Magnetic resonance imaging of muscle in nemaline myopathy
Introduction
Nemaline myopathy (NM) is a congenital myopathy characterized by an abundance of rod-like structures in muscle that stain red with the modified Gomori trichrome technique [1]. NM is genetically heterogeneous and has been associated with mutations in five different genes [2], [3], [4], [5], [6]. The clinical spectrum of nemaline myopathy is wide and ranges from the fetal akinesia sequence [7] to only mildly affected adults [8], although the majority of patients share a common (or ‘typical’) phenotype characterized by onset in infancy with marked hypotonia and often disproportionate feeding difficulties [9]. Recessive mutations in the nebulin gene (NEB) are most commonly involved in the ‘typical’ form of nemaline myopathy, whereas mutations in the skeletal muscle α-actin (ACTA1) gene are predominantly autosomal dominant (often de novo) and only rarely recessive [10]. Mutations in this gene appear to be the second most common cause of nemaline myopathy and account for both severe neonatal cases and cases of later onset with significant clinical overlap with the form due to mutations in the NEB gene [4], [10].
Nemaline myopathy shows considerable histopathological and clinical overlap with other congenital myopathies. Nemaline rod formation is observed in a number of different clinical situations and has been recently described as an additional finding in central core disease secondary to mutations in the skeletal muscle ryanodine receptor (RYR1) gene [11]. Marked scoliosis, spinal rigidity and respiratory impairment are features in both nemaline and the subgroup of minicore myopathy (Multi-minicore disease, MmD) due to mutations in the selenoprotein N (SEPN1) gene [12].
The clinician confronted with an often non-specific combination of histopathological and clinical features has to consider an ever-increasing number of confirmatory genetic tests, many currently still being offered only on a research basis. Magnetic resonance imaging (MRI) demonstrates characteristic patterns of selective muscle involvement in genetically distinct neuromuscular disorders [13], [14], [15] and has been suggested as a useful ancillary tool to further inform the choice of appropriate genetic tests in some forms of the muscular dystrophies [16]. Our own group has recently demonstrated a consistent and specific pattern of selective muscle involvement on muscle MRI in congenital myopathies secondary to mutations in the RYR1 gene [17], but systematic studies comparing genetic and imaging findings in other congenital myopathies are currently not available.
The aim of the following study was (1) to identify the pattern of muscle involvement in patients with nemaline myopathy due to mutations in the NEB or the ACTA1 gene; (2) to correlate muscle MRI findings with clinical severity in individual patients; and (3) to compare MRI findings in nemaline myopathy with MRI findings reported in other neuromuscular disorders with similar clinical or histopathological features.
Section snippets
Patients
During the period from July 1998 to October 2002, 10 patients from 8 families (F1–F8) attending the Neuromuscular Unit at the Hammersmith Hospital in London were invited to take part in our study. Five patients were female and five patients were male. Mean age at the time of the muscle MRI scan was 17 years (median 8.5 years; range 3–44 years). The phenotype of each patient was classified depending on the degree of clinical severity:
The severe phenotype (n=0) was characterized by predominant
Muscle magnetic resonance imaging
All 10 patients had both thighs and lower leg muscles scanned. There was a consistent and recognizable pattern of selective muscle involvement in nemaline myopathy secondary to NEB involvement (Fig. 1), with variations in signal intensity according to clinical severity. Muscle involvement in NEB-related myopathy was pronounced in the lower leg, and there was often marked segmental involvement. Patients with mutations in the ACTA1 gene had diffuse involvement of thigh and lower leg muscles, with
Discussion
Systematic studies correlating muscle MRI and genetic data have not previously been reported in nemaline myopathy. A combined ultrasound, CT and MRI study of 12 patients with autosomal recessive congenital nemaline myopathy [20], performed before the identification of the causative genes, already suggested a sequential evolution of changes correlated to clinical severity. Corresponding to our findings in patients with NEB-related nemaline myopathy, CT findings in this study indicated early
Acknowledgements
The continuous support of the Muscular Dystrophy Campaign to the Hammersmith Hospital Neuromuscular Centre is gratefully acknowledged.
Katarina Pelin was supported by grants to Carina Wallgren-Pettersson from the Association Française contre les Myopathies, the University of Helsinki, the Finska Läkaresällskapet, the Jusélius Foundation and the Medicinska understödsföreningen Liv och Hälsa.
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