Alternative titles; symbols
SNOMEDCT: 764859001; ORPHA: 59135; DO: 0070197;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q11.2 | Laing distal myopathy | 160500 | Autosomal dominant | 3 | MYH7 | 160760 |
A number sign (#) is used with this entry because distal myopathy-1 (MPD1), also known as Laing distal myopathy, is caused by heterozygous mutation in the MYH7 gene (160760), which encodes the myosin heavy chain of type 1 fibers of skeletal muscle and cardiac ventricles, on chromosome 14q11.
The MYH7 gene is mutated in both hypertrophic (see 192600) and dilated (see 115200) cardiomyopathy as well as in myosin storage myopathy (608358).
Distal myopathy-1 (MPD1) is an autosomal dominant myopathy in which selective weakness of the anterior tibial muscles is followed by weakness of the finger extensors and of selected proximal muscle groups, such as the hip abductors and rotators, the shoulder abductors, and in some patients the sternocleidomastoids. Age of onset, at 4 to 25 years, is earlier than in other autosomal dominant distal myopathies (summary by Meredith et al., 2004).
Laing et al. (1995) described a family with an autosomal dominant distal myopathy closely resembling that described in the original report of Gowers (1902).
Scoppetta et al. (1995) and Voit et al. (2001) reported 2 families with autosomal dominant distal myopathy with clinical features similar to those reported by Laing et al. (1995). Characteristics common to both families included onset in the second or third year of life, selective wasting and weakness of the anterior tibial and extensor digitorum longus muscles, a slowly progressive course, and, at later stages, involvement of hand extensors, neck flexor, and abdominal muscles. Some patients developed tremor. Zimprich et al. (2000) described an Austrian family with a similar phenotype.
In a family with 9 affected members spanning 3 generations, Mastaglia et al. (2002) described selective weakness of the ankle dorsiflexors and toe extensors, in particular the extensor hallucis longus. Ankle plantar flexors were normal, even in the most advanced cases. There was also weakness and atrophy of the anterior compartment muscles. Most cases had selective weakness of the long finger extensor muscles. None of the affected individuals had cardiomyopathy. Age at onset varied from 4 to 5 years to the early twenties. Muscle MRI showed atrophy of affected muscles, EMG gave a myopathic pattern, and muscle biopsy of 2 affected patients showed myopathic changes without rimmed vacuoles.
Hedera et al. (2003) reported a large Italian American kindred in which at least 11 members spanning 3 generations were affected with an autosomal dominant distal myopathy. Clinical features included weakness of foot and toe extensor muscles, and some patients had proximal weakness. No patient had distal weakness of the upper extremities or neck muscles, even in advanced stages of the disease. The average age at symptom onset was 20 years. Two affected patients had signs of idiopathic dilated cardiomyopathy. Hedera et al. (2003) noted that their family differed from the family reported by Laing et al. (1995) by the absence of upper extremity weakness and neck muscle weakness.
Darin et al. (2007) reported a Tanzanian boy with distal myopathy and mild dilated cardiomyopathy. He began walking on the toes at age 11 months and had Achilles tenotomy at age 6 years. Examination at age 7 showed weakness of the great toe and ankle dorsiflexors, atrophy of the anterior tibial muscles, weakness of the hip flexors, and decreased reflexes. Echocardiography showed mild left atrial enlargement and prolonged isovolumetric relaxation time. Skeletal muscle biopsy showed hypotrophy of type 1 fibers and apparent absence of type 2B fibers. Serum creatine kinase was mildly elevated.
