A number sign (#) is used with this entry because of evidence that autosomal dominant myopathy with rimmed ubiquitin-positive autophagic vacuolation (MRUPAV) is caused by heterozygous expansion of a 99-bp repetitive sequence in the PLIN4 gene (613247) on chromosome 19p13. Normal repeat length is 29 to 31, whereas disease-associated repeats range from 39 to 50.

Autosomal dominant myopathy with rimmed ubiquitin-positive autophagic vacuolation (MRUPAV) is characterized by adult onset of slowly progressive skeletal muscle weakness variably affecting the distal or proximal lower limbs. Some patients may also have upper limb involvement or neck muscle weakness, but respiratory and bulbar involvement only rarely occurs. EMG studies show a myopathic process, and myotonia may also be observed. Skeletal muscle biopsy shows myopathic features, rimmed vacuoles, and abnormal subsarcolemmal protein aggregation with activation of the autophagy pathway (Ruggieri et al., 2020).

Di Blasi et al. (2004) reported a large Italian family with adult-onset autosomal dominant distal myopathy characterized by rimmed vacuoles on muscle biopsy. There were 19 affected members spanning 4 generations. Six of 10 examined patients were severely affected, with marked bilateral weakness of foot dorsiflexors and neck flexors and mild involvement of wrist and finger extensor muscles without fasciculations. Shoulder muscles were also mildly involved. Serum creatine kinase was twice normal and EMG studies showed myopathic changes. Two mildly affected patients had mild distal lower limb and scapular girdle muscle weakness with normal creatine kinase levels, and 2 patients were clinically asymptomatic, although 1 had scapular weakness and both had abnormal myopathic findings on EMG. Di Blasi et al. (2004) noted that dysphagia and dysphonia were not present. Muscle biopsies from 6 patients showed myopathic changes and rimmed vacuoles in all biopsies. The vacuoles were variable in size, contained basophilic granular material, and clustered at the fiber surface and abutted the extracellular space. Filamentous inclusions were never observed. Immunohistochemical findings suggested dysregulation of lysosomal pathways and activation of the ubiquitin-proteasomal pathway. The authors noted that the vacuole characteristics were similar to those seen in Danon disease (300257), a disorder of lysosomal processing.

Maggi et al. (2023) reported follow-up of the family first reported by Di Blasi et al. (2004) and described the clinical features of 15 affected individuals. The patients presented at a mean age of 46 years (range, 30-66) mostly with distal muscle weakness affecting the lower limbs; some also had distal upper limb involvement. Two patients presented with proximal muscle weakness of the upper or lower limbs affecting the scapular or pelvic regions. The disorder was slowly progressive, and many patients eventually developed proximal weakness of the upper and lower limbs. Eight patients had neck muscle weakness, but only 2 individuals showed mild facial weakness, dysphagia, or tongue weakness. None had ptosis or oculoparesis. One patient had respiratory involvement and underwent tracheostomy at age 71, and another patient had mildly decreased forced vital capacity. One patient had late-onset cardiac atrial fibrillation without evidence of cardiomyopathy. About half of patients developed ankle contractures late in the disease stages. Approximately 40% of patients became wheelchair-bound about 17 years after disease onset. EMG showed diffuse myopathic findings and myotonic discharges. About half of patients had clinical myotonia, mostly as thenar eminence percussion. Serum creatine kinase was normal or mildly increased. Muscle biopsy showed myopathic changes, rimmed vacuoles, and positive immunostaining for PLIN4, FK2, p62 (601530), and NBR1 (166945) (Ruggieri et al., 2020). Five patients died at a median age of 74 years, all of whom had been wheelchair-bound. Cause of death was mainly respiratory or cardiac.

