Ceroid–lipofuscinosis (Batten's Disease): Pathogenesis and Sequential Neuropathological Changes in the Ovine Model

Abstract

A sequential morphological study of ovine ceroid-lipofuscinosis showed that brains of affected lambs were normal at birth, grew until four months of age but then atrophied. Laminar necrosis of cerebral cortex was noted at 10 weeks, occurring first in the parietal area, then spreading to involve frontal and occipital areas while the temporal lobe was least and last affected. With progression of the disease, the laminar pattern was lost. Neuronal necrosis was accompanied by a severe astrocytosis. The granular and multilamellar storage cytosomes increased in size with age. Their structure was interpreted as paracrystalline in which repeating molecules of the dominantly stored lipid binding subunit of mitochondrial ATP synthase interact with neutral lipids and phospholipids. Abnormal cytosomes in neurons of lamb fetuses and a neonate were interpreted as early lesions which contained whorls or stacks of bilayered membrane as well as the more complex multilamellar material. The underlying anomaly leading to the storage of the lipid binding subunit of mitochondrial ATPsynthase remains to be defined. However, it is noted that this disease should be regarded as a lipid binding protein proteinosis or alternatively as a proteolipid proteinosis.

Neuronal ceroid lipofuscinosis in Merino sheep

“…The age of onset, course of clinical disease and pathological findings in NCL-affected Merino sheep in this study were similar to those reported in South Hampshire 10,11 and Rambouillet 12 sheep, although lipopigment in Rambouillet sheep was detected only in the nervous system (including the retina) .…”

Computed tomography provides enhanced techniques for longitudinal monitoring of progressive intracranial volume loss associated with regional neurodegeneration in ovine neuronal ceroid lipofuscinoses

“…This has also been described in other models (ovine and canine) of NCL (Armstrong et al, 1983; Woods et al, 1993). The specific gravity of brains from affected animals was not increased even though the brains of affected sheep have been described as firmer in texture than those of controls (Jolly et al, 1989). The range of HU values representing brain tissue and CSF spaces reported here are in close agreement with findings from similar investigations in humans, where the mean HU value of grey matter was 39, that of white matter 32 and that of CSF ranged between −5 and 20 (Arimitsu et al, 1977; Hacker & Artmann, 1978).…”

“…A flock of sheep with a mutation in the CLN5 gene and two with mutations in the CLN6 gene provide well‐established large animal models that largely mirror the human pathological changes including the intracellular accumulation of subunit c of the mitochondrial ATP synthase (Cook et al, 2002; Frugier et al, 2008; Jolly et al, 1989; Jolly, Arthur, Kay, & Palmer, 2002; Palmer, 2015). Other common features of the ovine and human NCLs include progressive cerebral atrophy and enlargement of the cerebral ventricles (Frugier et al, 2008; Jolly et al, 2002, 1989 ; Woods et al, 1993). Neuroimaging techniques, such as magnetic resonance imaging (MRI) and computed tomography (CT), have been used to monitor changes of brain size and intracerebroventricular volumes in both human and ovine NCLs (Dyke et al, 2016; Jadav et al, 2014; Lobel et al, 2013; Sawiak et al, 2015; Valavanis, Friede, Schubinger, & Hayek, 1980; Woods et al, 1993).…”

Pathogenesis of brain dysfunction in Batten disease

“…Cortical and cerebellar atrophy is well established as a principal characteristic of Batten disease in humans [Lake, 19841 and in animal models [Jolly et al, 1989;Koppang, 19821. Cortical atrophy is conspicuous in South Hampshire sheep by the midpoint of the disease process (Fig.…”