3 to 6% of the human genome is composed of microsatellite sequences, which are short DNA elements composed of 2 to 6 nucleotide motifs repeated in tandem. Expansion of a subset of these microsatellites is the leading cause of >60 diseases. However, most of these mutations are located in sequences annotated as non-coding, thus questioning how they are pathogenic. Here, we found that GGC repeat expansions causing oculopharyngodistal myopathy with or without leukoencephalopathy (OPDM/OPML) are located within previously unrecognized open reading frames (ORFs), resulting in their translation into novel polyglycine-containing proteins. Antibodies developed against these proteins stain the p62-positive inclusions typical of these diseases. Moreover, expression of these polyglycine proteins causes locomotor and skeletal muscle alterations associated with neurodegeneration in cell, fly and mouse models. Finally, we identified a compound, the cationic porphyrin TMPyP4, targeting expression of these polyglycine proteins, raising hope to develop a therapy for these disorders. Overall, this work highlights the complexity and richness of the human genome and the importance of mutations in yet unrecognized small ORFs.