Absence of Acanthocytosis in Huntington’s Disease-like 2: A Prospective Comparison with Huntington’s Disease

David G Anderson,Russell L Margolis,Dobrila D Rudnicki,Theresa L Coetzer,Ruth H Walker,Kubendran Naidoo,Amanda Krause,Sergio Carmona,Jonathan Carr

doi:10.5334/tohm.349

Abstract

Background: Huntington’s Disease-like 2 (HDL2) is classified as a neuroacanthocytosis; however, this remains unverified. We aim to determine if acanthocytes are present in HDL2 and whether acanthocytes can differentiate HDL2 from Huntington’s disease (HD). Methods: We prospectively compared 13 HD and 12 HDL2 cases against 21 unaffected controls in Johannesburg. Blood smears were prepared using international standards and reviewed by at least two blinded reviewers. An acanthocytosis rate of greater than 1.2% in the dry smear or greater than 3.7% in the wet smear was designated a priori as the threshold for clinical significance based on previously established standards. Flow cytometry was performed on all but four of the cases. Red cell membrane protein analysis was performed on all participants. Results: There were 12 HDL2, 13 HD, and 21 controls enrolled. None of the HD or HDL2 participants had defined acanthocytosis or other morphological abnormalities. None of the HD or HDL2 cases had evidence of an abnormal band 3. Discussion: Acanthocytosis was not identified in either HDL2 or HD in our patient population. Our results, based on the first prospective study of acanthocytes in HDL2 or HD, suggest that screening for acanthocytes will not help establish the diagnosis of HD or HDL2, nor differentiate between the two disorders and raises the question if HDL2 should be placed within the neuroacanthocytosis syndromes.

Highlights

Huntington’s disease-like 2 (HDL2) is an autosomal dominant neurodegenerative disorder caused by a CTG/CAG expansion mutation in exon 2A of junctophilin-3 (JPH3) on chromosome 16q24.3, which occurs in patients of African ancestry.[1]
We conclude that acanthocytosis is not a significant component of Huntington’s Disease-like 2 (HDL2) or HD in our patient population
In the first three cases the technique for obtaining the smear described not stressing the erythrocytes with saline or aging them and that up to 5% acanthocytes/echinocytes was accepted as being within the normal range.[5]

Summary

Introduction

Huntington’s disease-like 2 (HDL2) is an autosomal dominant neurodegenerative disorder caused by a CTG/CAG expansion mutation in exon 2A of junctophilin-3 (JPH3) on chromosome 16q24.3, which occurs in patients of African ancestry.[1]. Anecdotal case reports suggested that, compared to HD, eye movement abnormalities are less common and parkinsonism more common in HDL2.3. Acanthocytes were documented in some of the early reported cases of HDL2, resulting in diagnostic confusion with chorea–acanthocytosis.[4,5]. A Prospective, Blinded Case Controlled Study of Acanthocytes in HDL2. Acanthocytes are erythrocytes with spiky deformations of their membranes, and when found in high numbers are associated with many diseases. Methods: We prospectively compared 13 HD and 12 HDL2 cases against 21 unaffected controls in Johannesburg. Our results, based on the first prospective study of acanthocytes in HDL2 or HD, suggest that screening for acanthocytes will not help establish the diagnosis of HD or HDL2, nor differentiate between the two disorders and raises the question if HDL2 should be placed within the neuroacanthocytosis syndromes

Objectives

Methods

Conclusion