Hicks et al. (2008) found that immunofluorescent labeling of collagen VI in skin biopsy-derived fibroblast cultures from patients suspected of having Bethlem myopathy was highly predictive of a COL6A mutation compared to immunofluorescence for collagen VI and basal ... Hicks et al. (2008) found that immunofluorescent labeling of collagen VI in skin biopsy-derived fibroblast cultures from patients suspected of having Bethlem myopathy was highly predictive of a COL6A mutation compared to immunofluorescence for collagen VI and basal lamina-located perlecan (HSPG2; 142461) in muscle samples. Abnormalities in the fibroblast labeling pattern of collagen VI were detected in more than 78% of genetically confirmed patients. Among 19 patients with an unknown genotype, the fibroblast technique providing a 75% positive predictive value, 100% sensitivity and negative predictive values, and specificity of 63%.
Bethlem and van Wijngaarden (1976) described 3 Dutch families in which 28 patients suffered from benign myopathy with autosomal dominant inheritance. The onset was in early infancy, progression was slow, and many patients reached an advanced age. The ... Bethlem and van Wijngaarden (1976) described 3 Dutch families in which 28 patients suffered from benign myopathy with autosomal dominant inheritance. The onset was in early infancy, progression was slow, and many patients reached an advanced age. The patients had moderate weakness and atrophy of the muscles of the trunk and limbs, the proximal muscles being more involved than the distal muscles, and the extensors more than the flexors. Early flexion contractures of the elbow and interphalangeal joints of the last 4 fingers, and plantar flexion contractures of the ankles were constant findings. In contrast to Emery-Dreifuss muscular dystrophy (310300), contractures of the neck and spine were rarely seen (Mohire et al., 1988). Moreover, 4 of the 28 patients had congenital torticollis. The serum creatine phosphokinase activity was usually not elevated, and histopathologic findings were nonspecific. Genealogic investigations showed no relationship between these 3 families which had lived in the Netherlands from at least the beginning of the 18th century. Arts et al. (1978) described another family of Polish descent in which 6 members in 4 generations suffered from what appeared to be the same disorder. Congenital torticollis was a feature in 1 patient. Schmalbruch et al. (1987) described a family in which members of both sexes in 3 generations had a benign form of congenital muscular dystrophy. Onset of symptoms was in early childhood and progression, if any, was slow. The proximal limb muscles, the sternocleidomastoid, and anterior tibial muscles were affected. One patient had torticollis and all had heel-cord shortening. There was no cardiomyopathy. Creatine kinase was elevated, and a histologic study showed necrotizing myopathy with pronounced regeneration and formation of aberrant myofibrils (ringbinden) and fibrosis. Leyten et al. (1986) described father and daughter with congenital muscular dystrophy. Mitochondrial abnormalities were found on muscle biopsy. Merlini et al. (1994) described 2 families with early-onset, benign, autosomal dominant myopathy with contractures and reviewed 6 previously reported families with Bethlem myopathy. In both families, there were several instances of male-to-male transmission. Fifteen of the 21 examined members proved to have myopathy with contractures, although several of them were so mildly affected that they considered themselves asymptomatic. Electromyography demonstrated a myopathic pattern, and nerve conduction tests were normal. CT scan demonstrated unexpectedly severe fatty replacement of paravertebral muscles and relatively preserved gluteal muscles. Merlini et al. (1994) suggested that the hallmark of Bethlem myopathy was contractures of the last 4 fingers. Elbow contractures were also present in more than half the subjects, but the severity was not as great as that seen in Emery muscular dystrophy. There was no cardiac or respiratory involvement. Tohyama et al. (1994) described an affected mother and daughter with contractures and mild proximal weakness. Muscle biopsy showed dystrophic features with evidence of fiber necrosis and regeneration. CT scanning demonstrated decreased volume of paravertebral muscles and low densities in various proximal muscles with essentially normal distal musculature. Tohyama et al. (1994) distinguished their cases from Bethlem myopathy because of dystrophic changes seen in muscle biopsy. However, the clinical presentation of both the Bethlem cases and these reported were similar. Bethlem myopathy shows a distribution of proximal muscle weakness similar to that observed in dominant limb-girdle muscular dystrophy (see, e.g., LGMD1A; 159000). However, Bethlem myopathy differs from most LGMDs in 2 ways: first, Bethlem myopathy presents with joint contractures, most commonly observed at the elbows, ankles, and neck; second, onset in Bethlem myopathy is in early childhood, whereas most dominant LGMDs show adult onset. It is now evident that Bethlem myopathy is a progressive disorder in adulthood (Jobsis et al., 1999). Many patients with Bethlem myopathy need a wheelchair after the age of 50 years, and some die of respiratory failure caused by diaphragmatic paralysis (Haq et al., 1999). Lampe and Bushby (2005) provided a review of collagen VI-related muscle disorders. The development of contractures is a hallmark of Bethlem myopathy. The contractures may appear and disappear in various joints during childhood, but nearly all patients eventually show flexion contractures of the fingers, wrists, elbows, and ankles, and these, in addition to weakness, contribute to disability. Lampe and Bushby (2005) pictured unusual skin features that may be present in some Bethlem myopathy patients, including follicular hyperkeratosis, keloid formation, and 'cigarette paper' scarring over the knees.
