Other entities represented in this entry:
DO: 0060942;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 21q22.3 | Ullrich congenital muscular dystrophy 1B | 620727 | Autosomal dominant; Autosomal recessive | 3 | COL6A2 | 120240 |
A number sign (#) is used with this entry because of evidence that Ullrich congenital muscular dystrophy-1B (UCMD1B) is caused by homozygous, compound heterozygous, or heterozygous mutation in the COL6A2 gene (120240) on chromosome 21q22. Digenic inheritance has also been reported.
See also Bethlem myopathy-1B (BTHLM1B; 620725), an allelic disorder that shows a milder phenotype.
Ullrich congenital muscular dystrophy-1 (UCMD1) is characterized by generalized muscle weakness and striking hypermobility of distal joints in conjunction with variable contractures of more proximal joints and normal intelligence. Additional findings may include kyphoscoliosis, protruded calcanei, and follicular hyperkeratosis. Some patients manifest at birth and never achieve independent ambulation, whereas others maintain ambulation into adulthood. Progressive scoliosis and deterioration of respiratory function is a typical feature (summary by Kirschner, 2013).
For general phenotypic information and a discussion of genetic heterogeneity of Ullrich congenital muscular dystrophy, see UCMD1A (254090).
Camacho Vanegas et al. (2001) described 3 boys from 2 Italian families with Ullrich congenital muscular dystrophy and mutation in the COL6A2 gene. In the first family, the boy reduced fetal movements. At birth he was unusually long (55 cm), showed multiple joint contractures of his knees and elbows, a kyphotic contracture of the spine, a left hip dislocation, bilateral congenital convex pes valgus, long and slender fingers and toes with adducted thumbs, ogival palate, micrognathia, and a short neck with torticollis. He also showed marked bilateral distal hyperlaxity of fingers, toes, calcanei, and wrists. He walked at the age of 13 months, but generalized muscle weakness persisted thereafter, and progressive scoliosis and respiratory failure developed. He underwent tracheostomy and nocturnal positive pressure mechanical ventilation at the age of 8 years, with signs of diaphragmatic insufficiency. At the age of 11 years, he was still ambulant and had normal intelligence. In the second family, severe contractures of elbows and knees, rigidity of the spine, ogival (gothic) palate, and hypotonia were present. In 1 brother there was distal hyperlaxity and marked weakness of head flexors but almost complete disappearance of limb joint contractures at the age of 2 years.
Lucarini et al. (2005) reported a 5-year-old Caucasian boy with UCMD1B who presented at the age of 3 months with hypotonia, bilateral hip dislocation, and recurrent chest infections. His motor milestones were severely delayed: he stood at 31 months but had never achieved independent ambulation. On examination, he showed generalized muscle weakness, affecting more severely the proximal muscle in the limbs and distal laxity involving elbow, fingers, and ankles. Flexion contractures of hips and knees were also present. He also had mild spine rigidity.
Higuchi et al. (2001) reported a 20-year-old man with UCMD whose parents had no apparent clinical symptoms. The patient had neonatal hypotonia and was able to walk supported only between 3 and 5 years of age. On examination he showed generalized muscle weakness and atrophy, hyperextensibility of the distal joints, contractures of the proximal joints, a high-arched palate, posterior protrusion of the calcaneus, and kyphoscoliosis. His intellectual development and sensory systems were normal.
The transmission pattern of UCMD1B in the patients reported by Camacho Vanegas et al. (2001) was consistent with autosomal recessive inheritance.
In an Italian boy with UCMD1B, Camacho Vanegas et al. (2001) identified homozygosity for a 1-bp insertion in the COL6A2 gene (120240.0002). In 2 affected brothers in another Italian family, they identified compound heterozygous splice site mutations in the COL6A2 gene (120240.0003 and 120240.0004). In both families, the unaffected parents were carriers.
In a 20-year-old man with UCMD1B, Higuchi et al. (2001) identified homozygosity for a 26-bp deletion in the COL6A2 gene (120240.0006).
In a Caucasian boy with UCMD1B, Lucarini et al. (2005) identified a homozygous splice site mutation in the COL6A2 gene (120240.0007).
