PLIN4-related myopathy: clinical, histological and imaging data in a large cohort of patients

Maggi, Lorenzo; Gibertini, Sara; Iannibelli, Eliana; Gallone, Annamaria; Bonanno, Silvia; Cazzato, Daniele; Gerevini, Simonetta; Moscatelli, Marco; Blasevich, Flavia; Riolo, Giorgia; Mantegazza, Renato; Ruggieri, Alessandra

doi:10.1007/s00415-023-11729-8

Cited by 5 publications

(5 citation statements)

References 17 publications

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“…A single large family with 13 patients presented a defect in PLIN4. 14,15 12 patients were diagnosed with distal filaminopathy. 6 patients carried variants in TTN (4 diagnosed with recessive distal titinopathy 24 and 2 with tibial muscular dystrophy 25 ), and the same number were affected by RYR1related distal myopathy 26 (Table 1, eTable 1).…”

Section: Genetic Featuresmentioning

confidence: 99%

“…12 Similar to MFM, the number of disease-causing genes and causative variants has considerably and rapidly increased up to include, among others, ACTN2 13 and PLIN4. 14,15 The boundaries between MFM and DM are blurry because they may show clinical, histopathologic, and genetic overlap. Most of the MFM-causing genes can have a distal presentation or involvement.…”

Section: Introductionmentioning

confidence: 99%

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Clinical, Histopathologic, and Genetic Features of Patients With Myofibrillar and Distal Myopathies

Bortolani,

Savarese,

Vattemi

et al. 2024

Neurology

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Background and ObjectivesThe diagnostic process for myofibrillar myopathies (MFM) and distal myopathies (DM) is particularly complex because of the large number of causative genes, the existence of still molecularly undefined disease entities, and the overlapping features between the 2 categories. This study aimed to characterize a large cohort of patients affected by MFM and DM and identify the most important diagnostic and prognostic aspects of these diseases.MethodsPatients with either a myopathological diagnosis of MFM or a clinical diagnosis of DM were included in this retrospective multicentric national study. Demographic, genetic, clinical, and histopathologic data of anonymized patients were collected from the neuromuscular centers of the Italian Association of Myology network.ResultsData regarding 132 patients with MFM (mean age 57.0 ± 15.8 years, 49% female) and 298 patients with DM (mean age 50.7 ± 15.9 years, 40% female) were gathered from 20 neuromuscular centers. 69 patients fulfilled the criteria for both groups (distal myopathies with myofibrillar pathology, DM-MP). Molecular confirmation was achieved in 63% of the patients. Fifty-two percent of the patients with MFM carried pathogenic variants in either DES (n = 30), MYOT (n = 20), or DNAJB6 (n = 18), which were also the most frequent disease-causing genes in DM-MP, while GNE (n = 44) and MYH7 (n = 23) were the genes most commonly carrying pathogenic variants in DM. The mean age at onset varied from <25 years in patients with causative variants in MYH7 and DYSF to 59 years in patients with myotilinopathies. Cardiac involvement was reported in 29% of patients with MFM and 16% of patients with DM, with DES and MYH7 variants significantly associated with the development of cardiomyopathy. Respiratory impairment was more prevalent in patients with TTN and DES variants and rare in other disorders such as GNE myopathy and dysferlinopathies, which were instead associated, together with DNAJB6-related and PLIN4-related myopathies, with the risk of losing ambulation during the disease course.DiscussionThe Italian cohort of patients with MFM and DM recapitulates the phenotypic heterogeneity and the partial overlap between the 2 groups. However, in relative contrast to the encountered phenotypic variability, only 5 genes accounted for most of the molecular diagnoses. Specific genetic entities are associated with significantly increased risk of developing cardiorespiratory complications or loss of ambulation, which has relevant prognostic implications.

