In the last few years a number of therapeutical approaches have become available for patients affected by Duchenne muscular dystrophy (DMD). The majority of the approaches proposed so far are specifically targeting distinct group of mutations, such as stop codon point mutations or groups of deletions as in exon skipping studies. Because of this, the number of patients eligible for these studies is limited to those having specific mutations or groups of mutations. This has raised the question of whether natural history data should be used as controls in studies with few eligible patients and, more specifically, whether individual groups of mutations follow the general natural history of boys of DMD or have distinct profiles of progression of functional impairment. The aim of this study was to report 12 month longitudinal changes of the 6 min walk test (6MWT) in a large cohort of DMD ambulant patients subdivided according to type and site of mutations. 6MWT was performed in 198 DMD ambulant boys, older than 4 years at baseline and repeated after 12 months. 137 had deletions, 18 had duplications and 43 point mutations. Patients with deletions were further subdivided into subgroups according to whether they had mutations eligible for skipping in different exons, selecting those who were currently or likely to be part of clinical trials, eligible for skipping 44 ( n = 18), eligible for skipping 45 ( n = 16), eligible for skipping 51 ( n = 27), eligible for skipping 53 ( n = 28). Patients with point mutations were also subdivided identifying those with stop codon mutations. The 6MWD showed 12 months changes between −325 and 175 (mean −10) m. There was no significant difference between deletions, duplications and point mutations neither at baseline nor in the 12 month changes. When patients were subdivided into different subgroups of deletions according to their eligibility to skip specific exons, there was little difference between the individual subgroups and the patients with the whole cohort. The subgroup eligible for skipping exon 44 however had a trend to perform better at baseline and to show less deterioration than the other subgroups.