Alternative titles; symbols
SNOMEDCT: 719989007; ORPHA: 55595; DO: 0110304;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q32.1 | Muscular dystrophy, limb-girdle, autosomal dominant 2 | 608423 | Autosomal dominant | 3 | TNPO3 | 610032 |
A number sign (#) is used with this entry because of evidence that autosomal dominant limb-girdle muscular dystrophy-2 (LGMDD2) is caused by heterozygous mutation in the TNPO3 gene (610032) on chromosome 7q32.
Autosomal dominant limb-girdle muscular dystrophy-2 (LGMDD2) is a myopathy characterized by proximal muscle weakness primarily affecting the lower limbs, but also affecting the upper limbs in most patients. Affected individuals also have distal muscle weakness of the hands and lower leg muscles. There is variability in presentation and progression. Some patients present in early childhood with mildly delayed walking and difficulty running and jumping, whereas others present as adults with mainly pelvic-girdle weakness. Patients with early onset tend to have a more severe disorder, and may develop contractures, loss of independent ambulation, and respiratory insufficiency. Muscle biopsy shows dystrophic changes with abnormal nuclei, rimmed vacuoles, and filamentous inclusions (summary by Melia et al., 2013).
For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant limb-girdle muscular dystrophy, see LGMDD1 (603511).
At the 229th ENMC international workshop, Straub et al. (2018) reviewed, reclassified, and/or renamed forms of LGMD. The proposed naming formula was 'LGMD, inheritance (R or D), order of discovery (number), affected protein.' Under this formula, LGMD1F was renamed LGMDD2.
Gamez et al. (2001) reported a large Spanish kindred in which 32 members spanning 5 generations were affected with autosomal dominant limb-girdle muscular dystrophy. Two forms were delineated based on age at onset: a juvenile form with onset before age 15 years (66%), and an adult-onset form starting around the third or fourth decade (28%). All affected patients showed characteristic pelvic and shoulder girdle proximal weakness. Pelvic girdle impairment was more severe and occurred earlier than shoulder girdle weakness, and distal weakness often occurred later. Respiratory muscles were clinically affected in 4 patients with juvenile onset. Muscle biopsies of 5 patients showed myopathic changes, including abnormal fiber size and variation, increased connective tissue, degenerative fibers, occasional central nuclei, and in 3 cases, rimmed vacuoles. There was no cardiac involvement, dysarthria, calf hypertrophy, or contractures.
Melia et al. (2013) reported follow-up of the family reported by Gamez et al. (2001). There was variable distribution of affected muscles as well as variable severity and rate of progression. A predominant group of juvenile-onset patients showed mildly delayed walking followed by difficulty running and jumping. A small number of these patients also had joint contractures or rigid spine and developed respiratory insufficiency or lost independent ambulation in the third decade. A second group of patients had adult-onset of pelvic-girdle muscle weakness, followed by shoulder-girdle weakness in some. Other features of the disorder in all patients included thin legs and thenar muscle atrophy with hand weakness. Muscle biopsy showed dystrophic changes as well as abnormally enlarged nuclei with central pallor and filamentous or paracrystalline inclusions in muscle fibers.
Torella et al. (2013) reported a patient with sporadic LGMD1F. He had young adult-onset of characteristic limb-girdle weakness. Muscle biopsy showed dystrophic features with mitochondrial alterations, sporadic ragged-red fibers, and cytochrome c oxidase-negative fibers.
The transmission pattern of LGMD1F in the family reported by Gamez et al. (2001) was consistent with autosomal dominant inheritance.
In the family with autosomal dominant limb-girdle muscular dystrophy reported by Gamez et al. (2001), Palenzuela et al. (2003) found linkage to a 3.68-Mb region on chromosome 7q32.1-q32.2, termed LGMD1F (maximum 2-point lod score of 7.56 at marker D7S2544). All affected members had a common disease haplotype. No mutation was identified in the filamin C gene (FLNC; 102565). Palenzuela et al. (2003) noted that LGMD1E (LGMDD1; 603511) had been mapped to chromosome 7q, but determined that LGMD1E is approximately 24 cM telomeric to D7S2544, which defines the distal boundary of the LGMD1F critical region, indicating that the 2 disorders are distinct.
Independently and simultaneously, Melia et al. (2013) and Torella et al. (2013) identified a heterozygous mutation in the TNPO3 gene (610032.0001) in affected members of the large Spanish family with LGMD reported by Gamez et al. (2001). The mutation, which was identified by whole-genome sequencing (Melia et al., 2013) and whole-exome sequencing (Torella et al., 2013), segregated with the disorder in the family. Studies in patient muscle cells and HeLa cells showed that the mutant protein was unevenly distributed and often limited to the periphery of nuclei compared to control muscle. Melia et al. (2013) postulated a dominant-negative toxic effect.
Torella et al. (2013) identified a heterozygous missense mutation in the TNPO3 gene (R818P; 610032.0002) in 1 of 64 additional individuals with sporadic LGMD who were screened using a next-generation sequencing approach.
Gamez, J., Navarro, C., Andreu, A. L., Fernandez, J. M., Palenzuela, L., Tejeira, S., Fernandez-Hojas, R., Schwartz, S., Karadimas, C., DiMauro, S., Hirano, M., Cervera, C. Autosomal dominant limb-girdle muscular dystrophy: a large kindred with evidence for anticipation. Neurology 56: 450-454, 2001. [PubMed: 11222786] [Full Text: https://doi.org/10.1212/wnl.56.4.450]
Melia, M. J., Kubota, A., Ortolano, S., Vilchez, J. J., Gamez, J., Tanji, K., Bonilla, E., Palenzuela, L., Fernandez-Cadenas, I., Pristoupilova, A., Garcia-Arumi, E., Andreu, A. L., Navarro, C., Hirano, M., Marti, R. Limb-girdle muscular dystrophy 1F is caused by a microdeletion in the transportin 3 gene. Brain 136: 1508-1517, 2013. [PubMed: 23543484] [Full Text: https://doi.org/10.1093/brain/awt074]
Palenzuela, L., Andreu, A. L., Gamez, J., Vila, M. R., Kunimatsu, T., Meseguer, A., Cervera, C., Fernandez Cadenas, I., van der Ven, P. F. M., Nygaard, T. G., Bonilla, E., Hirano, M. A novel autosomal dominant limb-girdle muscular dystrophy (LGMD 1F) maps to 7q32.1-32.2. Neurology 61: 404-406, 2003. [PubMed: 12913210] [Full Text: https://doi.org/10.1212/01.wnl.0000073984.46546.4f]
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]
Torella, A., Fanin, M., Mutarelli, M., Peterle, E., Del Vecchio Blanco, F., Rispoli, R., Savarese, M., Garofalo, A., Piluso, G., Morandi, L., Ricci, G., Siciliano, G., Angelini, C., Nigro, V. Next-generation sequencing identifies transportin 3 as the causative gene for LGMD1F. PLoS One 8: e63536, 2013. Note: Electronic Article. [PubMed: 23667635] [Full Text: https://doi.org/10.1371/journal.pone.0063536]