Clinical Variability
Muelas et al. (2010) identified the same mutation in the MYH7 gene (lys1729del; 160760.0044) in 29 clearly affected individuals from 4 unrelated families in the Safor region of Spain. There was great phenotypic variability. The age at onset ranged from congenital to 50 years, with a mean of 14 years. All patients presented with weakness of great toe/ankle dorsiflexors, and many had associated neck flexor (78%), finger extensor (78%), mild facial (70%), or proximal muscle (65%) weakness. There was atrophy of the anterior lower leg compartment muscles, which contrasted with calf hypertrophy. Some had more widespread proximal muscle involvement, resembling that seen in the allelic disorder myosin storage myopathy (608358). Variable findings included quadriceps atrophy, ankle retraction, pes cavus, scoliosis, claw toes, and high-arched palate. Five patients had cardiac abnormalities, including dilated cardiomyopathy, left ventricular relaxation impairment, and conduction abnormalities. The spectrum of disability ranged from asymptomatic to wheelchair-confined, but life expectancy was not affected. EMG showed myopathic as well as neurogenic features, and muscle biopsies yielded various findings, such as fiber type disproportion, core/minicore lesions, and mitochondrial abnormalities. Most patients had slow progression, but some were severely disabled, and many had myalgias. These findings expanded the phenotypic spectrum of Laing myopathy, but the wide spectrum associated with a single mutation was noteworthy. Muelas et al. (2010) also noted that the variable features could lead to misdiagnosis of neurogenic atrophy, congenital myopathies, or even mitochondrial myopathies.
The disorder in the family studied by Laing et al. (1995) showed linkage of the locus, symbolized MPD1, to chromosome 14. A multipoint analysis assuming 100% penetrance and using MYH7 (160760) and 5 other markers gave a lod score of exactly 3 at MYH7. Analysis at a penetrance of 80% gave a lod score of 2.8 at this marker.
Linkage analysis in a large family with autosomal dominant distal myopathy reported by Mastaglia et al. (2002) yielded a maximum 2-point lod score of 2.9 at marker D14S262, and further analysis refined the candidate locus to a 24-cM region between D14S283 and D14S49.
In a large family with autosomal dominant distal myopathy, Hedera et al. (2003) found linkage to chromosome 14q11-q13 (maximum 2-point lod score of 3.99 at marker D14S1459). Mutation analysis excluded the PABP2 gene (602279).
The transmission pattern of MPD1 in the families reported by Meredith et al. (2004) was consistent with autosomal dominant inheritance.
In affected members of 7 separate families with Laing distal myopathy, Meredith et al. (2004) sequenced the MYH7 gene, a positional candidate for the site of the causative mutation. They identified 5 heterozygous mutations in 6 families (see 160760.0029-160760.0030) and no mutations in the seventh family. The family reported by Hedera et al. (2003) had a deletion of lys1729 (160760.0044).
In a Tanzanian boy with Laing myopathy and mild cardiac involvement, Darin et al. (2007) identified a heterozygous mutation in the MYH7 gene (160760.0036).
Meredith et al. (2004) identified a heterozygous mutation in the MYH7 gene (lys1729del; 160760.0044) in affected members of an Italian American family with Laing distal myopathy reported by Hedera et al. (2003). Muelas et al. (2010) identified the lys1729del mutation in 29 clearly affected individuals from 4 unrelated families in the Safor region of Spain. Muelas et al. (2012) demonstrated a common 41.2-kb short haplotype including the lys1729del mutation in both Spanish patients from the Safor region and in the Italian American family reported by Hedera et al. (2003), indicating a founder effect. However, microsatellite markers both up- and downstream of the mutation did not match, indicating multiple recombination events. The mutation was estimated to have been introduced into the Safor population about 375 to 420 years ago (15 generations ago). The region is located in the southeast of Valencia on the Mediterranean coast of Spain. Muelas et al. (2012) hypothesized that the families from Safor were descendants of the Genoese who had repopulated this Spanish region in the 17th century after the Muslims were expelled; in fact, many of the surnames of the Safor families with Laing myopathy had an Italian origin.
