The collagen VI-related myopathies Ullrich congenital muscular dystrophy and Bethlem myopathy

Abstract

Mutations in the genes COL6A1, COL6A2, and COL6A3, coding for three α chains of collagen type VI, underlie a spectrum of myopathies, ranging from the severe congenital muscular dystrophy-type Ullrich (UCMD) to the milder Bethlem myopathy (BM), with disease manifestations of intermediate severity in between. UCMD is characterized by early-onset weakness, associated with pronounced distal joint hyperlaxity and the early onset or early progression of more proximal contractures. In the most severe cases ambulation is not achieved, or it may be achieved only for a limited period of time. BM may be of early or later onset, but is milder in its manifestations, typically allowing for ambulation well into adulthood, whereas typical joint contractures are frequently prominent. A genetic spectrum is emerging, with BM being caused mostly by dominantly acting mutations, although rarely recessive inheritance of BM is also possible, whereas both dominantly as well as recessively acting mutations underlie UCMD.

Figure 5.1

Neonatal presentation of Ullrich congenital muscular dystrophy. Note elbow contracture and flaccid-appearing hands in (A) and kyphosis in (B).

Figure 5.2

Ullrich congenital muscular dystrophy (UCMD). The patient in (A) is able to walk, but note knee and elbow contractures. This patient lost the ability to walk at 9 years of age. The patient in (B) shows typical contractures in the nonambulatory patient, affecting the pectoralis, elbows, hips, knees, and Achilles tendons. The feet in (C) show the typical prominent calcaneus and the soft plantar skin, whereas (D) demonstrates the striking distal hyperlaxity seen in the fingers in a patient with UCMD. (D: Courtesy of Marjo van der Knaap, Amsterdam, Netherlands)

Figure 5.3

(A) Adult patient with Bethlem myopathy (BM). Note typical elbow and Achilles tendon contractures. (B) demonstrates the typical finger flexor contractures in BM that make it impossible to put the fingers close together with the elbows extended. (C) demonstrates excessive keloid formation in a patient with BM. (C: Courtesy of Claudia Castiglione, Santiago, Chile.)

Figure 5.4

Schematic depiction of the three α chains, α1(VI), α2(VI), and α3(VI), highlighting the domain structure and the triple helical domains with the cysteine residues that are involved in higher-order assembly.

Figure 5.5

Schematic of the collagen VI assembly process. Upper panel depicts intracellular assembly from the heterotrimeric monomer composed of all three α chains (*), via antiparallel dimer (†) to tetramer (‡) formation. The lower panel depicts the formation of the beaded microfilaments with 100-nm periodicity, formed by close interaction of the C- and N-terminal globular domains. Also note the interchain disulfite bridges. (Reproduced with permission from Bertini and Pepe (2002), incorporating a modified schematic from Timpl and Chu (1994).)

Figure 5.6

Immunolocalization of collagen VI in the muscle of a patient with a dominant negative mutation in collagen VI. In the normal biopsy, collagen VI (red) overlaps with the basement membrane (green), resulting in a yellow color. In the patient’s biopsy there is a considerable amount of collagen VI immunoreactivity in the matrix; however, the colocalization with the basement membrane is lost, resulting in the green color of the basement membrane. Nuclear counterstain in blue.