Duchenne muscular dystrophy: Clinical, genetic and pathological changes in preclinical and early stages

Duchenne muscular dystrophy (DMD) is the most common and severe form of dystrophinopathy, with diagnosis around 4 years. We aim to describe the relationship between clinical characteristics and muscle histological changes, particularly comparing biopsies under and above the age of 1 year. Retrospective observational study of DMD with muscle biopsy performed in patients below five years followed in our centre. All biopsies were from the deltoid muscle. Data on demographics, clinical and molecular characteristics was collected. Muscle biopsies were re-analyzed blinded to demographic and clinical features. We present descriptive and inferential statistics using chi-square test. Twenty muscle biopsies were available, all from boys, before steroid treatment. Median age at the time of the biopsy was 2 years. Twelve children were already able to walk at the time of biopsy. One was a 16 week fetus with a dystrophin gene mutation, with an older brother with DMD. Apart from the fetus all muscle biopsies revealed marked atrophy and hypertrophy, necrotic and basophilic regenerating fibers. Endomysial fibrosis was present in all biopsies being more prominent and severe in older patients. Discrete adipose tissue substitution was observed in patients older than 19 months (n = 6). Immunohistochemistry revealed absent dystrophin staining in all cases but two, presenting discrete and irregular staining. Nine cases showed scattered revertant fibers. Molecular genetic analysis revealed DMD gene deletions (n = 12), point mutations (n = 7) and duplications (n = 1). No correlations between clinical features, histological changes and molecular diagnosis were found. The muscles studied showed severe pathological changes even at preclinical stages of DMD. The morphologic study of DMD skeletal muscle should be considered to help define the correct age for clinical trials and tailored therapy.