Alternative titles; symbols
ORPHA: 603;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p13.3 | Welander distal myopathy | 604454 | Autosomal dominant; Autosomal recessive | 3 | TIA1 | 603518 |
A number sign (#) is used with this entry because Welander distal myopathy (WDM) is caused by heterozygous mutation in the TIA1 gene (603518) on chromosome 2p13. Some patients may have a homozygous mutation, which is associated with a more severe phenotype.
Welander distal myopathy (WDM) is an autosomal dominant disorder characterized by adult onset of distal muscle weakness predominantly affecting the distal long extensors of the hands, with slow progression to involve all small hand muscles and the lower legs. Skeletal muscle biopsy shows myopathic changes and prominent rimmed vacuoles. Rare homozygous patients showed earlier onset, faster progression, and proximal muscle involvement. This disorder is common in Sweden and Finland (summary by Hackman et al., 2013).
On the basis of 78 probands and 171 secondary cases, Welander (1951) delineated this form of distal myopathy as a distinct entity with dominant inheritance. The 249 affected persons were distributed in 72 kindreds. The mean age at onset was 47 years (range, 20-77 years). Weakness and wasting of the small muscles of the hands were the first manifestations in 89%. Fasciculations, myotonia, and sensory changes were notably absent. About 70% of the probands were aware of their hereditary predisposition at the time of first examination. The disorder was very slowly progressive and apparently did not shorten life.
Ahlberg et al. (1999) referred to Welander distal myopathy as a model for hereditary distal myopathies. They stated that it is seen almost only in Sweden and some parts of Finland. Typical manifestations include weakness of the long extensor muscles of the hands and feet. Sensory dysfunction becomes evident on thermal screening, where hypoesthesia and abnormal thermal thresholds in the hands and in the lower extremities are demonstrated. The first symptom is clumsiness in performing fine motor skills with the index finger and thumb. This weakness subsequently progresses to all fingers and makes it difficult to extend the fingers. Atrophy of the thenar and intrinsic hand muscles becomes manifest after several years' duration. In the lower leg, weakness of the anterior tibial muscle develops, and gradually the gait becomes stumbling with inability to raise the forefoot appropriately. The most prominent finding on light microscopy is that of rimmed vacuoles in atrophic as well as normal-sized muscle fibers. On ultrastructural examination, the rimmed vacuoles correspond to autophagic vacuoles that contain membranous bodies.
Klar et al. (2013) found that muscle biopsies from patients with Welander myopathy showed variable fiber diameter, atrophic fibers, and rimmed vacuoles. Immunohistochemical studies showed TIA1 staining confined mainly to areas adjacent to the vacuolar structures, whereas staining of the cytoplasm was weak or absent. A similar staining pattern was observed for antibodies against stress granule proteins and the ubiquitin binding protein p62 (601530).
Homozygosity
Welander (1957) described the homozygous state. Both parents were affected, 7 of 16 children had distal myopathy, and 2 of these were unusually severe with early proximal involvement.
Ahlberg et al. (1999) also identified an apparent homozygote. Both parents were affected with classic symptoms of WDM. The patient demonstrated an early onset, with symptoms of hand weakness at around 30 years of age. When examined at age 45, she had marked hand and distal leg weakness, as well as atrophy of the tibialis anterior muscle. Walking had become difficult because of stumbling and frequent falls, and proximal muscle weakness was present in the leg. The distal myopathy was almost of the same severity as that in her eldest brother, who was 18 years older, and more severe than that in her sister, who was 16 years older. This patient was homozygous for the characteristic haplotype. All others of the 17 affected members in her immediate family were heterozygous.
Ahlberg et al. (1999) performed a genomewide screen in 2 Swedish families with Welander distal myopathy and demonstrated linkage to 2p13. They subsequently mapped 7 additional unrelated families to the same area, where a maximum 2-point lod score of 17.97 was obtained with marker D2S2113 at a recombination fraction of 0.0. The region was further restricted by recombinations and the finding of a common shared haplotype through all analyzed families. This restricted the gene locus to a region of 2.4 cM. This region overlaps with those of Miyoshi myopathy (254130) and limb-girdle muscular dystrophy-2B (253601), both of which are due to mutation in the dysferlin gene (DYSF; 603009). Ahlberg et al. (1999) considered this gene to be a prime candidate gene for WDM.
