Shape alterations in the striatum in chorea-acanthocytosis
Introduction
The neuroacanthocytoses are a group of disorders that present with neurological and psychiatric manifestations, and acanthocytes, spiculated red blood cells. Chorea-acanthocytosis (ChAc; MIM 200150) is an autosomal recessive disorder associated with mutations or deletions in the VPS13A gene on chromosome 9q. This gene codes for the membrane protein chorein (Ueno et al., 2001, Rampoldi et al., 2002), which is strongly expressed in the brain (Dobson-Stone et al., 2002). Loss of function of chorein appears to affect basal ganglia neurons, especially those in the caudate and putamen (Bader et al., 2008). Onset of neurological disturbance in ChAc is usually between ages 25 and 45, commonly with limb chorea that may be indistinguishable from Huntington's disease (Dobson-Stone et al., 2002), but also with distinctive lingual feeding dystonia (Bader et al., 2010). Identification and sequencing of the VPS13A gene (Rampoldi et al., 2001, Ueno et al., 2001) have enabled definitive diagnosis of ChAc and differentiation from related neuroacanthocytosis syndromes such as McLeod syndrome (Danek et al., 2005). Diagnosis have been facilitated by the development of a Western blot screening test for decreased or absent levels of chorein (Dobson-Stone et al., 2004).
Histopathologically, the relatively rare ChAc cases with confirmed VPS13A mutations have shown marked striatal neuronal loss with reactive astrocytic gliosis, particularly in the head of the caudate nucleus, with the globus pallidus less affected; and with minimal changes in the thalamus and substantia nigra, with the cortex almost universally spared (Bader et al., 2008). Magnetic resonance imaging (MRI) findings in established ChAc cases mirror these findings, showing marked striatal atrophy in the absence of significant cortical atrophy (Hardie et al., 1991, Kutcher et al., 1999, Walterfang et al., 2008).
The functional consequences of these changes in the striatum are the characteristic choreiform movements, thought to be the result of disruption of motor loops in the putamen and pallidum (Danek et al., 2005), and behavioural and neuropsychiatric symptoms. The involvement of non-motor frontostriatal loops that run through the caudate nucleus, in particular, may be responsible for the characteristic executive impairment seen in the illness (Hardie et al., 1991, Danek et al., 2005). Patients with ChAc have very high rates of obsessive–compulsive disorder (Walterfang et al., 2008), unique for any neurodegenerative condition, suggesting disruption to the caudate's central role in the function of the lateral orbitofrontal loop (LOFL) in subserving the choice of behavioural actions relevant to emotional and cognitive inputs from frontal cortex (Chamberlain et al., 2005).
Aside from case reports, only two systematic analyses of striatal volume have been undertaken in ChAc patients. Henkel et al. used a voxel-based morphometry (VBM) approach to compare six ChAc patients to 15 age-matched controls, and showed a focal and symmetrical atrophy of the caudate nucleus, but no reduction in any other brain region, including in the putamen (Henkel et al., 2006). Huppertz et al. expanded the dataset to nine ChAc patients, and utilised the normalization component of the VBM approach of Henkel et al. to create caudate and putamen masks from a large control group average to determine normalized volume of these structures. They demonstrated a significant volumetric reduction in both structures, and showed complete separation of ChAc patients and controls on measures of caudate volume (Huppertz et al., 2008). However, the methodology of these studies did not extend beyond analysing the total volume of striatal structures in ChAc. One study analysed striatal volume in three brothers with McLeod syndrome (a related neuroacanthocytosis syndrome) and 20 matched controls, and showed that patients' striatal volumes were significantly reduced compared with those of controls, with caudate nuclei showing a trend towards significant volume reduction over a 7-year follow-up period (Valko et al., 2010).
We sought to confirm and extend upon the findings of Huppertz et al. (2008) with an expanded dataset, using a standardized and validated traditional manual tracing methodology for each structure, followed by a morphometric analysis to determine whether the shape or morphology of the caudate and putamen differed between ChAc patients and controls. This allowed us to explore whether there are regional neuroanatomical changes to striatal structures in ChAc that may relate to the characteristic symptoms of the illness. Our hypothesis was that the caudate nucleus would be disproportionately affected, and that we would find a predilection for involvement of the head of the caudate nucleus, in particular regions that form a crucial component of the LOFL, in the patient group.
Section snippets
Subjects
Patients with ChAc (n = 13) were recruited from multiple centres worldwide, including the United Kingdom, Europe, North and South America, and Australia. Patients 1–8 include the six patients described in the previously published VBM study (Henkel et al., 2006) and patients 1–7 reported by Huppertz et al. (2008). Patient 9 has been previously described by Robertson et al. (2008) and Walterfang et al. (2008a), and patient 11 corresponds to case 2 of Rodrigues et al. (2008). Patients 12 and 13 are
Demographic and symptom data
The characteristics of the patient group are presented in Table 1, and between-group comparisons of demographic and volumetric data in Table 2. The patient group was not significantly different in age (t = − 0.418, p = 0.680) and was identical in gender mix. The mean duration of illness in the patient group was 12.57 ± 6.87 years.
Volumetric data
Whilst ICV was 9% smaller in the ChAc group, this was not significant (t = − 1.692, p = 0.107). However, individual striatal structures were all significantly smaller in the ChAc
Discussion
We have corroborated and extended the findings of two previous studies examining striatal volume in ChAc (Henkel et al., 2006, Huppertz et al., 2008), demonstrating in the largest cohort to date that both caudate and putaminal volumes are markedly reduced bilaterally in ChAc. This reduction in volume was greater for the caudate nuclei than for the putamen. Additionally, we showed that there was a significant morphometric difference for both structures between controls and ChAc cases, suggesting
Financial disclosures
The authors declare they have no financial conflict of interest.
Acknowledgements
Dr Walterfang was supported by a grant from the Advocacy for Neuroacanthocytosis Patients (www.naadvocacy.org). Dr Walterfang takes responsibility for the integrity of the data and the accuracy of the data analysis. Furthermore, Dr Styner's work was funded by the UNC Neurodevelopmental Disorders Research Centre HD 03110, and the NIH Roadmap Grant U54 EB005149-01, National Alliance for Medical Image Computing. Dr. B. Bader performed the chorein Western blot with the help of G. Kwiatkowski at the
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