Phenotypic variability in chorea-acanthocytosis associated with novel VPS13A mutations

Discussion

Here, we add to the number of VPS13A mutations associated with variable phenotypic expression in 4 cases of ChAc. Similar to HD, structural neuroimaging for ChAc demonstrated both caudate atrophy with dilatation of the anterior horns and variable cortical atrophy.^1,4 Other MRI findings include increased T2-weighted signal in the caudate and putamen and hippocampal sclerosis and atrophy,¹ in contrast to some patients with ChAc with normal findings in the basal ganglia (BG).⁵ In addition, iron accumulation in the BG in patient 2 is in line with previous findings in ChAc¹. Caudate atrophy is progressive in MLS,² but this is, to our knowledge, the first report on progressive caudate atrophy in ChAc.

Consistent with previous studies on ChAc, we identified severe hypometabolism in the BG, loss of dopaminergic nigrostriatal projections, and dopamine transporter binding sites in all assessed patients.^6,–,9 Importantly, hypometabolism in the BG is not specific for ChAc, as it occurs also in MLS and HD. Furthermore, patients 1 and 3 had increased metabolism in the thalamus. Whereas thalamic hypermetabolism has been reported in patients with blepharospasm,¹⁰ we noted that only patient 3 has generalized dystonia and blepharospasm. The only previous MRS study in genetically confirmed ChAc demonstrated decreased NAA/Cr ratio in the atrophic striatum of 2 brothers.⁸ This abnormality reflects neuronal loss and gliosis. In contrast, the myo-inositol/Cr ratio was increased in this part of the BG. MRS abnormalities have previously been described in cortical areas of 5 patients with MLS, but abnormalities in the striatum were not determined.¹¹ In HD, MRS abnormalities are widespread and depend on disease stage. Our results showing reduced NAA, reflecting neuronal loss and gliosis, are in line with previous observations. The elevations of Cho, reflecting increased cellular membrane turnover and glutamate/Glx, suggest a possible role of glutamate excitotoxicity in ChA as a potential biomarker in the pathophysiology of ChAc.

A common clinical feature is the progression into bradykinesia, observed in 2 of 4 patients. The low binding of DaTscan to dopamine transporter in the striatum is a reasonable correlate to parkinsonism in patients 1 and 3; neuronal loss has been described in patients with ChAc with parkinsonism.¹ On the other hand, reduced binding in patient 4 is likely a premonitory sign of hypokinesia and no a side effect of neuroleptic since DaTscan is a presynaptic tracer. To date, there are only 5 reports on genetically confirmed ChAc in Scandinavia.^{3,e2,e3,e8,e9} All 6 mutations reported herein are truncating, and 3 of them are novel. This is consistent with previously reported VSP13A gene mutations, of which the majority predict a complete or partial loss of protein function.^e3 Low or absent chorein levels in 3 of our patients strengthen the notion that the VPS13A variants are indeed pathogenic. The reasons for the wide clinical variability in ChAc remain elusive.¹ Patient 3 presented with tourettism during adolescence and was diagnosed with ChAc at age 30 years, followed by a disease course spanning 17 years. This is remarkable considering that the mean disease duration in ChAc is 11 years.^e4 Furthermore, sudden unexpected death in epilepsy (SUDEP) appears to be common in ChAc and was recently reported in 6 of 52 patients.^e4 Patient 2 died during sleep at age 42 years, raising the suspicion of SUDEP. However, it cannot be excluded that the presence of sarcoidosis in her heart could have predisposed to a lethal arrhythmia.

Although our report brings additional information to the genetic and clinical variability in ChAc, the retrospective nature of our study precluded volumetric MRI analyses. Finally, our study calls for further longitudinal neuroimaging studies using different modalities to assess their potential role as biomarkers in ChAc.