ORPHA: 610;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 21q22.3 | Bethlem myopathy 1B | 620725 | Autosomal dominant; Autosomal recessive | 3 | COL6A2 | 120240 |
A number sign (#) is used with this entry because of evidence that Bethlem myopathy-1B (BTHLM1B) is caused by heterozygous mutation in the COL6A2 gene (120240) on chromosome 21q22. Rare cases have been reported with homozygous or compound heterozygous mutations in the COL6A2 gene.
See also Ullrich congenital muscular dystrophy-1B (UCMD1B; 620727), an allelic disorder with a more severe phenotype.
Bethlem myopathy-1 (BTHLM1) is a congenital muscular dystrophy characterized by proximal muscle weakness and a combination of distal and proximal flexion joint contractures. The age at onset is highly variable, ranging from infancy to adulthood, and there is intrafamilial variability. Muscle biopsy may show myopathic and dystrophic features; serum creatine kinase is elevated. The progression is slow and ambulation is usually retained into adulthood (summary by Butterfield et al., 2013; Scacheri et al., 2002).
For a discussion of genetic heterogeneity of Bethlem myopathy, see BTHLM1A (158810).
At the 229th ENMC international workshop, Straub et al. (2018) reclassified Bethlem myopathy caused by mutation in one of collagen VI genes as a form of limb-girdle muscular dystrophy. Autosomal dominant forms were designated LGMDD5 (limb-girdle muscular dystrophy, autosomal dominant, 5) and autosomal recessive forms as LGMDR22 (limb-girdle muscular dystrophy, autosomal recessive, 22).
Arts et al. (1978) described a family of Polish descent in which 6 members spanning 4 generations had a nonprogressive 'benign myopathy' with onset in infancy. Congenital torticollis was a feature in 1 patient. Clinical features included mildly delayed motor milestones with difficulty or inability to run, mild proximal muscle weakness of the head and shoulder and pelvic girdles, often with positive Gowers sign, contractures of the elbows, weakness of the extensor muscles of the fingers, feet, and toes, leading to distal flexion contractures, and mild atrophy of the affected muscles. Tendon reflexes were normal or mildly decreased. Serum creatine kinase was increased. Skeletal muscle biopsy showed marked variation in fiber size diameter and increased internal nuclei. In general, there was no progression of muscle weakness, except for deterioration after pregnancy in affected females. All remained ambulatory and many survived into old age.
Scacheri et al. (2002) reported 9 members of a Caucasian family (family 3) from Mississippi and North Carolina with Bethlem myopathy-1B. The age at symptom onset was highly variable, ranging from infancy (1 patient) to childhood (5 patients) to adulthood (3 patients). Some showed delayed motor milestones. Features included proximal muscle weakness of the upper and lower limbs, distal muscle weakness in some, muscle cramps, flexion contractures of the elbows, knees, fingers (interphalangeal joints), and ankles. However, 4 patients did not have contractures. One adult was wheelchair-bound at 55 years of age, and another required a walking cane around 40 years of age. Muscle biopsies from 2 patients showed necrosis, fiber size variation, fiber splitting, internal nuclei, endomysial connective tissue, and fat infiltration. Serum creatine kinase was increased. The phenotype was consistent with limb-girdle muscular dystrophy. The authors noted the intrafamilial variability.
Baker et al. (2007) reported 2 unrelated men (BM10 and BM273) with BTHLM1B confirmed by genetic analysis. Clinical details were limited, but both men were in their forties with proximal muscle weakness and contractures of the elbows, knees, and ankles. BM10 had limited walking ability and dystrophic changes on muscle biopsy. BM273 had normal motor capacity, but also showed weakness of the feet and hands and more extensive contractures, including of the fingers and spine extensor muscles, leading to a rigid spine.
