LON protease degrades the oxidized, hydrophobic form of aconitase. Accumulation of aconitase may compromise mitochondrial function and cellular viability. Mutations of the LONP1 gene have been associated with CODAS (Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies) syndrome. Bi-alleleic mutations of LONP1 has also been described causing pyruvate dehydrogenase deficiency and profound neurodegeneration with progressive cerebellar atrophy.
Neuroimaging of CODAS showed cortical atrophy, subcortical hypomyelination, and a thin corpus callosum,. These patients may have hypoplasia of the dens
Neuroimaging of patients with Bi-allelic mutations of LONP1 causing pyruvate dehydrogenase deficiency showed progressive vermian and cerebellar atrophy, mild progressive brainstem thinning, increased T2/FLAIR of the cerebellar cortex and hippocampi, progressive atrophy of the cerebral hemispheres and hippocampi, thinning of the corpus callosum, progressive loss of normal T2/FLAIR myelin signal in the cerebral white matter, progressive T2/FLAIR low signal in the globi pallidi and thalami, and failure of odontoid tip ossification.
References
Strauss, KA, Jinks, RN, Puffenberger EG, et al. CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease. Am. J. Hum. Genet. 96: 121-135, 2015.
Nimmo GAM, Venkatesh S, Pandey AK, et al. Bi-allelic mutations of LONP1 encoding the mitochondrial LONP1 protease cause pyruvate dehydrogenase deficiency and profound neurodegeneration with progressive cerebellar atrophy. Human Molecular Genetics. 28(2), 290-306, 2019