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Perilipins are a family of proteins that coat the surface of lipid droplets and regulate lipid turnover. Perilipin 4, encoded by PLIN4 on chr 9, is highly expressed in skeletal muscle where it mainly localizes to the subsarcolemmal regions of type 1 myofibres. An expansion of the perilipin 4 amphipathic domain (40 x 99 repetitive sequences in exon 3) was recently identified in a family suffering from an autosomal (AD) distal vacuolar myopathy. We aim to describe two unrelated Spanish families suffering from a highly similar distal myopathy caused by two different size repeat expansions in PLIN4 , respectively. Affected patients in both families presented around the age of 30 with distal weakness in the anterior compartment of legs eventually progressing to involve proximal and distal muscles of four limbs, with loss of ambulation and respiratory insufficiency later in the course of the disease. Muscle biopsies showed unique pathological features characterized by large numbers of rimmed vacuoles, located under the sarcolemma and within the cytoplasm. Under EM these autophagic vacuoles were often located at the periphery of myofibres. There were large numbers of membrane-bound lysosomes often in continuity with the extracellular space indicating exocytosis. The basal lamina showed abundant duplications and multiple folds. In addition, there were collections of tubulofilaments within the sarcoplasm. Immunohistochemical analysis showed prominent p62 co-localizing with PLIN4 at the sarcolemma and within the cytoplasm. WB analysis for PLIN4 revealed a band of higher molecular weight corresponding to mutated PLIN4 when compared to controls. Targeted ONT sequencing of affected individuals revealed a single 'normal' PLIN4 allele of 29 x 99bp repeats and a single expanded allele of 39 x 99bp repeats in the proband of family 1, and an expanded allele of 37 x 99bp repeats in affected individuals of family two. Unaffected members of both families harboured two copies of the 'normal' PLIN4 allele. We report two new size expansions of the perilipin 4 amphipathic domain in two unrelated families suffering from an AD distal myopathy. Subsarcolemmal p62 expression seems to be a unique marker of this disease. No correlation between the size of the expansion and clinical severity could be established. PLIN4 expansions should be considered in the diagnosis of distal vacuolar myopathies when conventional NGS technologies fail to identify. [ABSTRACT FROM AUTHOR]