In a patient with UCMD1B, Baker et al. (2007) identified heterozygosity for a 1.3-kb deletion in the COL6A2 gene (120240.0008).
Nadeau et al. (2009) identified a homozygous COL6A2 mutation (C777R; 120240.0012) in 3 patients with autosomal recessive UCMD. Two additional patients had different heterozygous COL6A2 mutations (see, e.g., G283R, 120240.0013), consistent with autosomal dominant inheritance. Another patient was compound heterozygous for a mutation in the COL6A1 gene (G281R; 120220.0014) and a mutation in the COL6A2 gene (R498H; 120240.0014), consistent with digenic inheritance.
In Brazilian girl (patient UC3) with UCMD1B, Zhang et al. (2010) identified a homozygous missense mutation in the COL6A2 gene (E624K; 120240.0015).
In a young man (patient UC15), born of consanguineous Filipino parents, with UCMD1B, Zhang et al. (2010) identified a homozygous missense mutation in the COL6A2 gene (R876S; 120240.0016).
In a girl with UCMD1B (patient UCMD21), Tooley et al. (2010) identified compound heterozygous mutations in the COL6A2 gene (120240.0020-120240.0021). Each mutation was inherited from an unaffected parent.
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]
Camacho Vanegas, O. C., Bertini, E., Zhang, R.-Z., Petrini, S., Minosse, C., Sabatelli, P., Giusti, B., Chu, M.-L., Pepe, G. Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI. Proc. Nat. Acad. Sci. 98: 7516-7521, 2001. [PubMed: 11381124] [Full Text: https://doi.org/10.1073/pnas.121027598]
Higuchi, I., Shiraishi, T., Hashiguchi, T,, Suehara, M., Niiyama, T., Nakagawa, M., Arimura, K., Maruyama, I., Osame, M. Frameshift mutation in the collagen VI gene causes Ullrich's disease. Ann. Neurol. 50: 261-265, 2001. [PubMed: 11506412] [Full Text: https://doi.org/10.1002/ana.1120]
Kirschner, J. Congenital muscular dystrophies. Handb. Clin. Neurol. 113: 1377-1385, 2013. [PubMed: 23622361] [Full Text: https://doi.org/10.1016/B978-0-444-59565-2.00008-3]
Lucarini, L., Giusti, B., Zhang, R.-Z., Pan, T.-C., Jimenez-Mallebrera, C., Mercuri, E., Muntoni, F., Pepe, G., Chu, M.-L. A homozygous COL6A2 intron mutation causes in-frame triple-helical deletion and nonsense-mediated mRNA decay in a patient with Ullrich congenital muscular dystrophy. Hum. Genet. 117: 460-466, 2005. [PubMed: 16075202] [Full Text: https://doi.org/10.1007/s00439-005-1318-8]
Nadeau, A., Kinali, M., Main, M., Jimenez-Mallebrera, C., Aloysius, A., Clement, E., North, B., Manzur, A. Y., Robb, S. A., Mercuri, E., Muntoni, F. Natural history of Ullrich congenital muscular dystrophy. Neurology 73: 25-31, 2009. [PubMed: 19564581] [Full Text: https://doi.org/10.1212/WNL.0b013e3181aae851]
Tooley, L. D., Zamurs, L. K., Beecher, N., Baker, N. L., Peat, R. A., Adams, N. E., Bateman, J. F., North, K. N., Baldock, C., Lamande, S. R. Collagen VI microfibril formation is abolished by an alpha-2(VI) von Willebrand factor type A domain mutation in a patient with Ullrich congenital muscular dystrophy. J. Biol. Chem. 285: 33567-33576, 2010. [PubMed: 20729548] [Full Text: https://doi.org/10.1074/jbc.M110.152520]
Zhang, R.-Z., Zou, Y., Pan, T.-C., Markova, D., Fertala, A., Hu, Y., Squarzoni, S., Reed, U. C., Marie, S. K. N., Bonnemann, C. G., Chu, M.-L. Recessive COL6A2 C-globular missense mutations in Ullrich congenital muscular dystrophy: role of the C2a splice variant. J. Biol. Chem. 285: 10005-10015, 2010. [PubMed: 20106987] [Full Text: https://doi.org/10.1074/jbc.M109.093666]