of chorea–acanthocytosis. Subsequently the affected individuals were found to have a mutation in the JPH3 gene [7].

In Johannesburg, in 2002, seven additional cases were identified from a laboratory based cohort [8]. In black South African patients who tested positive for an HD-causing mutation, approximately 35% had a JPH3 mutation and 65% an HD mutation. This added further weight to the hypothesis that HDL2 is an African disease. Larger studies have confirmed the high frequency of JPH3 mutations in patients of African ancestry with a HD phenotype [4].

The HDL2 phenotype was established as an autosomal dominant inherited disorder that manifests in the third or fourth decade, characterized by chorea, dystonia, and/or Parkinsonism, progressive weight loss, and cognitive deficits. The disease progresses to death over the course of approximately 20years [9].

Knowledge of the HDL2 phenotype remains fragmentary and incomplete, with the likely consequence that HDL2 is underdiagnosed. Improved understanding of the phenotype will be essential for the treatment and education of patients and their families. To achieve this, we need to more fully describe the phenotype, including its presentation, course, and complications.

We have systematically reviewed all the available published cases of HDL2, and analysed the available clinical data, to provide a more detailed description of the phenotype. This review is designed to assist the clinician in recognizing clinical features of HDL2, differentiating HDL2 from HD, and defining aspects of the HDL2 phenotype which are not yet clear and will therefore require future study.

METHODOLOGY

The details of the review process are summarized in Fig. 1. We searched MEDLINE, Google Scholar, EMBASE and Scopus in December 2016. The terms “Huntington’s Disease Like 2” or “HLD2” or “junctophilin 3” or “JPH3” or “Huntington Disease” were always used in combination with the terms “phenotype” or “case report” or “case series” or “clinical” or “report” or “acanthocytosis” or “neuroacanthocytosis” or “Africa” or “African” or “phenocopy”. Where possible, filters were set for studies pertaining to humans, and included articles written in all languages. No time limits were set to gather all articles published to the end of December 2016.

Articles were excluded if they did not have an association with HDL2, were purely laboratory based, did not describe HDL2 clinically, relied on previously described cases or did not add to the clinical description of previously described cases. Available clinical data were extracted and descriptive statistical analysis performed.

Descriptive analysis of the data was carried out using SAS version 9.4 for Windows. We analysed repeat size, age of onset, duration of disease, presenting symptoms (cognitive, psychiatric, or movement disorder), and the presence or absence of Parkinsonism, bradykinesia, chorea, dystonia, dementia, psychiatric symptoms, and acanthocytes. Age of onset was defined as the age of first onset of symptoms stated or implied in a publication.

RESULTS

We initially identified 30 articles in which new clinical features or new cases of HDL2 were described. Once publications with repeat descriptions of the same patients were excluded, 19 articles remained. These articles provided descriptions of clinical features in 69 novel cases of HDL2. All of these cases were confirmed to have the causative genetic mutation, although the size of the abnormal repeats were not always reported. Table 1 shows a breakdown of the origins of the cases. Authors were contacted for confirmation where doubt remained about duplicated cases.

While clinical descriptions were available for the 69 cases, many of these were incomplete. Positive clinical features were noted, but there were few records of negative or absent features. The majority of publications were case reports with minimal longitudinal follow up data available. Table 2 summarises the available clinical data on the 69 patients. Publications seldom provided family history or inheritance pattern information, and insufficient transmissions were documented to comment on anticipation inHDL2.

Demographic and genetic findings

The majority of the patients were identified in South Africa and the USA, and were of African or African-American ancestry respectively (Table 3). The ancestry of patients with HDL2 is likely African in all cases, even if the ancestry is relatively distant. The shared common origin of these mutations is supported by studies that have shown a shared core haplotype in all patients tested, including those from South Africa, the USA, Mexico and the French West Indies [4] Although haplotyping has not been performed in the patients from Brazil and Venezuela, the historical links of these countries with Africa would suggest the origin of these patients is similar [9, 10].

The repeat length distribution is shown in Fig. 2. Although the median repeat expansion size (47 repeats) in HDL2 appears somewhat larger than in HD (43 repeats) [11], the mean age of onset for HDL2 is 41 years, very similar to that of HD of 40 years [12]. In HD the age of onset is defined as the age when movement abnormalities reportedly began; in the HDL2 publications initial symptoms included psychiatric and cognitive features. The age of onset showed a normal distribution with a range of 12 to 66 years. Gender was reported in 35 cases (12 females and 23 males). The ratio of 1.9 : 1 was not significantly different from 1 : 1 as seen in HD (chi-square test; p = 0.10).