By an extended linkage analysis, von Tell et al. (2003) reduced the WDM locus to a critical interval of approximately 1.2 Mb flanked by markers D2S358 and PAC3-H52. The DYSF gene, which is located centromeric to PAC3-H52, was thereby formally excluded as the causative gene for WDM.
By linkage analysis of 114 Finnish and Swedish patients with WDM, Hackman et al. (2013) reduced the linked region to less than 806 kb between SNP rs722265 and D2S443. A shared haplotype indicated a founder mutation in all these patients.
The transmission pattern of WDM in the patients reported by Hackman et al. (2013) was consistent with autosomal dominant inheritance.
By targeted high-throughput sequencing and Sanger sequencing of the candidate WDM region, Hackman et al. (2013) identified a heterozygous mutation in the TIA1 gene (E384K; 603518.0001) that segregated with the disorder in all 57 Swedish and Finnish patients studied. The same mutation was also found in 3 patients from Great Britain who had a partially shared haplotype at 2p13 with the Nordic patients, indicating common ancestry. Most of the patients had previously been reported by Ahlberg et al. (1999). Immunofluorescence microscopy of patient muscle showed diffuse TIA1-labeled cytoplasmic aggregates or granules in some atrophic fibers and fibers containing rimmed vacuoles. Expression of the mutant protein in HeLa cells resulted in a mild increase (10-20%) of stress granule numbers compared to controls. The increased number was apparently due to a change in stress-granule dynamics, which Hackman et al. (2013) concluded resulted from a gain of function.
Klar et al. (2013) also restricted the WDM-associated haplotype and performed exome sequencing of 43 patients from 35 families with the disorder. They identified a heterozygous E384K mutation in the TIA1 gene in all patients. Patient muscle biopsies showed increased splicing of exon 7 of the SMN2 gene (601627), reflecting impaired TIA1 function. Klar et al. (2013) hypothesized that reduced activity of TIA1 may result in decreased response to cellular stress, such as oxidative stress, that may cause age-related cellular atrophy in patients carrying the mutation.
Welander distal myopathy is found predominantly in Sweden and Finland, with some patients reported in Great Britain. Klar et al. (2013) estimated that the TIA1 mutation arose 1,050 years earlier, coinciding with the epoch of early seafaring across the Baltic Sea.
The first description of distal myopathy is attributed to Gowers (1902). The relationship to the 4 cases with onset in childhood described by Dahlgaard (1960) and to that with onset in infancy described by Magee and DeJong (1965) (see 160300) is uncertain.
Sumner et al. (1971) described an English family with 5 of 6 sibs affected by distal myopathy. The father may have been affected. They considered this a distinct entity from the Swedish cases described by Welander because of the earlier onset (age 15 to 20 years). The clinical course, however, did not appear appreciably different.
Scoppetta et al. (1984) described 2 sisters with late-onset distal muscular dystrophy and proposed autosomal recessive inheritance. It seemed possible that this was the usual autosomal dominant form with an unusual mechanism such as germinal mosaicism in a parent.
By linkage analysis, Ahlberg et al. (1997) demonstrated that Welander distal myopathy did not represent an allelic form of any of the distal myopathies having rimmed vacuoles as the common histopathologic feature. Furthermore, Ahlberg et al. (1998) excluded linkage of Welander distal myopathy to the locus on 14q (160500).
