Tibial Muscular Dystrophy, Tardive

A number sign (#) is used with this entry because of evidence that tibial muscular dystrophy (TMD) is caused by heterozygous mutation in the gene encoding the giant skeletal muscle protein titin (TTN; 188840) on chromosome 2q31.

Homozygous mutation in the titin gene causes the more severe limb-girdle muscular dystrophy type 2J (LGMD2J; 608807).

Clinical Features

Markesbery et al. (1974) reported a late adult-onset, autosomal dominant form of distal myopathy with onset in the anterior compartment of the legs rather than in the hands, which is the presenting feature of Welander myopathy (604454). In addition, they reported the occurrence of cardiomyopathy. Edstrom et al. (1980) thought that the family of Markesbery et al. (1974) had a distinct disorder because the affected members showed cardiomyopathy (which was never found in Welander myopathy) and had different histopathologic findings (compare Edstrom, 1975 and Markesbery et al., 1977).

Udd (1992) reported a large consanguineous Finnish pedigree with 2 separate muscle disease phenotypes: mild late-onset distal myopathy inherited in an autosomal dominant pattern and severe limb-girdle muscular dystrophy (see LGMD2J) inherited in an autosomal recessive pattern. 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 et al. (1992), who referred to the distal myopathy as 'tibial muscular dystrophy,' reported follow-up on the large affected Finnish pedigree.

Partanen et al. (1994) studied a family with very late-onset (fifth or sixth decade) or asymptomatic hereditary myopathy of the anterior tibial muscle. The muscles of the upper extremity were spared. The anterior tibial muscles had a characteristic myopathic alteration with rimmed vacuoles. Twelve persons, both male and female, were affected, and male-to-male transmission was demonstrated. Partanen et al. (1994) noted the similarity of their cases to those of Markesbery et al. (1974) in that there was late adult onset in the anterior compartment of the legs. However, Partanen et al. (1994) thought that the patients reported by Markesbery et al. (1974) had a far wider involvement and earlier onset of disease.

Partanen et al. (1994) distinguished 6 types of distal myopathy: (1) Welander myopathy; (2) a late-onset autosomal dominant form with onset in the anterior compartment of the legs; (3) an early adult-onset recessive or sporadic form with onset in the anterior compartment of the legs with vacuolar myopathy on biopsy (Sunohara et al., 1989); (4) an early adult-onset recessive distal myopathy of the posterior compartment of the legs (Miyoshi et al., 1986; 254130); (5) an autosomal recessive vacuolar myopathy sparing the quadriceps (Sadeh et al., 1993; 600737); and (6) a late-onset autosomal dominant tibial dystrophy as described by Udd et al. (1991, 1992) and Udd (1992).

Udd et al. (1993) investigated 66 Finnish patients with late adult-onset tibial muscular dystrophy. Symptoms appeared after the age of 35 years with reduced ankle dorsiflexion, and progression was slow without marked disability. Facial muscles, upper extremities, and proximal muscles were usually spared. Pedigree data suggested autosomal dominant inheritance. The clinical studies suggested homogeneity in the various families affected with this rather frequent disorder in Finns.

Van den Bergh et al. (2003) reported a Belgian family with tibial muscular dystrophy. The proband had onset of gait difficulties in his late 40s, and clinical examination showed steppage gait and weakness and atrophy of the anterior compartment muscles of the lower legs without proximal weakness or sensory loss. CT scan of the lower leg muscles showed marked atrophy and low density, suggestive of fatty degeneration. Family investigation revealed that the proband's father, a paternal uncle, and one of his daughters had mild tibialis anterior weakness and atrophy, although all were asymptomatic. In affected members of the family, Van den Bergh et al. (2003) identified a heterozygous mutation in the Mex6 exon of the titin gene (188840.0006). The authors noted that the family showed incomplete disease penetrance.

Pathologic Findings

In 12 affected members of a large Finnish pedigree with distal myopathy, Udd et al. (1992) found that muscle biopsy did not show vacuolar degeneration, which was in contrast to most adult-onset distal myopathies. Histopathologic changes correlating with the muscular dystrophy were extensive in tibial anterior muscles in patients with distal myopathy and in all muscles of those family members who had a severe limb-girdle muscular dystrophy phenotype.

Among 66 Finnish patients with TMD, Udd et al. (1993) found that muscle biopsies showed nonspecific dystrophic changes in clinically affected muscles and severe adipose replacement in the anterior tibial muscles. Asymptomatic muscles had mild myopathic changes only. Vacuolar degeneration was detected in a minority of patients. Electromyography showed profound myopathic changes in the anterior tibial muscle, but extensor brevis muscles were well preserved. Computed tomography or magnetic resonance imaging of muscles disclosed marked involvement of tibial extensor muscles and focal patches of fatty degeneration in various asymptomatic muscles.

In tibial muscular dystrophy, some biopsies showed rimmed vacuoles and others did not. Udd (1997) concluded that the presence or absence of rimmed vacuoles was not indicative of heterogeneity because there was intrafamilial variation and families with or without rimmed vacuoles were shown to be genealogically linked.

Mapping

In a Finnish tibial muscular dystrophy family with 11 affected individuals, Haravuori et al. (1997, 1998) found a region of interest on 2q by a genomewide scan with microsatellite markers. Further analyses with additional family members and additional families, 1 of whom was the large Finnish family reported by Udd et al. (1992), yielded a maximum 2-point lod score of 10.14 at theta = 0.05 with marker D2S364. Multipoint likelihood calculations assigned the TMD locus to the proximity of marker D2S324 with a maximum multipoint lod score of 12.4 at theta = 0.0. Haplotype analysis revealed the same core haplotype in all analyzed families, thus providing evidence for an ancestral mutation and further restricting the critical chromosomal region to about 1 cM. The location of the locus was determined to be 2q31 (Udd, 1997; Haravuori et al., 1998).

De Seze et al. (1998) described a French family with TMD and confirmed the linkage to 2q31 with a different haplotype for linked markers.

Heterogeneity

Genetic Heterogeneity

Felice et al. (1999) reported a family with autosomal dominant distal myopathy spanning 4 generations in whom linkage to Nonaka distal myopathy (605820) on 9p, MPD1 (160500) on 14q, Miyoshi myopathy on 2p13, and TMD on 2q31 was excluded. Clinical features included onset in the second to third decade of foot drop, difficulty in stair climbing, and progressive leg weakness. Some had later involvement of proximal lower limb muscles and distal upper limb muscles. Laboratory studies showed increased serum creatine kinase and nonspecific myopathic changes without rimmed vacuoles.

Molecular Genetics

Because of the map location of TMD on 2q31, the gene encoding the giant skeletal muscle protein titin (188840) was a strong positional as well as functional candidate for the site of causative mutations. Hackman et al. (2002) demonstrated a heterozygous 11-bp deletion/insertion in the last exon (exon 363) of the TTN gene (188840.0004) as the cause of TMD in 81 Finnish patients from 12 unrelated families. One of the families with the 11-bp deletion was the large Finnish family reported by Udd et al. (1992). A different mutation in the TTN gene, a missense mutation that was also located in the last exon (188840.0005), was identified in an affected French family.