Zamurs et al. (2015) reported a 61-year-old man (UCMD65), born of consanguineous parents, with slowly progressive proximal limb muscle weakness beginning in the first decade of life. He initially had clumsiness while playing sports or running, but could walk normally. In his thirties, he developed gait difficulties and genu valgus deformities. At age 40, he showed proximal muscle weakness and atrophy of the upper limbs, and by age 60, he needed a walker for assistance. Additional features included joint contractures of the upper and lower limb joints, dysphagia, limb muscle weakness and atrophy, and absent deep tendon reflexes. MRI showed muscle atrophy with fatty infiltration predominantly in the proximal limb muscles. Muscle biopsy showed some mitochondrial abnormalities with paracrystalline inclusions and COX-negative fibers. Collagen VI was not detected in muscle biopsy. The clinical features suggested Bethlem myopathy.
Caria et al. (2019) reported 2 sibs, born of unrelated parents, with autosomal recessive BTHLM1B. The patients, who were 40 and 23 years of age, had proximal muscle weakness since childhood. Physical examination showed waddling gait, positive Gowers sign, diffuse muscle atrophy and weakness of the upper and lower limbs, scapular winging, contractures of the elbows and Achilles tendons, and lumbar hyperlordosis. The older sib also had keratosis pilaris. Serum creatine kinase was moderately increased, and EMG studies showed a myopathic pattern. Skeletal muscle biopsies showed dystrophic changes with variability of fiber diameter, internal nuclei, atrophic fibers, and endomysial fibrosis.
The transmission pattern of BTHLM1B in the families reported by Jobsis et al. (1996), Scacheri et al. (2002), Lucioli et al. (2005), and Baker et al. (2007) was consistent with autosomal dominant inheritance.
Gualandi et al. (2009) reported 2 unrelated patients with Bethlem myopathy who had biallelic mutations in the COL6A2 gene (120240.0011, 120240.0017-120240.0019), consistent with autosomal recessive inheritance. Both patients remained ambulatory as adults, and muscle biopsies and studies of fibroblasts showed variable degrees of aberrant collagen VI microfilament formation. Gualandi et al. (2009) noted that autosomal recessive inheritance had not previously been reported in Bethlem myopathy, suggesting that collagen VI-related myopathies comprise a spectrum of conditions with variable severity. The findings in these patients did not support pure haploinsufficiency as a causative mechanism for Bethlem myopathy, and suggested that some previously reported patients may harbor a second missed mutation.
The transmission pattern of BTHLM1B in the family reported by Caria et al. (2019) was consistent with autosomal recessive inheritance.
In 6 Dutch families, Jobsis et al. (1996) demonstrated linkage to highly polymorphic microsatellite markers on chromosome 21q22.3. A maximum 2-point lod score of 6.86 was observed for marker PFKL with a sex averaged recombination fraction of 0.05. One recombination event was thought to exclude the collagen VI alpha-1 gene (120220) as a candidate.
Autosomal Dominant Bethlem Myopathy 1B
In 9 families with the Bethlem form of autosomal dominant myopathy with contractures Jobsis et al. (1996) demonstrated genetic linkage to the COL6A1-COL6A2 gene cluster on 21q22.3. By sequence analysis, Jobsis et al. (1996) identified a heterozygous missense mutation in the COL6A2 gene (G250S; 120240.0001) in affected members of 2 of these families (families 4 and 5; family 4 had been reported by Arts et al., 1978). The mutation disrupted the Gly-X-Y motif of the triple helical domain by substitution of gly for either val or ser. 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 (156225), the observation suggested a similar mechanism in Bethlem myopathy.
In affected members of a Caucasian family from Mississippi and North Carolina (family 3) with Bethlem myopathy, who had a limb-girdle muscular dystrophy-type phenotype, Scacheri et al. (2002) identified a causative heterozygous missense mutation (D620N; 120240.0005) in the COL6A2 gene. Scacheri et al. (2002) suggested that their studies widened the clinical spectrum of Bethlem myopathy.
In 2 unrelated men (BM10 and BM273) with Bethlem myopathy, Baker et al. (2007) identified different heterozygous mutations in the COL6A2 gene (120240.0009; 120240.0010). In vitro studies indicated defective collagen VI synthesis and secretion.
