Mild phenotype of nemaline myopathy with sleep hypoventilation due to a mutation in the skeletal muscle α-actin (ACTA1) gene
Introduction
Nemaline myopathy is a clinically and genetically heterogeneous condition characterized by an abundance of rod-like structures in muscle that stain red with the modified Gomori technique.
Three genes have been implicated in nemaline myopathy to date, the gene for slow α-tropomyosin on chromosome 1q21 (NEM1) [1], [2], [3], nebulin on chromosome 2q22 (NEM2) [4], [5], [6], and, more recently, skeletal muscle α-actin on 1q42 (ACTA1) [7]. Further genetic heterogeneity in nemaline myopathy is expected as some families show no linkage to any of the three known loci [8].
Clinically, the common autosomal-recessive form (NEM2), due to mutations in the nebulin gene, is characterized by onset in infancy with hypotonia, general weakness, predominantly affecting facial and axial muscles, and disproportionate feeding and respiratory difficulties. Mutations in the skeletal muscle α-actin gene cause a predominantly severe form of nemaline myopathy with neonatal onset [7], and are also responsible for some cases of a severe congenital myopathy with accumulation of actin filaments [9].
We report the case of a 39-year-old woman with a diagnosis of nemaline myopathy established at the age of 12 years. Her presentation, clinical features and further course were milder than in the ‘typical’ autosomal-recessive form of nemaline myopathy due to mutations in the nebulin gene [10], but she developed life-threatening respiratory failure in the fourth decade of life. A dominant missense mutation was identified in ACTA1.
Section snippets
History
This woman was the second child of healthy, non-consanguineous Caucasian parents. An older sister and younger brother were both healthy. Another younger brother had died in infancy, but no further details were available. There was no family history of neuromuscular disorders. She had been delivered at term by Caesarean section for cephalopelvic disproportion. There were no respiratory or feeding difficulties in the neonatal period.
Both motor and speech development were normal. She sat
Discussion
We have presented a 39-year-old patient with the clinical picture of a mild congenital myopathy and histological features of nemaline myopathy. Long-term follow-up over 25 years demonstrated only a slow progression of weakness, but severe respiratory involvement. A dominant mutation in the ACTA1 gene on chromosome 1q42 has been identified.
Nemaline myopathy is clinically and genetically heterogeneous. A mutation in the first exon of the slow α-tropomyosin (TPM3) gene on chromosome 1q21 [1], [2]
Conclusion
The spectrum of conditions caused by mutations in the ACTA1 gene is wide. The phenotype ranges from a severe form with neonatal presentation and actin accumulation to a mild form of nemaline myopathy with disproportionate respiratory involvement, as demonstrated in our patient. Late presentation and absence of significant facial and bulbar weakness are at variance with the common form of nemaline myopathy linked to the nebulin gene on chromosome 2q22. Molecular genetic analysis of the ACTA1
Note added in proof
Since the preparation of this manuscript, we have identified another similar mild case of nemaline myopathy secondary to a dominant mutation in the ACTA1 gene. This lady is now aged 24 years, and also presented in childhood with mild proximal weakness and excess nemaline rods in her muscle biopsy. The progression has also been very slow. On examination, small pes cavus-like feet were noted, as in our original patient. The diaphragm was clinically involved, but an overnight sleep study was
Acknowledgements
The continuous support of the Muscular Dystrophy Campaign of Great Britain is gratefully acknowledged. Heinz Jungbluth is a Muscular Dystrophy Campaign Research Fellow. Nigel G. Laing is supported by the Australian National Health and Medical Research Council Project grant 970104, K.J. Nowak is supported by a Murdoch University PhD scholarship. Katarina Pelin was supported by grants to Carina Wallgren-Pettersson from the Association Francaise contre les Myopathies, the Swedish Cultural
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