There is a strong negative correlation between repeat length and age of onset in HDL2 (Pearson’s r = –0.76; p < 0.0001; large effect size) (Fig. 3). This supports the findings of smaller HDL2 studies that showed similar correlations [1 , 13]. The co-efficient of determination (r²) value in this HDL2 group is = 0,585 as seen in Fig. 3. This is quite similar to the r² value of 0.642 in HD in a North American, European, and Australian sample (the HD MAPS cohort) [14].

The youngest age of onset, 12 years, was reported in a patient from Mexico with a repeat length of 49 repeats and a presentation of depression, mild chorea and aggressiveness [7]. The case is unusual for two reasons: the much younger than expected age at onset based on repeat length, and the absence of the Parkinsonian symptoms typically found in juvenile onset HD [15]. This case may demonstrate that patients with HDL2 may present at younger ages than would be predicted by their triplet repeat size and with unexpected clinical features. Alternatively, clinical signs unrelated to HDL2 may have led to the serendipitous finding of the HDL2 mutation.

Clinical features

The presence or absence of chorea was reported in 57 cases. Chorea was present in 48 cases (84%). Parkinsonism was reported in seven of the cases with chorea, and dystonia was reported in six of these seven. The median expanded repeat length was significantly lower for those with chorea (47; IQR 44–51) compared to those without chorea (52.5; IQR 50–54) (n = 51; Wilcoxon rank sum test; p = 0.030). The average repeat size for the group with chorea was 48 and age of onset was 41 years of age. The average disease duration for this group was 6.5 years.

Parkinsonism was reported present in 26 (38%) cases. Of the 26, 23 were reported to have bradykinesia, 17 rigidity and 10 dystonia. The mean repeat length for this group was 51 triplets, age of onset 39 years, and disease duration 8.7 years.

Dysarthria was reported in 21 of the 69 cases, and was noted as moderate or mild. Eye movements were reported to be abnormal in only 8/19 cases [1 , 17]. Generalized epilepsy was not reported, but four cases were reported to have myoclonus[13, 18].

The presence of dementia was noted in 51 of the 65 cases, with only one case from a retrospective record review from South African specifically recording its absence [4]. Prominent dementia is described in most cases, and in the single report which explored this further, there were prominent frontal lobe features, working memory deficits and psychiatric features, similar to HD [19]. The presence of primitive reflexes were reported in 10/16 cases, all in patients with an associated dementia. The Unified Huntington Disease Rating Scale (UHDRS) has only been reported in three more recently published papers [13 , 20]. In one paper the verbal fluency, Stroop and symbol digit modalities tests could not be completed due to mutism or severe dementia [13].

There were 44 out of 47 cases reported to have psychiatric findings, and only three cases in which there were no psychiatric features present. These three were again from the South African retrospective record review [4]. The psychiatric findings included depression (seven reports), hallucinations (two reports) and aggression (four reports). It has been suggested that the heterogeneous psychiatric phenotype is similar to that found in HD [19].

From the original family described, worsening of the chorea and an increase in bradykinesia was reported with disease progression [1]. With longitudinal descriptions in patients there have been reports of generalized spasticity, hyperactive deep tendon reflexes, and extensor plantar responses. Clinical progression has been described in only five of the papers reviewed [1 , 21–23].

Acanthocytes

Acanthocytes were detected in only four of the thirteen patients tested. [6 , 23]. In those four patients, more than 30% of the erythrocyte population were acanthocytes, significantly greater than the normal population (less than 6.3% of erythrocytes are acanthocytes on a blood smear) but similar to the findings in chorea-acanthocytosis (typically higher than 28% [24]). To the best of our knowledge acanthocytosis has never been reported in HD.

Neuroimaging

There have been 20 reported MRIs in HDL2 cases; 19 were reported as abnormal. Generalized atrophy was described in all the cases with more severe atrophy of the caudate nucleus and putamen [1 , 25]. The single normal MRI is unexpected as this patient had a CT scan of the brain three years later which showed diffuse atrophy [6]. This is remarkable as this patient was found with two triplet expansion diseases and was also diagnosed with Fragile X syndrome. White matter lesions and atrophy are MRI features in Fragile X syndrome as well as in Fragile X-Associated Tremor/Ataxia Syndrome [26]. In two advanced cases, atrophy was generalized but affecting the parietal–occipital regions severely [13]. The brainstems and cerebellar regions are comparatively well preserved when described.

DISCUSSION

Since HDL2 was first described in 2001 there have only been a small number of cases reported and the descriptions have often been incomplete. There are however a number of consistent observations that are useful.

Demographic and genetic findings

Mutations of C9ORF72, spinocerebellar ataxia (SCA) 17 and HDL2 are variably reported as the most common HD phenocopies globally [2, 27]. In South Africa, HDL2 accounts for one third of patients of black and mixed ancestry with an HD phenotype and a confirmed diagnosis [4]. In a recent study of HD and HDL2 in South Africa the estimated combined minimum disease frequency was found to be higher than previously thought. A figure of 0.25 : 100 000 in black and 2.10 : 100 000 in mixed ancestry populations was described as an underestimate due to the probable under-reporting of both diseases in an under-resourced country [28]. HDL2 is therefore an important consideration in the differential diagnosis of HD phenocopies.

