DO: 0060943;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q37.3 | Ullrich congenital muscular dystrophy 1C | 620728 | Autosomal dominant; Autosomal recessive | 3 | COL6A3 | 120250 |
A number sign (#) is used with this entry because of evidence that Ullrich congenital muscular dystrophy-1C (UCMD1C) is caused by homozygous or heterozygous mutation in the COL6A3 gene (120250) on chromosome 2q37.
See also Bethlem myopathy-1C (BTHLM1C; 620726), 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).
Demir et al. (2002) reported 5 patients (ranging from 3 to 18 years of age) from 3 unrelated consanguineous families (from Morocco, Italy, and Turkey) with UCMD1C. Although the severity of the disorder was variable, features included neonatal hypotonia, diffuse muscle weakness, muscle atrophy, proximal joint contractures, and distal hyperlaxity. Axial muscles (mainly neck flexors), pelvic girdle muscles, and intrinsic muscles in hands and feet were the most severely affected ones. Lower limbs tended to be more severely affected than upper limbs; in most cases, hip extensors and abductors were weaker than hip flexors, leading to hip contractures that interfered with standing position. All could walk, but most needed support or had reduced motor capacity. No significant facial weakness was observed. Muscle biopsies showed fiber size variation and increased connective tissue. Serum creatine kinase was normal or moderately increased.
Nadeau et al. (2009) reported 2 unrelated patients with UCMD1C caused by a recurrent de novo heterozygous splice site mutation in the COL6A3 gene (120250.0004). The first patient was a 30-year-old individual who had onset at birth with hypotonia, congenital hip dislocation, delayed motor development, and feeding difficulties. Independent walking was not achieved, and the patient became wheelchair-bound at age 12 years. There was spinal rigidity, scoliosis, and kyphosis, as well as follicular hyperkeratosis, keloid formation, and need for nocturnal ventilation. The second patient had onset at age 1.5 years but never achieved independent walking and was wheelchair-bound by age 3.5 years. This patient died at age 10 years during a respiratory illness.
The transmission pattern of UCMD1C in the families reported by Demir et al. (2002) was consistent with autosomal recessive inheritance.
The heterozygous mutations in the COL6A3 gene that were identified in patients with UCMD1C by Baker et al. (2005) and Nadeau et al. (2009) occurred de novo.
Demir et al. (2002) demonstrated linkage of UCMD to 2q37 in 3 families, each of which had a homozygous mutation in the COL6A3 gene (see, e.g., 120250.0002 and 120250.0003). One family had a phenotype of intermediate severity, a second an unusually mild phenotype, and a third with a severe phenotype as previously described in patients with UCMD. This was the first description of mutations in COL6A3 in UCMD; mutations had previously been described in COL6A1 (120220) and COL6A2 (120240).
In a patient with Ullrich congenital muscular dystrophy, Baker et al. (2005) identified a de novo heterozygous splice site mutation in intron 16 of the COL6A3 gene (120250.0004). Nadeau et al. (2009) identified the same de novo heterozygous mutation in the COL6A3 gene in 2 unrelated individuals with autosomal dominant UCMD.
Baker, N. L., Morgelin, M., Peat, R., Goemans, N., North, K. N., Bateman, J. F., Lamande, S. R. Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy. Hum. Molec. Genet. 14: 279-293, 2005. [PubMed: 15563506] [Full Text: https://doi.org/10.1093/hmg/ddi025]
Demir, E., Sabatelli, P., Allamand, V., Ferreiro, A., Moghadaszadeh, B., Makrelouf, M., Topaloglu, H., Echenne, B., Merlini, E., Guicheney, P. Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy. Am. J. Hum. Genet. 70: 1446-1458, 2002. [PubMed: 11992252] [Full Text: https://doi.org/10.1086/340608]
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]
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]