An atypical case of neuronal ceroid lipofuscinosis

24 Background: The neuronal ceroid lipofuscinoses (NCLs, or Batten disease) comprise the 25 most common Mendelian form of childhood-onset neurodegeneration, but the functions 26 of the known underlying gene products remain poorly understood. The clinical 27 heterogeneity of these disorders may shed light on genetic interactors that modify disease 28 onset and progression. 29 Case presentation: We describe a proband with congenital hypotonia and an atypical 30 form of infantile-onset, biopsy-proven NCL. Pathologic and molecular work-up of this 31 patient identified CLN5 mutations, which are typically associated with late-infantile or 32 juvenile-onset NCL. We also demonstrated a mutation―previously described as 33 incompletely penetrant or a variant of unknown significance―in POLG1, a nuclear gene 34 essential for maintenance of mitochondrial DNA (mtDNA) copy number. Assessment of 35 relative mtDNA copy number and mitochondrial membrane potential in the proband and 36 control subjects suggested a pathogenic effect of the POLG1 change as well as a 37 functional interaction with CLN5 mutations. 38 Conclusions: These findings suggest that an incompletely penetrant variant in POLG1 39 may modify the clinical phenotype in a case of CLN5 and are consistent with emerging 40 evidence of interactions between NCL-related genes and mitochondrial physiology. 41