Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies

Abstract

Nemaline myopathy (NM) is a muscle disorder with broad clinical and genetic heterogeneity. The clinical presentation of affected individuals ranges from severe perinatal muscle weakness to milder childhood-onset forms, and the disease course and prognosis depends on the gene and mutation type. To date, 14 causative genes have been identified, and ACTA1 accounts for more than half of the severe NM cases. ACTA1 encodes α-actin, one of the principal components of the contractile units in skeletal muscle. We established a homogenous cohort of ten unreported families with severe NM, and we provide clinical, genetic, histological, and ultrastructural data. The patients manifested antenatal or neonatal muscle weakness requiring permanent respiratory assistance, and most deceased within the first months of life. DNA sequencing identified known or novel ACTA1 mutations in all. Morphological analyses of the muscle biopsy specimens showed characteristic features of NM histopathology including cytoplasmic and intranuclear rods, cytoplasmic bodies, and major myofibrillar disorganization. We also detected structural anomalies of the perinuclear space, emphasizing a physiological contribution of skeletal muscle α-actin to nuclear shape. In-depth investigations of the nuclei confirmed an abnormal localization of lamin A/C, Nesprin-1, and Nesprin-2, forming the main constituents of the nuclear lamina and the LINC complex and ensuring nuclear envelope integrity. To validate the relevance of our findings, we examined muscle samples from three previously reported ACTA1 cases, and we identified the same set of structural aberrations. Moreover, we measured an increased expression of cardiac α-actin in the muscle samples from the patients with longer lifespan, indicating a potential compensatory effect. Overall, this study expands the genetic and morphological spectrum of severe ACTA1-related nemaline myopathy, improves molecular diagnosis, highlights the enlargement of the perinuclear space as an ultrastructural hallmark, and indicates a potential genotype/phenotype correlation.

Case report: A novel ACTA1 variant in a patient with nemaline rods and increased glycogen deposition

“…To date, more than 250 ACTA1 pathogenic variants have been reported as pathogenic, spanning all the coding exons of the gene, hence affecting the entire 3D structure of the encoded actin protein ( 20 , 24 , 30 ). Several variants associated with congenital myopathy are known to be located in close proximity to the proposed actin–tropomyosin contact sites ( 31 ).…”

“…Clinically, the ACTA1 -related NM often exhibits severe congenital forms leading to respiratory failure with death within the first year of life, though mild or childhood onset forms have also been reported ( 20 , 32 ).…”

“…In early-onset NM linked to ACTA1 variants, affected newborns present with floppy appearance due to neonatal hypotonia and severe congenital muscle weakness impairing the achievement of developmental milestones ( 2 , 20 ). The weakness also affects the respiratory muscles, leading to breathing difficulties within the first hours of life.…”

Neuropathologie I: Muskuläre Erkrankungen

“…„reducing bodies“ oder „hyaline bodies“, abgrenzen (Abb. 1 b; [ 14 ]). Eine CNM hat neben zentralisierten Kernen diagnostisch wichtige elektronenmikroskopische Eigenheiten wie „radial strands“ oder „necklace fibers“, welche bei molekular nicht sicher zu interpretierbaren Befunden eine Diagnose erlauben oder bestätigen können (Abb.…”

Muscle cofilin alters neuromuscular junction postsynaptic development to strengthen functional neurotransmission

“…Thus, it is possible that disruption of actin and actin-binding proteins would affect the NMJ in NM patients. Recently, a case report of two NM patients with a mutation in alpha-actin describes abnormal postsynaptic muscle membrane at the NMJ, but it is unknown whether this finding is generalizable all NM patients (Labasse et al, 2022). At the widely-used Drosophila larval NMJ, proper actin organization at the muscle postsynapse is important for synaptic development, neurotransmitter receptor localization, and neurotransmission (Chen et al, 2005; Pielage et al, 2006; Wang et al, 2010).…”