Autosomal Recessive Bethlem Myopathy 1B
In 2 patients with Bethlem myopathy-1B, Gualandi et al. (2009) identified compound heterozygous mutations in the COL6A2 gene. One patient was a 25-year-old woman who was compound heterozygous for a Q819X (120240.0011) mutation and a complex missense allele (R830Q/R843W; 120240.0017). Although this genotype suggested autosomal recessive inheritance, the Q819X mutation escaped nonsense-mediated decay and was thought not to be pathogenic in the heterozygous state, based on a report by Merlini et al. (2008); however, the fact that the woman reported by Gualandi et al. (2009) carried COL6A2 mutations on both alleles had implications for genetic counseling. The other patient was a 47-year-old man with an R366X mutation (120240.0018) inherited from his unaffected mother and a de novo D871N mutation (120240.0019). The authors stated that the combination of a missense and a nonsense mutation in the COL6A2 gene had not previously been reported, yielding implications for genetic counseling.
In a 61-year-old man, born of consanguineous parents, with autosomal recessive Bethlem myopathy-1B, Zamurs et al. (2015) identified a homozygous missense mutation in the COL6A2 gene (D871N; 120240.0019). His unaffected parents were each heterozygous for the variant. Detailed studies of patient fibroblasts showed that the mutant protein interfered with collagen VI assembly, secretion, and microfibril formation, all of which were reduced compared to controls. Some collagen VI was assembled, albeit more slowly than normal, and was secreted; these molecules contained the minor COL6A2 C2a splice form that has an alternative C terminus and does not contain the mutation. When expressed in HEK293 cells, the mutant D871N protein was retained in the endoplasmic reticulum due to abnormal protein folding and was selectively degraded by the proteosome.
In 2 adult sibs with autosomal recessive Bethlem myopathy-1B, Caria et al. (2019) identified compound heterozygous mutations in the COL6A2 gene: a nonsense mutation in exon 28, resulting in a gln889-to-ter (Q889X; 120240.0022) and an in-frame insertion (120240.0023) in exon 5. The mutations, which were found by next-generation panel sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent. Western blot analysis of patient fibroblasts showed low levels of the canonical 1,019-residue COL6A2 chain and presence of a truncated 889-residue mutant protein; a normal 918-residue splice variant (C2a) was also detected. There were normal amounts of collagen VI dimers and tetramers in the cell layer, but not in the cell media, indicating instability of the secreted protein. Immunofluorescence studies of patient fibroblasts showed markedly reduced expression of collagen VI that was poorly organized in the extracellular matrix.
Arts, W. F., Bethlem, J., Volkers, W. S. Further investigations on benign myopathy with autosomal dominant inheritance. J. Neurol. 217: 201-206, 1978. [PubMed: 75955] [Full Text: https://doi.org/10.1007/BF00312962]
Baker, N. L., Morgelin, M., Pace, R. A., Peat, R. A., Adams, N. E., Gardner, R. J. M., Rowland, L. P., Miller, G., De Jonghe, P., Ceulemans, B., Hannibal, M. C., Edwards, M., Thompson, E. M., Jacobson, R., Quinlivan, R. C. M., Aftimos, S., Kornberg, A. J., North, K. N., Bateman, J. F., Lamande, S. R. Molecular consequences of dominant Bethlem myopathy collagen VI mutations. Ann. Neurol. 62: 390-405, 2007. [PubMed: 17886299] [Full Text: https://doi.org/10.1002/ana.21213]
