Rapid and Progressive Regional Brain Atrophy in CLN6 Batten Disease Affected Sheep Measured with Longitudinal Magnetic Resonance Imaging.

Stephen J Sawiak,C Simon Bawden,Sunthara Rajan Perumal,Nadia L Mitchell,Timothy Kuchel,Loren Matthews,Clive J Mclaughlan,A Jennifer Morton,Skye R Rudiger,David N Palmer,Claire Wade

doi:10.1371/journal.pone.0132331

Abstract

Variant late-infantile Batten disease is a neuronal ceroid lipofuscinosis caused by mutations in CLN6. It is a recessive genetic lysosomal storage disease characterised by progressive neurodegeneration. It starts insidiously and leads to blindness, epilepsy and dementia in affected children. Sheep that are homozygous for a natural mutation in CLN6 have an ovine form of Batten disease Here, we used in vivo magnetic resonance imaging to track brain changes in 4 unaffected carriers and 6 affected Batten disease sheep. We scanned each sheep 4 times, between 17 and 22 months of age. Cortical atrophy in all sheep was pronounced at the baseline scan in all affected Batten disease sheep. Significant atrophy was also present in other brain regions (caudate, putamen and amygdala). Atrophy continued measurably in all of these regions during the study. Longitudinal MRI in sheep was sensitive enough to measure significant volume changes over the relatively short study period, even in the cortex, where nearly 40% of volume was already lost at the start of the study. Thus longitudinal MRI could be used to study the dynamics of progression of neurodegenerative changes in sheep models of Batten disease, as well as to assess therapeutic efficacy.

Highlights

Batten disease is the term by which the neuronal ceroid lipoficinoses (NCL), a group of rare genetic lysosomal diseases, are commonly known [1]
This study shows that 1) multiple magnetic resonance imaging (MRI) scans can be conducted in sheep affected by a severe and progressive neurological disease; 2) only small numbers of animals are needed for statistical significance; 3) in Batten disease sheep atrophy continues measurably in degenerating regions of the brain, even over the relatively short period of our study; 4) there is a differential time course of atrophy in different parts of the brain, with both magnitude and rate of atrophy varying between regions
There have only been a few case reports on late-infantile Batten disease caused by mutations in CLN6 that include MRI [28], and in these the pathology varied markedly between patients, even in consanguineous patients carrying the same gene mutation

Summary

Objectives

The aim of this study was to determine whether or not longitudinal MRI could be used to track in vivo the progressive brain atrophy in Batten disease affected sheep. The objective of the research was to determine if (1) longitudinal scans could be conducted on animals with overt signs of neurodegenerative disease; (2) progressive atrophy was measurable in animals in which frank atrophy had already occurred; (3) progression of regional atrophy could be detected with longitudinal scanning

Methods

Results

Conclusion