Muscle Ultrasound in Bethlem Myopathy

 

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Sir,

Bethlem myopathy is an autosomal dominant disease caused by mutations in the genes coding for collagen type VI, characterized clinically by early onset, delayed development of contractures and altogether slow progression [[2], [3]].

The diagnosis of Bethlem myopathy is based on the family history and on clinical findings of mild hypotonia and weakness early in childhood followed by the later development of typical contractures chiefly affecting the Achilles tendons, the elbow flexors, and the deep finger flexors in addition to weakness that often shows a mixed proximal and more distal pattern of distribution [[4]]. However, there is much variability, in particular as far as the extent of the contractures and the weakness are concerned [[4]]. The most important clinical differential diagnosis to consider is autosomal dominant Emery-Dreifuss muscular dystrophy (ADEDMD) caused by mutations in the LAMA/C gene [[1]]. Although patients can show a similar pattern of contractures, the cardiac involvement that is seen in ADEDMD does not occur in Bethlem myopathy. The ultimate diagnosis in Bethlem myopathy is based on the demonstration of a mutation in one of the three genes coding for the alpha chains of collagen type VI on chromosomes 21q22.3 and 2q37, a relatively labor and time intensive process.

Two families with Bethlem myopathy were seen recently in our Neuromuscular Clinic. In the first there was delayed walking in the mother who later developed a pattern of contractures typical of Bethlem myopathy. Her daughter was mildly hypotonic at birth, she developed a positive Gowers' sign and her joints were hyperextensible. In the second family the mother had congenital torticollis but walked at a normal age, she later developed weakness and a Bethlem-typical pattern of contractures. The daughter had mild proximal weakness, congenital torticollis, and hyperextensible joints. Completion of mutation analysis in the collagen type VI genes in the first family is still pending, however LAMA/C mutation analysis revealed no mutation (Dr G. Bonne, Paris, personal communication). In the second family a mutation was detected in the alpha1 (COL6A1) gene on chromosome 21 in mother and daughter (Dr G. Pepe, Florence, personal communication). This mutation has also been seen in other patients with Bethlem myopathy.

Muscle ultrasound in all four patients revealed a peculiar echodensity in the anterior middle of the rectus femoris muscle (Fig. [1] A - D), centered around the central fascia that is normally seen in this muscle (Fig. [1] E). This central shadow was more prominently seen in the mothers but could also be detected in the children with a higher frequency transducer (Fig. [1] B and D). Echodensities in this muscle in other myopathies or dystrophic conditions usually are more diffuse and within the belly of the muscle. A similar central shadow was also not seen in a patient with mutation proven ADEDMD (Fig. [1] F).

Fig. 1 A - F Muscle ultrasound in all four patients showed a similar unusual cloud like echodensity in the middle and anterior part of the rectus femoris muscle (arrow-heads in A mother family 1, B daughter family 1 (age at examination: 2 years 4 months), C mother family 2, D daughter family 2 (age at examination: 3 years 4 months). e Central fascia in the rectus femoris muscle in a normal ultrasound image. F Muscle ultrasound from 9-year-old patient with ADEDMD on the basis of a lamin A/C mutation, showing only mild diffuse increase of echogenicity within the entire rectus femoris, the central fascia remains visible (arrow). Muscle ultrasound images were acquired on a Sonoline Prima machine (Siemens, Erlangen, Germany) equipped with linear transducers at 5 MHz (A, C, E, F), respectively, 7.5 MHz (B, D) frequency.

The myopathic process in Bethlem myopathy proceeds in an unusual outside-in fashion, e.g., from the fascia inwards. This “central shadow sign” on muscle ultrasound is therefore likely a reflection of this process around the fascia separating the anterior portion of the rectus femoris. In fact, analysis of published CT images of the leg in Bethlem myopathy reveals a corresponding low-density lesion in the appropriate location within the rectus femoris muscle on the CT images as well [[3], [5]]. The peripheral predominance of the pathological process in Bethlem muscle has also been observed in a recent MRI study of a family with Bethlem myopathy [[6]]. Given the speed and convenience of muscle ultrasound particular in young patients, the “central shadow sign” may be a useful adjunct to the clinical examination in the initial assessment of patients with suggestive phenotypes and help initiate more extensive muscle imaging in order to detect other diagnostically helpful patterns of differential muscle involvement such as seen in ADEDMD [[7]].

References

• 1 Bonne G, Di Barletta M R, Varnous S, Becane H M, Hammouda E H, Merlini L. et al . Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy.  Nat Genet. 1999;  21 285-288
  PubMedGoogle Scholar
• 2 Jöbsis G J, Keizers H, Vreijling J P, de Visser M, Speer M C, Woltermann R A. et al . Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures.  Nat Genet. 1996;  14 113-115
  PubMedGoogle Scholar
• 3 Merlini L, Morandi L, Granata C, Ballestrazzi A. Bethlem myopathy: early-onset benign autosomal dominant myopathy with contractures. Description of two new families.  Neuromuscul Disord. 1994;  4 503-511
  PubMedGoogle Scholar
• 4 Pepe G, de Visser M, Bertini E, Bushby K, Camacho Vanegas O, Chu M L. et al . Bethlem myopathy (BETHLEM): 86th ENMC international workshop, 10 - 11 November 2000, Naarden, The Netherlands.  Neuromuscul Disord. 2002;  12 296-305
  PubMedGoogle Scholar
• 5 Tohyama J, Inagaki M, Nonaka I. Early onset muscular dystrophy with autosomal dominant heredity.  Brain Dev. 1994;  16 402-406
  CrossrefPubMedGoogle Scholar
• 6 Mercuri E, Cini C, Counsell S, Allsop J, Zolkipli Z, Jungbluth H, Sewry C. et al . Muscle MRI findings in a three-generation family affected by Bethlem myopathy.  Eur J Paediatr Neurol. 2002;  6 309-314
  PubMedGoogle Scholar
• 7 Mercuri E, Counsell S, Allsop J, Jungbluth H, Kinali M, Bonne G, Schwartz K. et al . Selective muscle involvement on magnetic resonance imaging in autosomal dominant Emery-Dreifuss muscular dystrophy.  Neuropediatr. 2002;  33 10-14
  PubMedGoogle Scholar

M. D. C. Bönnemann

Division of Neurology
The Children's Hospital of Philadelphia
Abramson Research Ctr., Rm 516 F

34th Street & Civic Ctr. Blvd.

Philadelphia, PA 19104

USA

Email: bonnemann@email.chop.edu