Phenotypic heterogeneity in consanguineous patients with a common CLN8 mutation

The most heterogeneous subtype of neuronal ceroid lipofuscinosis comprises the late infantile variant, which, in addition to the classic CLN2, was reported in children with CLN5, CLN6, CLN7/MFSD8, and CLN8 genes. Patients with CLN8 mutations usually present as the late-infantile-onset neuronal ceroid lipofuscinosis phenotype and are mostly Turkish and Italian, but three patients from Israel, Pakistan, and Germany were also reported. In 2007, we described the late infantile variant phenotype caused by a missense mutation at the CLN8 gene (763C>G). This child with rapidly progressive disease within 3 years lost his mobility and manifested dementia, seizures, and profound visual loss. Subsequently we identified two additional children in the same pedigree with the same mutation and a considerably milder phenotype. Six and 3 years, respectively, after their onset of signs, they do not manifest motor disabilities, their cognitive regression and visual deficit are less appreciable, and only one manifests epilepsy. The reason for this clinical heterogeneity is unclear, although the presence of additional unknown mutated regulatory genes or epigenetic factors may explain it.