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.

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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.