SPEG-related disease is a rare condition most frequently characterized by congenital myopathy (often, centronuclear myopathy) and/or early-onset dilated cardiomyopathy (DCM). Typical presenting features include neonatal or infantile hypotonia, generalized weakness, poor feeding, respiratory insufficiency and delayed motor milestones. Cardiac involvement may present in infancy or early childhood and can progress rapidly to dilated cardiomyopathy and heart failure; some patients have required transplantation. Additional findings reported include variable peripheral neuropathy, arthrogryposis in some cases, and less commonly multisystem manifestations.
Striated muscle preferentially expressed protein kinase (SPEG) interacts with myotubularin (MTM1)—a lipid phosphatase—and components of the desmin/Z-line network. Loss of SPEG leads to disruption of muscle triad structure, defective excitation-contraction (E-C) coupling, and abnormal calcium signalling. It also impairs cardiomyocyte mitochondrial function.
Prevalence is not well-established, but it is understood that the disorder is rare. Majority of reported pathogenic genotype are biallelic loss of function (homozygous or compound heterozygous) variants consistent with an autosomal recessive inheritance for severe congenital presentations; reported pathogenic variants include loss of function and missense changes. Genotype–phenotype correlations show variability and some missense alleles are associated with distinct or milder presentations.
SPEG