Muscle magnetic resonance imaging in patients with congenital muscular dystrophy and Ullrich phenotype
Introduction
In 1930 Ullrich described two children with generalized muscle weakness, hyperextensibility of the distal joints associated with contractures of the proximal joints, normal intelligence and myopathic or dystrophic changes on muscle biopsy [1]. This phenotype has been reported in several other cases [2], [3] and has been classified as a form of merosin positive congenital muscular dystrophy (CMD) [4].
Three recent studies have reported recessive mutations in collagen 6A2 and 6A3 (COL6A2 and COL6A3) in 10 patients with this form of CMD who also showed a reduction or absence of collagen VI in fibroblasts and muscle on immunofluorescence [5], [6], [7]. Following the identification of the gene defect, this form has been defined as Ullrich disease (UCMD).
We recently reported, however, that not all the patients with CMD, distal laxity, respiratory impairment and rigidity of the spine were linked to the COL6 loci or had deficiency of collagen VI in muscle [8]. Clinical and pathological findings in patients with linkage to the COL6 loci or deficiency of collagen VI in muscle were similar to those observed in patients with normal collagen on muscle biopsy. These results not only suggested further genetic heterogeneity of this disorder but also highlighted the difficulties in identifying patients with collagen VI abnormalities on clinical grounds only.
Several papers have recently demonstrated specific patterns of selective muscle involvement in a variety of genetically defined congenital myopathies and dystrophies [9], [10], [11] suggesting that muscle MRI can be used for phenotyping patients.
The aim of this study was to establish whether muscle MRI can be used as an additional tool to differentiate patients with and without evidence of collagen VI involvement in muscle.
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Subjects and methods
The patients included in this study were assessed and followed at the Dubowitz Neuromuscular Centre at Hammersmith Hospital, London. Patients were included if:
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they presented with clinical features compatible with Ullrich's diagnostic criteria, namely proximal joint contractures with severe hyperlaxity of distal joints presenting in early infancy, absence of severe mental retardation, and myopathic or dystrophic changes on muscle biopsy.
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muscle biopsy samples were available for collagen VI
Muscle magnetic resonance imaging
Muscle MRI was performed using conventional T1 weighted spin echo on a 1.0-tesla Picker HPQ system. Non-contrast images were obtained from pelvis, thighs and legs. The axial plane was selected with respect to the long axis of the body.
We obtained 15 slices from each site. Slices were 5 mm thick and the gap between slices varied from 10 to 50 mm dependent on the site and on the size of the child/adult.
A fast gradient echo was used for pilots. For images, a spin echo pulse sequence was used
Results
Fifteen patients fulfilled the inclusion criteria. Clinical, pathological and genetic results of 12 of these patients have already been reported [8].
Three of the 15 patients had reduced collagen in muscle. Two of the three were from informative families and had linkage to one of the COL6 loci. Another patient was linked to one of the COL6 loci but had normal expression of collagen in muscle. This patient had an affected brother who was also linked to the same COL6A1/A2 locus but in whom muscle
Discussion
In the last few years increased attention has been devoted to the use of muscle MRI in identifying specific patterns of muscle involvement in various neuromuscular disorders [10], [11], [16], [17]. This has proved particularly useful in recognising patients with genetically different conditions despite their similar clinical phenotype. We have recently reported that not all patients with Ullrich phenotype show linkage to the COL6 loci or a reduction of collagen VI in muscle. The aim of this
Acknowledgements
We wish to thank the Muscular Dystrophy Campaign grant to F.M. and the European Community grant (QLG1 CT 1999 00870) Myo-Cluster GENRE (Genetic Resolution of Congenital Muscular Dystrophy). The authors also wish to thank Dr Lucy Feng for technical assistance.
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