HDL2 joins many of the other repeat expansion neurodegenerative diseases with an inverse correlation of repeat length and age of onset, including the SCAs, spinobulbar muscular atrophy (SMA), dentatorubropallidoluysian atrophy (DRPLA) and HD [15 , 30]. This has important implications in an attempt to understand the pathophysiology and potentially unravel the mechanism whereby these diseases have similar phenotypic features [31].

Huntington’s disease and HDL2 have very similar repeat ranges associated with age of onset. Other CAG-repeat disorders have closely related, but somewhat different repeat ranges associated with age of onset. Examples are the HD phenocopies due to expansions in SCA17 and DRPLA with ranges of 47–63 and 49–88 respectively [32, 33].

There is a similar strong negative correlation between repeat length and age of onset in polyglutamine repeat diseases [31]. We have shown that the co-efficient of determination values in HDL2 and HD are similar when compared to SCA17 (r²–0.41) and DRPLA (r²–0.865) [32, 33].

Movement disorder

Chorea was the most commonly reported movement abnormality in all published cases. Chorea was described as generalized or axial in most cases where the distribution was mentioned. Orofacial chorea was highlighted in two cases [19, 21]. In the original pedigree, chorea and dystonia were present in all of the patients [1], although this does not hold true in all subsequent descriptions.

In the HD phenotype, chorea is not always present throughout the progression of the disease. In most cases it is a dominating feature. However, as the disease progresses, dystonia and rigidity become more prominent and chorea less noticeable [15]. In early-onset of the disease, with a high number of repeats, chorea may be absent. Parkinsonism has been reported to be more common in HDL2 than in HD [1, 13]. Bradykinesia has long been recognised as a feature of HD when chorea is present and is aggravated by antipsychotic medication use [34]. A speculative picture emerges for HDL2 patients in which patients with shorter repeat lengths are more likely to have chorea, but the confounding factors of duration of disease, possibly coincident bradykinesia, and use of dopamine-blocking medications need to be taken into account.

Mild to moderate dystonia was reported in 14 cases, however the presence or absence of dystonia was not mentioned in the majority of reports. In the few cases with dystonia it was usually noted in conjunction with other features of Parkinsonism. Dystonia is reported in 95% of HD cases [35]. It may be that in the HDL2 cases it was not noted due to the prominence of other movement abnormalities, specifically chorea. Alternatively, dystonia may not be as common as it is in HD.

Dysarthria was reported in less than a third of the HDL2 cases in the literature, and was classified as moderate or mild. Dysarthria is common in HD occurring in up to 89% of cases [36]. Dysphagia was reported only in one study of six patients, where it was present in four cases, and absent in two [13]. The frequency and characteristics of dysphagia in HD are poorly described [37].

Preserved ocular motor function was suggested in the original family reported with HDL2 [1]. Abnormal eye movements are a cardinal and early feature of HD [38]. A third of cases from the described patients with HDL2 in the literature had abnormal eye signs. Whether this is a potential distinguishing feature between the two conditions, or if the eye signs change with the progression of HDL2 warrants further observation. When described the specific eye movement abnormalities were hypometric or jerky saccades and interrupted ocular pursuit [9 , 16]. It has also been suggested that there may be two phenotypes of HDL2, the first an early onset form which is more Parkinsonian and lacks ocular motor involvement and a second, late onset variant which is more typical of HD with the typical jerky horizontal saccades [39]. Eye movements are not often described in juvenile HD but have been described as abnormal in individual cases [40]. If eye movements are normal in HDL2 it would predict that the disease spares the brainstem and ocular motor control centres. This needs to be investigated on imaging and in neuropathological studies and dedicated systematic oculographic recordings.

Myoclonus has been reported in four cases. In one case, somatosensory evoked potentials (SEP) showed enlarged N20-P25 and P25-N33 components, indicating a possible cortical origin [18]. Epilepsy and myoclonus are unusual features in HD and usually occur in the juvenile variant of the disease. When myoclonus does present itself, large SEPs [41] are usually not found.

Cognition

Dementia is likely a universal feature in HDL2, but there are several unanswered questions. Is HDL2 dementia similar to the frontal and subcortical dementia seen in HD as has previously been suggested? Is HDL2 dementia always a heralding sign of disease onset, and does the dementia progress more rapidly than in HD? A significant challenge, where cognitive testing was performed, was that the cases were reported late when the cognitive impairment was already advanced. In order to describe the spectrum of cognitive dysfunction in HDL2, premanifest patients and early onset patients will need to be studied.