Brinas et al. (2010) classified 49 patients with muscular dystrophy due to mutations in 1 of the 3 COL6A genes into 3 clinical groups: 9 (18%) had a severe phenotype with contractures and never achieved ambulation, 26 (53%) ... Brinas et al. (2010) classified 49 patients with muscular dystrophy due to mutations in 1 of the 3 COL6A genes into 3 clinical groups: 9 (18%) had a severe phenotype with contractures and never achieved ambulation, 26 (53%) had a moderate phenotype and were initially able to walk but tended to lose ambulation later in childhood, and 14 (29%) had a milder course and remained ambulatory at a mean age of 20 years. All patient fibroblasts showed absent or reduced COL6A secretion, with frequent intracellular retention, and the decreased levels correlated with increased disease severity. Genetic analysis showed equal distribution of mutations across the cohort: 17 (30%) in COL6A1, 26 (46%) in COL6A2, and 13 (23%) in COL6A3. Thirty patients (61%) had dominant de novo mutations, and 18 had recessive mutations. Fourteen patients (28.5%) had truncating mutations. Homozygous truncating mutations before or within the triple helix (TH) domain were associated with the most severe phenotypes. The moderate phenotype was associated with heterozygous mutations resulting in the skipping of part of the TH domains or affecting the glycine residue of the Gly-X-Y domain. RT-PCR analysis was helpful in defining the effect of splice site mutations. Substitutions in the conserved Gly-X-Y motif in the triple helix (TH) domain of collagen VI are the most commonly identified mutations in the collagen VI myopathies, accounting for almost one-third of all pathogenic mutations. Butterfield et al. (2013) analyzed genotype/phenotype correlations of 194 individuals with glycine substitutions in the TH domain of the COL6A1, COL6A2, or COL6A3 genes. The cohort included 97 newly reported cases and 97 published cases. In all 3 genes, 89% of the mutations clustered in the N-terminal regions before the 17th Gly-X-Y triplet (TH17). This important landmark is delineated by cysteine residues in the COL6A3 chain, which form disulfide bonds stabilizing tetramers. Patients with mutations inside the critical region of Gly-X-Y triplets 10-15 tended to have a more severe phenotype than those with mutations outside this critical region. However, identical glycine substitutions were associated with both severe and mild phenotypes. The most commonly observed mutation was G284R in the COL6A1 gene (120220.0012), found in 28 cases with variable phenotypes. Glycine substitutions in the TH domain were dominantly acting in 96% of cases, and recessive mutations tended to occur in the C-terminal end of the TH domain. Butterfield et al. (2013) concluded that the clustering of glycine substitutions in this region is not based on features of the primary sequence, but rather reflects a functional importance of this domain.
In affected members of a kindred with Bethlem myopathy, Jobsis et al. (1996) demonstrated a mutation in the COL6A1 gene (120220.0001). In affected members from 2 other kindreds, Jobsis et al. (1996) identified a mutation in the COL6A2 ... In affected members of a kindred with Bethlem myopathy, Jobsis et al. (1996) demonstrated a mutation in the COL6A1 gene (120220.0001). In affected members from 2 other kindreds, Jobsis et al. (1996) identified a mutation in the COL6A2 gene (120240.0001). Analogous to the putative perturbation of the anchoring function of the dystrophin-associated complex in congenital muscular dystrophy with mutations in the alpha-2-subunit of laminin, these observations suggested to Jobsis et al. (1996) a similar mechanism in Bethlem myopathy. In affected members of an Italian family with Bethlem myopathy previously reported by Merlini et al. (1994), Vanegas et al. (2002) identified a heterozygous splice site mutation in the COL6A1 gene (120220.0008). Lampe et al. (2005) sequenced all 3 COL6 genes from genomic DNA in 79 patients with Ullrich congenital muscular dystrophy (UCMD; 254090) or Bethlem myopathy, and found putative mutations in 1 of the COL6 genes in 62% of patients. Some patients showed changes in more than one of the COL6 genes, and some UCMD patients appeared to have dominant rather than recessive disease. Lampe et al. (2005) concluded that these findings may explain some or all of the cases of UCMD that are unlinked to the COL6 gene under a recessive model and noted that the large number of SNPs generated in this study may be of importance in determining the major phenotypic variability seen in this group of disorders. Lucioli et al. (2005) identified 8 different mutations in the COL6A1 gene in 16 of 30 unrelated probands with a clinical diagnosis of Bethlem myopathy; 2 of the 30 probands had a mutation in the COL6A2 gene and the COL6A3 gene, respectively. The most common COL6A1 mutation was a splice site mutation (120220.0006). In 2 unrelated patients with Bethlem myopathy, Baker et al. (2007) identified 2 different heterozygous mutations in the COL6A2 gene (120240.0009; 120240.0010). In vitro studies indicated defective collagen VI synthesis and secretion. In 2 unrelated patients with Bethlem myopathy, Baker et al. (2007) identified 2 different heterozygous mutations in the COL6A3 gene (120250.0005; 120250.0006).