In this Journal Club episode, we review the publication by Yang et al., 2024, which presents the first Chinese case of Myofibrillar Myopathy type 13 with Rimmed Vacuoles (MFM13) in a pediatric patient. Unlike previously reported MFM13 cases, this young patient exhibits axial and limb-girdle muscle involvement, highlighting a novel early-onset presentation.

This episode is ideal for researchers, clinicians, and patients interested in MFM13, HSPB8 myopathy, rare pediatric neuromuscular cases, and autophagy-related mechanisms.

Please note that the article refers to the MFM13 disease as HSPB8-related myopathy.

In this episode, we summarize what is known about Myofibrillar Myopathy type 13 (MFM13), previously referred to as HSPB8 Myopathy. Drawing on nine published case studies, we outline the main clinical features — progressive muscle weakness and atrophy, usually starting in the distal lower limbs and leading to foot drop and steppage gait. In some cases, weakness extends to proximal and axial muscles, occasionally affecting breathing or cardiac function.

We also discuss the characteristic pathological findings seen in muscle biopsies: rimmed vacuoles, myofibrillar disorganization, and accumulation of proteins like HSPB8, BAG3, and TDP-43. MRI scans often reveal selective fatty degeneration of paraspinal and leg muscles.

Finally, we highlight the key discovery that frameshift mutations in HSPB8 result in an abnormal C-terminal peptide extension, creating a toxic gain-of-function mechanism that disrupts autophagy and cellular proteostasis — defining the molecular basis of MFM13.

Learn more about our work at curemfm13.org, and follow us on Facebook, LinkedIn, X, and Bluesky — just search for CureMFM13.

In this episode, we look at the 2025 study by Tedesco et al., “Novel HSPB8 mutations in severe early-onset myopathy with involvement of respiratory and cardiac muscles cause proteostasis defects in cell models,” published in the European Journal of Human Genetics. The researchers revealed three new mutations in HSPB8 that result in a previously undescribed frameshift. These mutations create a longer C-terminal end of the protein with a different amino acid sequence than those described before. This structural change is linked to an even more severe disease picture: earlier muscle weakness, sometimes combined with reduced involvement, breathing difficulties, and even cardiac problems. The study not only presents detailed case reports but also builds on Tedesco et al., 2023 (Episode 5), which showed how elongated C-terminal mutations disrupt the cell’s clean-up system. In the 2025 work, scientists demonstrate that these new frameshifts also cause toxic aggregation of CASA complex proteins, further impairing the cell’s ability to remove damaged proteins. These results highlight the vulnerability of the HSPB8 gene’s last exon and broaden both the molecular and clinical understanding of HSPB8-related myopathies and neuromyopathies

Episode 6 - What is Myofibrillar Myopathy type 13 (MFM13) with rimmed vacuoles?

In this episode, we take a deep dive into the molecular mechanisms behind Myofibrillar Myopathy type 13 (MFM13) with Rimmed Vacuoles also known as HSPB8 Myopathy —a rare myofibrillar disease caused by frameshift mutations in the HSPB8 gene. Learn how HSPB8 dysfunction disrupts the CASA complex and impairs autophagy, leading to toxic protein aggregation and muscle fiber degeneration. We place HSPB8 Myopathy within the broader context of Myofibrillar Myopathies, discussing shared histological features like rimmed vacuoles and protein aggregates. The episode also explores HSPB8’s role in proteostasis across tissues, its involvement in other neurodegenerative conditions, and available research tools such as patient fibroblasts and iPSCs. Whether you're new to the field or already engaged in neuromuscular disease research, this is your go-to introduction to HSPB8 Myopathy.

Episode 5 – Tedesco et al. 2023: Molecular Insights into HSPB8

In this episode, we dive into the 2023 study by Tedesco et al., titled "HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies," published in Autophagy. The research reveals how frameshift mutations in the HSPB8 gene lead to toxic protein aggregation and disrupt critical protein quality control systems. These mutations result in an elongated C-terminal end of the HSPB8 protein, promoting aggregates that sequester CASA complex components like BAG3 and autophagy markers such as p62—ultimately impairing the cell’s ability to clear damaged proteins. We explore how this toxic mechanism contributes to muscle fiber damage. A must-listen for patients, families, and professionals seeking a clearer understanding of the disease and the importance of genetic testing.

In this episode, we explore the key clinical features of HSPB8 Myopathy - an ultra-rare, autosomal dominant, progressive muscle-wasting condition. With fewer than 30 documented cases, awareness among clinicians is limited. We discuss when to suspect HSPB8 Myopathy, what signs to look for, and why genetic testing is essential for diagnosis.

If you're a healthcare professional working with patients experiencing progressive weakness, frequent falls, foot drop, or balance issues, especially in early to mid-adulthood, this episode is for you.

How can a small heat shock protein cause big problems in muscle and nerve cells?

This episode explores HSPB8, a key player in chaperone-assisted selective autophagy (CASA), which helps clear misfolded and damaged proteins. What neuromuscular disorders are linked to HSPB8 mutations? How do specific variants — from missense to frameshift — give rise to distal hereditary motor neuropathy (dHMN), Charcot–Marie–Tooth disease type 2L (CMT2L), and myopathy with rimmed vacuoles? We break down the toxic gain-of-function mechanisms driving disease and highlight emerging therapeutic strategies, from small molecules to RNA-based approaches. Based on the latest review by Professor Hebatallah R. Rashed, Dr Samir R. Nath, and Professor Margherita Milone in the International Journal of Molecular Sciences, this episode brings you cutting-edge insights into HSPB8 biology and pathogenesis.

Episode 2 – Introduction to HSPB8 Myopathy: What You Need to Know

In this episode, we break down HSPB8 Myopathy, a rare genetic condition that causes progressive muscle weakness and degeneration. We’ll explore how mutations in the HSPB8 gene lead to the formation of rimmed vacuoles in muscle fibers, and why genetic testing is so important for diagnosing the condition. Whether you're affected by the condition, a clinician, or a researcher, this episode will provide a clear understanding of the disease and its genetic basis.

Episode 1 – Our Mission, Our Vision, Our Voice

Welcome to the Cure HSPB8 Podcast. In this inaugural episode, we share how and why Cure HSPB8 came to be — and what drives our mission to improve the lives of everyone affected by HSPB8 Myopathy. You’ll hear about the challenges of diagnosing and treating this ultrarare disease, our strategic goals, and how we’re building a global community around hope, science, and advocacy. Whether you're newly diagnosed or a seasoned researcher, this series will inform, connect, and inspire.