Objective: Recessive mutations in the Gap Junction Protein Gamma 2 (GJC2) gene cause Pelizaeus-Merzbacher-like disease type 1, a severe infantile-onset hypomyelinating leukodystrophy. Milder, late-onset phenotypes including complicated spastic paraplegia in one family (SPG44), and mild tremor in one case, were reported associated to GJC2 homozygous missense mutations. Here, we report a new family with two siblings carrying a different homozygous GJC2 mutation, presenting with late-onset ataxic and pyramidal disturbances, and parkinsonism in one of them. Methods: Two affected siblings were studied by neurological examination and brain MRI. Genetic analyses included genome-wide homozygosity mapping in both siblings, and whole exome sequencing in one sib. The resulting candidate gene variant was validated by Sanger sequencing. Results: The affected siblings share a novel homozygous GJC2 missense mutation (c.820G>C, p.Val274Leu), predicted as pathogenic by all used in-silico tools. Brain MRI showed hyperintense signal in T2-weighted images in the internal capsule and subcortical and periventricular white matter, consistent with hypomyelination. Conclusions: Our findings confirm and further expand the late-onset phenotypes of GJC2 mutations, to include prominent ataxia, pyramidal disturbances and mild parkinsonism, and confirm the distinctive associated MRI pattern.

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doi.org/10.1016/j.parkreldis.2019.07.033, hdl.handle.net/1765/119017
Parkinsonism & Related Disorders
Erasmus MC: University Medical Center Rotterdam

Kuipers, D., Tufekcioglu, Z. (Zeynep), Bilgiç, B. (Başar), Olgiati, S., Dremmen, M., van IJcken, W., … Bonifati, V. (2019). Late-onset phenotype associated with a homozygous GJC2 missense mutation in a Turkish family. Parkinsonism & Related Disorders. doi:10.1016/j.parkreldis.2019.07.033