Butterfield, R. J., Foley, A. R., Dastgir, J., Asman, S., Dunn, D. M., Zou, Y., Hu, Y., Donkervoort, S., Flanigan, K. M., Swoboda, K. J., Winder, T. L., Weiss, R.B., Bonnemann, C. G. Position of glycine substitutions in the triple helix of COL6A1, COL6A2, and COL6A3 is correlated with severity and mode of inheritance in collagen VI myopathies. Hum. Mutat. 34: 1558-1567, 2013. [PubMed: 24038877] [Full Text: https://doi.org/10.1002/humu.22429]
Caria, F., Cescon, M., Gualandi, F., Pichiecchio, A., Rossi, R., Rimessi, P., Cotti Piccinelli, S., Gallo Cassarino, S., Gregorio, I., Galvagni, A., Ferlini, A., Padovani, A., Bonaldo, P., Filosto, M. Autosomal recessive Bethlem myopathy: A clinical, genetic and functional study. Neuromusc. Disord. 29: 657-663, 2019. [PubMed: 31471117] [Full Text: https://doi.org/10.1016/j.nmd.2019.07.007]
Gualandi, F., Urciuolo, A., Martoni, E., Sabatelli, P., Squarzoni, S., Bovolenta, M., Messina, S., Mercuri, E., Franchella, A., Ferlini, A., Bonaldo, P, Merlini, L. Autosomal recessive Bethlem myopathy. Neurology 73: 1883-1891, 2009. [PubMed: 19949035] [Full Text: https://doi.org/10.1212/WNL.0b013e3181c3fd2a]
Jobsis, G. J., Bolhuis, P. A., Boers, J. M., Baas, F., Wolterman, R. A., Hensels, G. W., de Visser, M. Genetic localization of Bethlem myopathy. Neurology 46: 779-782, 1996. [PubMed: 8618682] [Full Text: https://doi.org/10.1212/wnl.46.3.779]
Jobsis, G. J., Keizers, H., Vreijling, J. P., de Visser, M., Speer, M. C., Wolterman, R. A., Baas, F., Bohlhuis, P. A. Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures. Nature Genet. 14: 113-115, 1996. [PubMed: 8782832] [Full Text: https://doi.org/10.1038/ng0996-113]
Lucioli, S., Giusti, B., Mercuri, E., Vanegas, O. C., Lucarini, L., Pietroni, V., Urtizberea, A., Ben Yaou, R., de Visser, M., van der Kooi, A. J., Bonnemann, C., Iannaccone, S. T., Merlini, L., Bushby, K., Muntoni, F., Bertini, E., Chu, M.-L., Pepe, G. Detection of common and private mutations in the COL6A1 gene of patients with Bethlem myopathy. Neurology 64: 1931-1937, 2005. [PubMed: 15955946] [Full Text: https://doi.org/10.1212/01.WNL.0000163990.00057.66]
Merlini, L., Martoni, E., Grumati, P., Sabatelli, P., Squarzoni, S., Urciuolo, A., Ferlini, A., Gualandi, F., Bonaldo, P. Autosomal recessive myosclerosis myopathy is a collagen VI disorder. Neurology 71: 1245-1253, 2008. [PubMed: 18852439] [Full Text: https://doi.org/10.1212/01.wnl.0000327611.01687.5e]
Scacheri, P. C., Gillanders, E. M., Subramony, S. H., Vedanarayanan, V., Crowe, C. A., Thakore, N., Bingler, M., Hoffman, E. P. Novel mutations in collagen VI genes: expansion of the Bethlem myopathy phenotype. Neurology 58: 593-602, 2002. [PubMed: 11865138] [Full Text: https://doi.org/10.1212/wnl.58.4.593]
Straub, V., Murphy, A., Udd, B. 229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017. Neuromusc. Disord. 28: 702-710, 2018. [PubMed: 30055862] [Full Text: https://doi.org/10.1016/j.nmd.2018.05.007]
Zamurs, L. K., Idoate, M. A., Hanssen, E., Gomez-Ibanez, A., Pastor, P., Lamande, S. R. Aberrant mitochondria in a Bethlem myopathy patient with a homozygous amino acid substitution that destabilizes the collagen VI alpha2(VI) chain. J. Biol. Chem. 290: 4272-4281, 2015. [PubMed: 25533456] [Full Text: https://doi.org/10.1074/jbc.M114.632208]