Ampliación del espectro molecular y patológico de la miopatía por HSPB8 y la neuropatía motora distal

HSPB8 variants cause myopathy, distal motor neuropathy, and Charcot-Marie-Tooth disease. We describe 2 patients who expand the molecular and pathologic spectrum of HSPB8 disorder.

We reviewed clinical and laboratory data and performed molecular dynamics simulations to explore variant effect.

Patient 1 is an adult man presenting with childhood-onset, distal lower limb weakness, followed by proximal weakness. EMG detected predominant myopathic and neurogenic changes in upper and lower limbs, respectively. Biopsy revealed myopathy with rimmed vacuoles in the supraspinatus and neurogenic changes in the tibialis anterior. He carries a novel, predicted deleterious HSPB8 heterozygous variant, c.185G>A (p. Gly62Asp). Patient 2 is an adult man presenting with distal, asymmetric, progressive lower limb weakness that extended to proximal and neck muscles. Quadriceps biopsy showed myopathy with rimmed vacuoles and protein aggregates, especially TIA1, p62, and TDP-43. TIA1 aggregates were more prominent than Z-disk protein accumulation. He carries a known HSPB8 pathogenic variant, c.421 A>G (p.Lys141Glu). Molecular dynamics simulations suggested that p.Gly62Asp may exert its effects through post-translation modifications while p.Lys141Glu may disrupt dimerization.

HSPB8 p.Gly62Asp is the first N-terminal variant associated with myopathy. TIA1 aggregates, more prominent than Z-disk myofibril aggregates, suggest that p.Lys141Glu may affect stress granule dynamics more than Z-disk integrity.