Description
Intranuclear rod myopathy is a muscle disorder (myopathy) that causes severe weakness that is noticeable in infancy. This condition primarily affects the muscles used for movement (skeletal muscles) and breathing (respiratory muscles).
In infants with intranuclear rod myopathy, weak muscle tone (hypotonia) throughout the body can impair movement before and after birth. Infants with hypotonia can develop other problems in their bones and joints, including:
- Joint deformities (contractures)
- Joint stiffness (arthrogryposis)
- An abnormal side-to-side curvature of the spine (scoliosis
) - An inward- and upward-turning foot (clubfoot)
Other signs and symptoms of intranuclear rod myopathy that are apparent in infancy include:
- Feeding and swallowing difficulties
- A weak cry
- Poor control of head movements
Respiratory muscle weakness in infants with intranuclear rod myopathy can cause frequent respiratory infections and shallow breathing (hypoventilation). Hypoventilation, especially during sleep, can result in a shortage of oxygen and a buildup of carbon dioxide in the blood. In many cases, affected individuals do not have the muscle strength to breathe regularly on their own and must be supported with a machine to help them get enough oxygen (mechanical ventilation).
Because of these respiratory problems, most individuals with intranuclear rod myopathy do not survive past infancy. Those who survive often develop motor skills such as sitting, crawling, standing, and walking, more slowly than other children.
The name of the condition, intranuclear rod myopathy, comes from the abnormal rod-shaped structures that can be seen in the nucleus of muscle cells
when muscle tissue is viewed under a microscope.
Frequency
Intranuclear rod myopathy is a rare disorder that has been identified in only a small number of individuals. Its exact prevalence is unknown.
Causes
Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the ACTA1 gene cause intranuclear rod myopathy. The ACTA1 gene provides instructions for making skeletal alpha (α)-actin, which is part of the actin
protein family. Actin proteins are important for cell movement and the tensing of muscle fibers (muscle contraction). Muscle fibers
are primarily composed of thin filaments that are made up of actin molecules and thick filaments that are made up of another protein called myosin. The thin and thick filaments overlap each other and undergo cycles of attachment and release that allow the thin filaments to slide past the thick filaments, which shortens the muscle fiber and causes the muscle to contract.
The pathogenic variants in the ACTA1 gene that cause intranuclear rod myopathy allow rods of skeletal α-actin to accumulate in the nucleus of muscle cells. Normally, actin is found in the fluid surrounding the nucleus (the cytoplasm); only small amounts are in the nucleus itself.
Researchers suggest that the ACTA1 gene variants that cause intranuclear rod myopathy interfere with the normal transport of actin out of the nucleus and into the cytoplasm, resulting in the accumulation of actin in the nucleus and the formation of intranuclear rods. The buildup of these rods can interfere with the normal functioning of the nucleus, such as directing cell growth and producing proteins from genes. Abnormal accumulation of actin in the nucleus of muscle cells and a corresponding reduction of available actin in muscle fibers impairs muscle contraction and leads to the muscle weakness seen in people with intranuclear rod myopathy.
Some people with intranuclear rod myopathy do not have an identified pathogenic variant in the ACTA1 gene. The cause of the disorder in these individuals is unknown.
Intranuclear rod myopathy is one of several muscle disorders caused by pathogenic variants in the ACTA1 gene. Some researchers consider these disorders to be a single disorder with a spectrum of overlapping signs and symptoms and group them together under the umbrella term alpha-actinopathy.
Inheritance
Intranuclear rod myopathy is inherited in an autosomal dominant pattern
, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases of this condition result from new (de novo) variants in the gene that occur during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or in early embryonic development. These affected individuals have no history of the disorder in their family.
Other Names for This Condition
- Intranuclear nemaline rod myopathy
- Nemaline myopathy with exclusively intranuclear rods
Additional Information & Resources
Genetic Testing Information
Patient Support and Advocacy Resources
Catalog of Genes and Diseases from OMIM
Scientific Articles on PubMed
References
- Domazetovska A, Ilkovski B, Cooper ST, Ghoddusi M, Hardeman EC, Minamide LS, Gunning PW, Bamburg JR, North KN. Mechanisms underlying intranuclear rod formation. Brain. 2007 Dec;130(Pt 12):3275-84. doi: 10.1093/brain/awm247. Epub 2007 Oct 10. Citation on PubMed
- Feng JJ, Marston S. Genotype-phenotype correlations in ACTA1 mutations that cause congenital myopathies. Neuromuscul Disord. 2009 Jan;19(1):6-16. doi: 10.1016/j.nmd.2008.09.005. Epub 2008 Oct 30. Citation on PubMed
- Kaimaktchiev V, Goebel H, Laing N, Narus M, Weeks D, Nixon R. Intranuclear nemaline rod myopathy. Muscle Nerve. 2006 Sep;34(3):369-72. doi: 10.1002/mus.20521. Citation on PubMed
- Laing NG, Dye DE, Wallgren-Pettersson C, Richard G, Monnier N, Lillis S, Winder TL, Lochmuller H, Graziano C, Mitrani-Rosenbaum S, Twomey D, Sparrow JC, Beggs AH, Nowak KJ. Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1). Hum Mutat. 2009 Sep;30(9):1267-77. doi: 10.1002/humu.21059. Citation on PubMed or Free article on PubMed Central
- Ogasawara M, Nishino I. A review of major causative genes in congenital myopathies. J Hum Genet. 2023 Mar;68(3):215-225. doi: 10.1038/s10038-022-01045-w. Epub 2022 Jun 7. Citation on PubMed
- Romero NB, Clarke NF. Congenital myopathies. Handb Clin Neurol. 2013;113:1321-36. doi: 10.1016/B978-0-444-59565-2.00004-6. Citation on PubMed
- Ross JE, Flowers M, McNulty S, Patel M, Yang H, Palus B, Abdelmoneim Elnagheeb M, Eng L, Owens E, Beggs AH, Bertini E, D'Amico A, Donkervoort S, Dowling J, Fattori F, Ferreiro A, Genetti CA, Gonorazky H, Lek M, Lindy A, Medne L, Muntoni F, Pajusalu S, Pelin K, Rendu J, Sarkozy A, Vatta M, Winder T, Yoon G, Bonnemann CG, Ceyhan-Birsoy O. Clinical validity of congenital myopathy genes determined by the ClinGen Congenital Myopathies Expert Panel. J Neuromuscul Dis. 2025 Nov;12(6):778-792. doi: 10.1177/22143602251339369. Epub 2025 Jun 10. Citation on PubMed
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