Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that can rarely affect young individuals. Juvenile ALS (JALS) is defined for individuals with an onset of the disease before the age of 25. The contribution of genetics to ALS pathology is a field of growing interest. One of the differences between adult-onset ALS and JALS is their genetic background, with a higher contribution of genetic causes in JALS. We report a patient with JALS and a pathogenic variant in the TARDBP gene (c.1035C > G; p.Asn345Lys), previously reported only in adult-onset ALS, and with an atypical phenotype of marked upper motor neuron predominance. In addition, the proband presented an additional variant in the NEK1 gene, c.2961C > G (p.Phe987Leu), which is classified as a variant of unknown significance. Segregation studies showed a paternal origin of the TARDBP variant, while the variant in NEK1 was inherited from the mother. We hypothesize that the NEK1 variant acts as a disease modifier and suggests the possibility of a functional interaction between both genes in our case. This hypothesis could explain the peculiarities of the phenotype, penetrance, and the age of onset. This report highlights the heterogeneity of the phenotypic presentation of ALS associated with diverse pathogenic genetic variants.
Keywords: TARDBP; TDP-43; juvenile amyotrophic lateral sclerosis; upper motor neuron predominant disorder.