Psychiatric features

The psychiatric features of HDL2 are poorly documented but have been suggested to be similar to HD. In HD, depression is 4–6 times more common than in the general population but there is still no evidence to adequately guide antidepressant use [42]. Aggression is also a common feature, occurring in 66% of HD cases in some studies with no evidence-based treatment currently available [43].

First sign/s of disease (Table 2)

For the 24 cases in whom presenting signs and symptoms are described, similar frequencies of cognitive, psychiatric and movement features are documented. Some patients reported more than one presenting sign. It is important to define features of disease onset in HDL2. The TRACK-HD study defined clinical manifestations of HD and biomarkers longitudinally and has allowed for defined endpoints for therapeutic trials as well as a better understanding of the disease [44].

Disease progression

The papers that have described HDL2 patients longitudinally indicate a clinical picture of increasing Parkinsonism, corticospinal tract signs and worsening dementia similar to that in HD [1 , 21–23]. This might be expected as post mortem findings have shown that there is atrophy and disease pathology in the basal ganglia and both cortical and subcortical motor structures [45]. A similar progression has been noted in HD [46].

Acanthocytes

Neuroacanthocytosis syndromes are syndromes where acanthocytes are a cardinal feature in conjunction with neurological features. Mcleod Syndrome and Chorea Acanthocytosis are considered the “core” neuroacanthocytosis syndromes. Acanthocytes are not specific to these condtions and have been described in other conditions like pantothenate kinase–associated neurodegeneration [47].

HDL2 is currently classified as both an HD phenocopy and a neuroacanthocytosis syndrome, and often features in reviews of both disorders [2 , 49]. However, the association of HDL2 and acanthocytes remains unverified in the majority of patients [9]. No data exist on the relationship of acanthocytes to the trinucleotide repeat length or to duration ofdisease.

The association of HDL2 with acanthocytes may provide important clues about pathogenesis. Junctophilins are not thought to be present in red blood cell membranes [50]. In HDL2 and the core neuroacanthocytosis syndromes, chorea-acanthocytosis and Mcleod syndrome, abnormal phosphorylation of the proteins involved in connecting the membrane and cytoskeleton in the erythrocytes may be a common link to the production of acanthocytes [51].

Neuroimaging and neuropathology

Radiologically and pathologically, HDL2 is broadly similar to HD in its involvement of the neostriatum and basal ganglia and general atrophy with progression of disease [45]. HDL2 may differ, at least in some cases, in its degree of focal cortical involvement, notably of the occipital lobe. In one case with occipital lobe atrophy, visual failure was described. This patient had decreased visual acuity and was unable to follow visual commands [20]. HD was initially thought to preserve the nucleus accumbens but a strong correlation with poor functional and motor scores has now been found with atrophy of the nucleus accumbens [52]. In the HDL2 cases that have been studied, this nucleus was at least partially or significantly involved [21]. These differences between HD and HDL2 have been noted pathologically but only focal occipital atrophy has been noted radiologically in the cases of HDL2 and not nucleus accumbens involvement [13].

Research using a HDL2 mouse model has found overlapping polyQ-mediated mechanisms of pathogenesis in HD and HDL2 [53]. A more detailed understanding of HDL2 phenotype, an HD phenocopy caused by mutation in a gene with an entirely different function from huntingtin, may offer further evidence of a common pathogenesis and lead to the development of novel therapeutic approaches for both diseases.

CONCLUSION

The rarity of HDL2 makes describing the phenotype in a statistically meaningful way a challenge. Only 69 cases have been described over 15 years. This review has evaluated all published cases to the end of 2016 to consolidate the available data, and to provide the current view and understanding of the clinical phenotype. The data are all retrospective, of varying quality, largely anecdotal and based on small patient groups. They also tend to be biased by the reporting of positive features, and the failure to report the absence of features. There is clearly a need for a further systematic and focused prospective study of cases. To address this need, the South African Huntington Disease Like 2 Study (SAHDLS), based in Johannesburg, where the HDL2 prevalence is the highest in the world, is currently collecting standardised clinical neuropsychological and MRI data and blood samples. We invite other clinicians to collect data from HDL2 patients using similar standardized methods to generate an international HDL2 database.

CONFLICT OF INTEREST

Prof Russell L. Margolis has received a grant from the ABCD Charitable Trust.

Prof Amanda Krause has received a grant from the South African Medical Research Council.

The remaining authors declare that there are no conflicts of interest relevant to this work.

Footnotes

The terms genocopy and phenocopy have been used interchangeably to define diseases of similar phenotype with different genetic causes. Strictly speaking this is the definition for the term “genocopy”, where “phenocopy” refers to similar phenotypic traits caused by environmental factors. The term phenocopy will be used in this instance because it is most commonly used in the literature and in most cases, assumed to mean diseases with similar phenotypes of different genetic origins.

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