Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis.

Mouse models of the GM2 gangliosidoses [Tay-Sachs, late onset Tay-Sachs (LOTS), Sandhoff] and GM1 gangliosidosis have been studied to determine whether there is a common neuro-inflammatory component to these disorders. During the disease course, we have: (i) examined the expression of a number of inflammatory markers in the CNS, including MHC class II, CD68, CD11b (CR3), 7/4, F4/80, nitrotyrosine, CD4 and CD8; (ii) profiled cytokine production [tumour necrosis factor alpha (TNF alpha), transforming growth factor (TGF beta 1) and interleukin 1 beta (IL1 beta)]; and (iii) studied blood-brain barrier (BBB) integrity. The kinetics of apoptosis and the expression of Fas and TNF-R1 were also assessed. In all symptomatic mouse models, a progressive increase in local microglial activation/expansion and infiltration of inflammatory cells was noted. Altered BBB permeability was evident in Sandhoff and GM1 mice, but absent in LOTS mice. Progressive CNS inflammation coincided with the onset of clinical signs in these mouse models. Substrate reduction therapy in the Sandhoff mouse model slowed the rate of accumulation of glycosphingolipids in the CNS, thus delaying the onset of the inflammatory process and disease pathogenesis. These data suggest that inflammation may play an important role in the pathogenesis of the gangliosidoses.

The genetics of motor neuron diseases.

Motor neuron diseases may be divided into three categories: those with lower motor neuron involvement--spinal muscular atrophy (SMA) and spinobulbar muscular atrophy (SBMA or Kennedy's disease); those with upper motor neuron involvement--primary lateral sclerosis (PLS) and the spastic paraplegias; and those with combined upper and lower motor neuron involvement--amyotrophic lateral sclerosis (ALS). Other familial motor neuron disorders include hereditary neuronopathies, GM2 gangliosidosis, and possibly the ALS/PD syndrome of Guam. The contribution of genetics to the etiopathogenesis of motor neuron considerably, accounting for a high percentage of spinal muscular atrophies, but only a small fraction of cases of ALS. The mode of inheritance also varies, with examples of autosomal dominant (AD), autosomal recessive (AR), or X-linked kindreds. (Tables 1 and 2).