Alternative titles; symbols
SNOMEDCT: 725042001; ORPHA: 140922; DO: 0110283;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q31.2 | Muscular dystrophy, limb-girdle, autosomal recessive 10 | 608807 | Autosomal recessive | 3 | TTN | 188840 |
A number sign (#) is used with this entry because of evidence that autosomal recessive limb-girdle muscular dystrophy-10 (LGMDR10) is caused by homozygous or compound heterozygous mutation in the titin gene (TTN; 188840) on chromosome 2q31.
Heterozygous mutation in the titin gene causes tardive tibial muscular dystrophy (TMD; 600334).
For a general description and a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).
According to the report of the 105th ENMC workshop, the phenotype of the homozygous TTN gene mutation is termed 'LGMD2J' (Bushby and Beckmann, 2003).
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, LGMD2J was renamed LGMDR10.
Udd et al. (1991, 1992) reported a large consanguineous Finnish pedigree in which 12 members had mild late-onset distal tibial myopathy (see TMD) inherited in an autosomal dominant pattern and 8 members had a severe limb-girdle muscular dystrophy inherited in an autosomal recessive pattern. Both groups had nonspecific myopathic changes on muscle biopsy and progressive fatty infiltration of involved muscles. Onset of the severe LGMD phenotype was in the first to third decades and involved weakness of all proximal muscles. Severe disability with loss of ambulation occurred within 20 years (third to sixth decades). There was no facial muscle involvement or cardiomyopathy. Some patients later developed distal muscle involvement. Segregation analysis showed that the corrected proportion of affected persons with the severe proximal type was 0.246 and the proportion of affected persons with the distal myopathy was 0.58. The findings were compatible with the hypothesis that the severe LGMD phenotype was the homozygous manifestation of a dominant gene that in the heterozygous state caused the milder distal myopathy (Udd, 1992).
In muscle biopsies from a patient with limb-girdle muscular dystrophy who was homozygous for a TMD haplotype, Haravuori et al. (2001) found almost complete loss of calpain-3 (CAPN3; 114240), a ligand of titin. The authors concluded that the loss of calpain-3 is a secondary downstream effect of deficiency of the TMD gene protein and results in phenotypic overlap with LGMDR1, which is caused by mutation in the calpain-3 gene.
Dabby et al. (2015) reported a 29-year-old man of Romanian and Hungarian descent who presented with slowly progressive proximal muscle weakness of the lower limbs resulting in difficulty climbing stairs and getting up from a seated position. He also had mild weakness of the shoulder girdle muscles. Laboratory studies showed increased serum creatine kinase, a myopathic and irritative pattern on EMG, nonspecific myopathic changes on muscle biopsy, including variability in fiber size, necrotic and regenerating fibers, and a lymphocytic infiltrate, and fatty replacement of muscles of the lower limb on MRI. He was treated with various immunomodulatory medications with no improvement. Muscle biopsy showed some reduction of C-terminal titin compared to controls, but it was not as severe as had been reported in other patients.
Zheng et al. (2016) reported 3 adult sibs from a consanguineous Han Chinese family with LGMDR10. The patients presented between 13 and 16 years of age with difficulty running and climbing, frequent falls, and Gowers sign. They developed proximal muscle weakness and atrophy affecting the lower and upper limbs. The disorder was progressive, and they developed elbow and ankle joint contractures; none was able to walk or raise their arms above their shoulders after their thirties. One patient also had lordosis. Skeletal muscle biopsy of 1 patient showed variation in fiber diameter, cell necrosis, fibrosis, and some regenerating fibers. Serum creatine kinase was increased in 2 patients. There was no cardiac involvement.
The transmission pattern of LGMDR10 in the family reported by Dabby et al. (2015) was consistent with autosomal recessive inheritance.
By genomewide scan of the large Finnish family with LGMD and TMD reported by Udd et al. (1992), Haravuori et al. (1997, 1998) found a region of interest on 2q. Further analyses with additional family members and additional families with TMD, yielded a maximum multipoint lod score of 12.4 with marker D2S324. Haplotype analysis revealed the same core haplotype in all analyzed families, providing evidence for an ancestral mutation, further restricting the critical chromosomal region to about 1 cM, and mapping the disease locus to chromosome 2q31. Three patients with the more severe LGMD phenotype were homozygous for the haplotype, whereas those with the milder TMD phenotype were heterozygous.
