Muscle magnetic resonance imaging in patients with congenital muscular dystrophy and Ullrich phenotype

doi:10.1016/S0960-8966(03)00091-9

Neuromuscular Disorders

Volume 13, Issues 7–8, September 2003, Pages 554-558

https://doi.org/10.1016/S0960-8966(03)00091-9 Get rights and content

Abstract

The aim of this study was to evaluate muscle magnetic resonance imaging findings in patients with congenital muscular dystrophy and Ullrich phenotype. Fifteen children with congenital muscular dystrophy and Ullrich phenotype were included in the study. All patients had collagen VI studies in muscle and, when family structure was informative, linkage studies to the collagen 6 loci. Three of the 15 patients had reduced collagen in muscle. One of the three was from an informative family and linked to one of the collagen 6 loci. Another patient was linked to one of the collagen 6 loci but had normal expression of collagen in muscle. The remaining 11 all had normal collagen expression in muscle. Only two of these 11 were from informative families and linkage to collagen 6 loci was excluded in them. All patients had muscle magnetic resonance imaging of their leg muscles using transverse T1 sequences. With the exception of the two patients in whom linkage to the collagen 6 loci was excluded, the other 13 patients showed the same pattern of selective involvement on magnetic resonance imaging of thigh muscles. This consisted of relative sparing of sartorius, gracilis, adductor longus and rectus. This pattern was also found in the case linked COL6A1/A2 locus but with normal collagen. This finding, and the striking clinical and magnetic resonance imaging concordance between patients with normal and reduced collagen VI in muscle suggest that collagen VI could still be the culprit in several cases with normal collagen expression, or alternatively a primary defect in a protein that closely interacts with collagen VI. Mutation analysis of the collagen 6 genes in cases with normal collagen VI expression is needed to resolve this issue.

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.

Section snippets

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:

•
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.
•
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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Muscle magnetic resonance imaging in patients with congenital muscular dystrophy and Ullrich phenotype

Abstract

Introduction

Section snippets

Subjects and methods

Muscle magnetic resonance imaging

Results

Discussion

Acknowledgements

Brain Dev

Am J Hum Genet

Neuromuscul Disord

Neuromuscul Disord

Kongenitale, atonish-sklerotische Muskeldystrophie

Monatsschr Kinderheilkd

A clinical and histological study of Ullrich's disease (congenital atonic-sclerotic muscular dystrophy)

Neuropediatrics

Ullrich's congenital atonic sclerotic muscular dystrophy

J Neurol

Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI

PNAS

deficiency in Ullrich's disease

Ann Neurol

involvement in Ullrich syndrome: a clinical, genetic, and immunohistochemical study

Neurology