Primary lateral sclerosis (PLS) is a diagnosis of exclusion in patients with an adult-onset gradually progressive pure upper motor neuron (UMN) syndrome. It has been debated whether PLS is a separate disease or part of the spectrum of ALS. Adult-onset PLS is almost always sporadic; it can, however, be a rare manifestation of familial ALS (FALS).1 Homozygous mutations in the ALS2 gene are causative for autosomal recessive, early-onset forms of UMN diseases described as infantile–ascending hereditary spastic paralysis (IAHSP)2 and juvenile PLS (JPLS).3,4 They are also rarely associated with lower motor neuron (LMN) involvement (juvenile ALS, ALS2).3,4 Whether ALS2 mutations may also cause adult-onset PLS is not known. We, therefore, analyzed the ALS2 gene in 51 Dutch patients with adult-onset PLS. ### Methods. We included 51 Dutch patients (31 men and 20 women) with a progressive UMN syndrome of adult onset (median 51 years, range 18 to 76 years) and a median disease duration of 8 years (range 2 to 25 years). Onset was in the legs in 39, in the …