While CLP1 kinase-dead mice develop progressive loss of spinal motor neurons mimicking the pathology of amyotrophic lateral sclerosis, our patients showed instead a neurodegenerative disease with loss of cerebellar, brainstem and cortical volume, thinning of the corpus callosum, and loss of acquired motor and cognitive skills, with evidence for later loss of motor neurons. Certain forms of PCH show co-existent spinal motor neuron degeneration, notably PCH type I (also known as Norman's disease), and PCH due to EXOCS3 mutations (Goutieres et al., 1977; Wan et al., 2012), suggesting that both hindbrain and motor neurons may share susceptibility across the mutation spectrum. Cerebellar Purkinje cells and spinal motor neurons are among the largest neurons and thus likely most metabolically challenged of the cells in the nervous system, but why these specific neuronal cell types are vulnerable to reduced CLP1 activity is unclear.