Ahlberg, G., Borg, K., Edstrom, L., Anvret, M. Welander distal myopathy is not linked to other defined distal myopathy gene loci. Neuromusc. Disord. 7: 256-260, 1997. [PubMed: 9196908] [Full Text: https://doi.org/10.1016/s0960-8966(97)00451-3]
Ahlberg, G., Borg, K., Edstrom, L., Anvret, M. Welander hereditary distal myopathy, a molecular genetic comparison to hereditary myopathies with inclusion bodies. Neuromusc. Disord. 8: 111-114, 1998. [PubMed: 9608564] [Full Text: https://doi.org/10.1016/s0960-8966(98)00007-8]
Ahlberg, G., von Tell, D., Borg, K., Edstrom, L., Anvret, M. Genetic linkage of Welander distal myopathy to chromosome 2p13. Ann. Neurol. 46: 399-404, 1999. [PubMed: 10482271] [Full Text: https://doi.org/10.1002/1531-8249(199909)46:3<399::aid-ana16>3.0.co;2-q]
Dahlgaard, E. Myopathia distalis tarda hereditaria. Acta Psychiat. Scand. 35: 440-447, 1960. [PubMed: 13719327] [Full Text: https://doi.org/10.1111/j.1600-0447.1960.tb07613.x]
Edstrom, L. Histochemical and histopathological changes in skeletal muscle in late onset hereditary distal myopathy (Welander). J. Neurol. Sci. 26: 147-157, 1975. [PubMed: 126303] [Full Text: https://doi.org/10.1016/0022-510x(75)90027-1]
Gowers, W. R. A lecture on myopathy and a distal form. Brit. Med. J. 2: 89-92, 1902. [PubMed: 20760370] [Full Text: https://doi.org/10.1136/bmj.2.2167.89]
Hackman, P., Sarparanta, J., Lehtinen, S., Vihola, A., Evila, A., Jonson, P. H., Luque, H., Kere, J., Screen, M., Chinnery, P. F., Ahlberg, G., Edstrom, L., Udd, B. Welander distal myopathy is caused by a mutation in the RNA-binding protein TIA1. Ann. Neurol. 73: 500-509, 2013. [PubMed: 23401021] [Full Text: https://doi.org/10.1002/ana.23831]
Klar, J., Sobol, M., Melberg, A., Mabert, K., Ameur, A., Johansson, A. C. V., Feuk, L., Entesarian, M., Orlen, H., Casar-Borota, O., Dahl, N. Welander distal myopathy caused by an ancient founder mutation in TIA1 associated with perturbed splicing. Hum. Mutat. 34: 572-577, 2013. [PubMed: 23348830] [Full Text: https://doi.org/10.1002/humu.22282]
Magee, K. R., DeJong, R. N. Hereditary distal myopathy with onset in infancy. Arch. Neurol. 13: 387-390, 1965. [PubMed: 5834698] [Full Text: https://doi.org/10.1001/archneur.1965.00470040053008]
Scoppetta, C., Vaccario, M. L., Casali, C., Di Trapani, G., Mennuni, G. Distal muscular dystrophy with autosomal recessive inheritance. Muscle Nerve 7: 478-481, 1984. [PubMed: 6543900] [Full Text: https://doi.org/10.1002/mus.880070610]
Sumner, D., Crawfurd, M. D., Harriman, D. G. F. Distal muscular dystrophy in an English family. Brain 94: 51-60, 1971. [PubMed: 5552164] [Full Text: https://doi.org/10.1093/brain/94.1.51]
von Tell, D., Bruder, C. E. G., Anderson, L. V. B., Anvret, M., Ahlberg, G. Refined mapping of the Welander distal myopathy region on chromosome 2p13 positions the new candidate region telomeric of the DYSF locus. Neurogenetics 4: 173-177, 2003. [PubMed: 12836053] [Full Text: https://doi.org/10.1007/s10048-003-0154-z]
Welander, L. Myopathia distalis tarda hereditaria: 249 examined cases in 72 pedigrees. Acta Med. Scand. Suppl. 265: 1-124, 1951. [PubMed: 14894174]
Welander, L. Homozygous appearance of distal myopathy. Acta Genet. Statist. Med. 7: 321-325, 1957. [PubMed: 13469174] [Full Text: https://doi.org/10.1159/000150998]