In patients with LGMD2J from the large Finnish family reported by Udd et al. (1992), Hackman et al. (2002) identified homozygosity for an 11-bp deletion/insertion in the last exon (exon 363) of the TTN gene (188840.0004). Family members affected with the milder adult-onset TMD phenotype were heterozygous for the TTN deletion.
In a 29-year-old man of Romanian and Hungarian origin with a relatively mild form of LGMDR10, Dabby et al. (2015) identified compound heterozygous missense mutations at conserved residues in the TTN gene: K26320T (188840.0017) and A6135G (188840.0018). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed, but patient skeletal muscle biopsy showed a reduction in C-terminal titin compared to controls.
In 3 sibs from a consanguineous Han Chinese family with LGMDR10, Zheng et al. (2016) identified a homozygous missense mutation in the TTN gene (W35930R; 188840.0019). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
Bushby, K. M., Beckmann, J. S. The 105th ENMC sponsored workshop: pathogenesis in the non-sarcoglycan limb-girdle muscular dystrophies, Naarden, April 12-14, 2002. Neuromusc. Disord. 13: 80-90, 2003. [PubMed: 12467737] [Full Text: https://doi.org/10.1016/s0960-8966(02)00183-9]
Dabby, R., Sadeh, M., Hilton-Jones, D., Plotz, P., Hackman, P., Vihola, A., Udd, B., Leshinsky-Silver, E. Adult onset limb-girdle muscular dystrophy--a recessive titinopathy masquerading as myositis. J. Neurol. Sci. 351: 120-123, 2015. [PubMed: 25772186] [Full Text: https://doi.org/10.1016/j.jns.2015.03.001]
Hackman, P., Vihola, A., Haravuori, H., Marchand, S., Sarparanta, J., de Seze, J., Labeit, S., Witt, C., Peltonen, L., Richard, I., Udd, B. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am. J. Hum. Genet. 71: 492-500, 2002. [PubMed: 12145747] [Full Text: https://doi.org/10.1086/342380]
Haravuori, H., Makela-Bengs, P., Udd, B., Partanen, J., Pulkkinen, L., Somer, H., Peltonen, L. Assignment of the tibial muscular dystrophy locus to chromosome 2q31. Am. J. Hum. Genet. 62: 620-626, 1998. [PubMed: 9497249] [Full Text: https://doi.org/10.1086/301752]
Haravuori, H., Makela-Bengs, P., Udd, B., Pulkkinen, L., Partanen, J., Somer, H., Peltonen, L. Assignment of the tibial muscular dystrophy (TMD) locus on chromosome 2q31. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A29 only, 1997.
Haravuori, H., Vihola, A., Straub, V., Auranen, M., Richard, I., Marchand, S., Voit, T., Labeit, S., Somer, H., Peltonen, L., Beckmann, J. S., Udd, B. Secondary calpain3 deficiency in 2q-linked muscular dystrophy: titin is the candidate gene. Neurology 56: 869-877, 2001. [PubMed: 11294923] [Full Text: https://doi.org/10.1212/wnl.56.7.869]
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]
Udd, B., Kaarianen, H., Somer, H. Muscular dystrophy with separate clinical phenotypes in a large family. Muscle Nerve 14: 1050-1058, 1991. [PubMed: 1745277] [Full Text: https://doi.org/10.1002/mus.880141103]
Udd, B., Rapola, J., Nokelainen, P., Arikawa, E., Somer, H. Nonvacuolar myopathy in a large family with both late adult onset distal myopathy and severe proximal muscular dystrophy. J. Neurol. Sci. 113: 214-221, 1992. [PubMed: 1487757] [Full Text: https://doi.org/10.1016/0022-510x(92)90249-k]
Udd, B. Limb-girdle type muscular dystrophy in a large family with distal myopathy: homozygous manifestation of a dominant gene? J. Med. Genet. 29: 383-389, 1992. [PubMed: 1619633] [Full Text: https://doi.org/10.1136/jmg.29.6.383]
Zheng, W., Chen, H., Deng, X., Yuan, L., Yang, Y., Song, Z., Yang, Z., Wu, Y., Deng, H. Identification of a novel mutation in the titin gene in a Chinese family with limb-girdle muscular dystrophy 2J. Molec. Neurobiol. 53: 5097-5102, 2016. [PubMed: 26392295] [Full Text: https://doi.org/10.1007/s12035-015-9439-0]