Yang et al. (2022) reported 2 large multigenerational Chinese families with MRUPAV confirmed by genetic analysis. Six patients in family 1 presented between 45 and 65 years of age with slowly progressive proximal lower limb muscle weakness. The older patients had gait difficulties; 1 became wheelchair-bound at age 80. The older patients also developed mild to severe weakness of the upper limbs and mild distal involvement of the upper limbs, which was not observed in the younger patients. Two of the older patients showed neck muscle weakness. Serum creatine kinase was elevated, and EMG showed a myopathic pattern. Myotonic discharges were observed in 3 patients. Three additional female family members in their fifties were asymptomatic even though they carried the mutation and had myopathic changes on EMG. The number of abnormal repeats in the PLIN4 gene in this family was 40. Two sibs in family 2, who were 41 and 35 years of age, had a more severe disorder beginning in their mid-twenties. They had marked muscle weakness of the proximal lower and upper limbs, moderate distal involvement, and severe neck muscle weakness. One was wheelchair-bound at age 39 and the other walked with aids at age 34. EMG showed myopathic changes, and serum creatine kinase was elevated. The number of abnormal repeats in this family was 50, suggesting that increased number of repeats is associated with earlier onset and a more severe disease course. None of the patients in either family had bulbar, respiratory, or cardiac involvement. Muscle biopsy in both families showed myopathic changes with fiber size variation and rimmed vacuoles. Electron microscopy showed vacuoles filled with membranous bodies, partially degraded organelles, and amorphous or granular material. Immunofluorescence analysis revealed colocalization of PLIN4 with FK2 and SQSTM1, as well as with aggrephagy-related proteins, suggesting abnormal PLIN4 aggregation and triggering of autophagy.

Wang et al. (2022) reported a large 3-generation Chinese family and an unrelated patient with PLIN4-related myopathy. The patients presented in their forties to sixties with proximal muscle weakness of the lower limbs. The disorder was slowly progressive, with eventual involvement of the proximal upper limbs and distal muscles. At least 1 patient showed scapular winging. Deep tendon reflexes were decreased or absent. The patient with sporadic disease also presented with chest distress and restrictive ventilation dysfunction. Muscle imaging of some of the patients showed fatty replacement of muscle tissue, with the thigh muscles more severely affected than the calves. EMG showed a myopathic pattern with complex repetitive discharges. Muscle biopsy showed myopathic changes with rimmed vacuoles, fiber type variation, and internal nuclei. Immunofluorescence studies showed p62/ubiquitin-positive protein deposition that colocalized with PLIN4 under the sarcolemma and within myofibers, and electron microscopy showed vacuoles containing membranous material and membrane-bound inclusions with granulofilamentous material. There was evidence of codeposition of protein aggregates with disrupted lipid droplets. One individual in the family with the mutation was asymptomatic at age 22, but showed myopathic changes and complex repetitive discharges on EMG.

The transmission pattern of MRUPAV in the family reported by Di Blasi et al. (2004) was consistent with autosomal dominant inheritance and incomplete penetrance.

Linkage analysis in the family reported by Di Blasi et al. (2004) yielded positive lod scores (greater than 3.0) at several markers on 19p13.3 between D19S209 and D19S177. All affected individuals shared the same haplotype over the candidate region.

In affected members of a large multigenerational Italian family with MRUPAV, originally reported by Di Blasi et al. (2004), Ruggieri et al. (2020) identified a heterozygous expansion of a 99-bp repetitive sequence in exon 3 of the PLIN4 gene from the normal 31x99-nucleotide sequence in the amphipathic domain to 40x99 nucleotides, resulting in 297 (9x33) extra amino acids (613247.0001). The abnormal expansion, which was detected by long-range sequencing, segregated with the disorder in the family. Patient muscle tissue showed a major increase in PLIN4 expression in subsarcolemmal regions and vacuoles, which also stained positive for the ubiquitin antibody FK2, SQSTM1 (601530), NBR1 (166945), and WDFY3 (617485), consistent with activation of autophagy. The findings suggested that the disorder is characterized by progressively increasing mobilization of aggrephagy at sites of accumulation of the mutated protein, likely through misfolding. This process leads to formation of large vacuoles which disrupt the organization of myofibers, particularly slow-twitch type 1 fibers.

In affected members of 2 large multigenerational Chinese families with MRUPVA, Yang et al. (2022) identified a heterozygous coding 99-mer repeat expansion in exon 3 in the PLIN4 gene. The mutation, which was found by a combination of linkage analysis and long-read whole-exome sequencing, segregated with the disorder in the families. The repeat in family 1 was 40, whereas the repeat in family 2, which had a more severe disorder with earlier onset, was 50. The findings indicated that the size of the repeat expansion is correlated with the severity of the disorder.

In affected members of a Chinese family with MRUPAV, Wang et al. (2022) identified a pathogenic 99-bp repeat expansion in exon 3 of the PLIN4 gene; the repeat number was 39.