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Section: Genetic Featuresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinical, Histopathologic, and Genetic Features of Patients With Myofibrillar and Distal Myopathies

Bortolani,

Savarese,

Vattemi

et al. 2024

Neurology

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“…In two of these families, the PLIN4 expansion appears identical in size to the one initially described, containing 39-40 instead of 29-31 repeat units. Notably, approximately 10% of carriers of the PLIN4 expansion within the four MRUPAV families have been reported as asymptomatic, with one such carrier being over 50 years old [204]. Finally, in the third family, a larger expansion consisting of 50 repeat units was identified in more severely affected subjects with an earlier onset myopathy (in their twenties), suggesting a correlation between the size of the expansion and the severity of the disease [205].…”

Section: Mendelian Disorders Linked To Perilipin Genesmentioning

confidence: 91%

“…Using a multiomics approach, they showed in a large Italian family that an unusual expansion of a 99-nucleotide repeat sequence encoding the 33-mer unit of the PLIN4 repetitive AH domain [25] co-segregated with the myopathic trait. Maggi et al [204] recently summarized the clinical characteristics of this slowly progressive adultonset myopathy from 15 affected members of this exceptional four-generation family. Muscle biopsies of affected subjects showed the presence of rimmed vacuoles with subsarcolemmal aggregates, containing increased PLIN4 levels as well as the ubiquitinated protein FK2 and autophagy markers p62/SQSTM1, which colocalized with PLIN4.…”

Section: Mendelian Disorders Linked To Perilipin Genesmentioning

confidence: 99%

Molecular mechanisms of perilipin protein function in lipid droplet metabolism

Griseti,

Bello,

Bieth

et al. 2024

FEBS Letters

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Perilipins are abundant lipid droplet (LD) proteins present in all metazoans and also in Amoebozoa and fungi. Humans express five perilipins, which share a similar domain organization: an amino‐terminal PAT domain and an 11‐mer repeat region, which can fold into amphipathic helices that interact with LDs, followed by a structured carboxy‐terminal domain. Variations of this organization that arose during vertebrate evolution allow for functional specialization between perilipins in relation to the metabolic needs of different tissues. We discuss how different features of perilipins influence their interaction with LDs and their cellular targeting. PLIN1 and PLIN5 play a direct role in lipolysis by regulating the recruitment of lipases to LDs and LD interaction with mitochondria. Other perilipins, particularly PLIN2, appear to protect LDs from lipolysis, but the molecular mechanism is not clear. PLIN4 stands out with its long repetitive region, whereas PLIN3 is most widely expressed and is used as a nascent LD marker. Finally, we discuss the genetic variability in perilipins in connection with metabolic disease, prominent for PLIN1 and PLIN4, underlying the importance of understanding the molecular function of perilipins.

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“…Pourteymour et al have also shown that Plin4 is expressed in human skeletal muscle [101]. Indeed, genetic variation in the PLIN4 gene was recently identified in an Italian cohort, resulting in the accumulation of Plin4 within muscle fibers, disrupted fiber organization, and reduced muscle contractility [102,103]. Recently, the increased expression of Plin4 during chemically induced oxidative stress has been reported [16].…”

Section: Plin4mentioning

confidence: 98%

Role of Perilipins in Oxidative Stress—Implications for Cardiovascular Disease

Cinato,

Andersson,

Miljanovic

et al. 2024

Antioxidants

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Oxidative stress is the imbalance between the production of reactive oxygen species (ROS) and antioxidants in a cell. In the heart, oxidative stress may deteriorate calcium handling, cause arrhythmia, and enhance maladaptive cardiac remodeling by the induction of hypertrophic and apoptotic signaling pathways. Consequently, dysregulated ROS production and oxidative stress have been implicated in numerous cardiac diseases, including heart failure, cardiac ischemia–reperfusion injury, cardiac hypertrophy, and diabetic cardiomyopathy. Lipid droplets (LDs) are conserved intracellular organelles that enable the safe and stable storage of neutral lipids within the cytosol. LDs are coated with proteins, perilipins (Plins) being one of the most abundant. In this review, we will discuss the interplay between oxidative stress and Plins. Indeed, LDs and Plins are increasingly being recognized for playing a critical role beyond energy metabolism and lipid handling. Numerous reports suggest that an essential purpose of LD biogenesis is to alleviate cellular stress, such as oxidative stress. Given the yet unmet suitability of ROS as targets for the intervention of cardiovascular disease, the endogenous antioxidant capacity of Plins may be beneficial.

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PLIN4-related myopathy: clinical, histological and imaging data in a large cohort of patients

Cited by 5 publications

References 17 publications

Clinical, Histopathologic, and Genetic Features of Patients With Myofibrillar and Distal Myopathies

Clinical, Histopathologic, and Genetic Features of Patients With Myofibrillar and Distal Myopathies

Molecular mechanisms of perilipin protein function in lipid droplet metabolism

Role of Perilipins in Oxidative Stress—Implications for Cardiovascular Disease

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