Darin, N., Tajsharghi, H., Ostman-Smith, I., Gilljam, T., Oldfors, A. New skeletal myopathy and cardiomyopathy associated with a missense mutation in MYH7. Neurology 68: 2041-2042, 2007. [PubMed: 17548557] [Full Text: https://doi.org/10.1212/01.wnl.0000264430.55233.72]
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]
Hedera, P., Petty, E. M., Bui, M. R., Blaivas, M., Fink, J. K. The second kindred with autosomal dominant distal myopathy linked to chromosome 14q: genetic and clinical analysis. Arch. Neurol. 60: 1321-1325, 2003. [PubMed: 12975303] [Full Text: https://doi.org/10.1001/archneur.60.9.1321]
Laing, N. G., Laing, B. A., Meredith, C., Wilton, S. D., Robbins, P., Honeyman, K., Dorosz, S., Kozman, H., Mastaglia, F. L., Kakulas, B. A. Autosomal dominant distal myopathy: linkage to chromosome 14. Am. J. Hum. Genet. 56: 422-427, 1995. [PubMed: 7847377]
Mastaglia, F. L., Phillips, B. A., Cala, L. A., Meredith, C., Egli, S., Akkari, P. A., Laing, N. G. Early onset chromosome 14-linked distal myopathy (Laing). Neuromusc. Disord. 12: 350-357, 2002. [PubMed: 12062252] [Full Text: https://doi.org/10.1016/s0960-8966(01)00287-5]
Meredith, C., Herrmann, R., Parry, C., Liyanage, K., Dye, D. E., Durling, H. J., Duff, R. M., Beckman, K., de Visser, M., van der Graaff, M. M., Hedera, P., Fink, J. K., Petty, E. M., Lamont, P., Fabian, V., Bridges, L., Voit, T., Mastaglia, F. L., Laing, N. G. Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause Laing early-onset distal myopathy (MPD1). Am. J. Hum. Genet. 75: 703-708, 2004. [PubMed: 15322983] [Full Text: https://doi.org/10.1086/424760]
Muelas, N., Hackman, P., Luque, H., Garces-Sanchez, M., Azorin, I., Suominen, T., Sevilla, T., Mayordomo, F., Gomez, L., Marti, P., Maria Millan, J., Udd, B., Vilchez, J. J. MYH7 gene tail mutation causing myopathic profiles beyond Laing distal myopathy. Neurology 75: 732-741, 2010. [PubMed: 20733148] [Full Text: https://doi.org/10.1212/WNL.0b013e3181eee4d5]
Muelas, N., Hackman, P., Luque, H., Suominen, T., Espinos, C., Garces-Sanchez, M., Sevilla, T., Azorin, I., Millan, J. M., Udd, B., Vilchez, J. J. Spanish MYH7 founder mutation of Italian ancestry causing a large cluster of Laing myopathy patients. Clin. Genet. 81: 491-494, 2012. [PubMed: 21395566] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01667.x]
Scoppetta, C., Casali, C., La Cesa, I., Sermoni, A., Mercuri, B., Pierelli, F., Vaccario, M. L. Infantile autosomal dominant distal myopathy. Acta Neurol. Scand. 92: 122-126, 1995. [PubMed: 7484058] [Full Text: https://doi.org/10.1111/j.1600-0404.1995.tb01024.x]
Voit, T., Kutz, P., Leube, B., Neuen-Jacob, E., Schroder, J. M., Cavallotti, D., Vaccario, M. L., Schaper, J., Broich, P., Cohn, R., Baethmann, M., Gohlich-Ratmann, G., Scoppetta, C., Herrmann, R. Autosomal dominant distal myopathy: further evidence of a chromosome 14 locus. Neuromusc. Disord. 11: 11-19, 2001. [PubMed: 11166161] [Full Text: https://doi.org/10.1016/s0960-8966(00)00158-9]
Zimprich, F., Djamshidian, A., Hainfellner, J. A., Budka, H., Zeitlhofer, J. An autosomal dominant early adult-onset distal muscular dystrophy. Muscle Nerve 23: 1876-1879, 2000. [PubMed: 11102913] [Full Text: https://doi.org/10.1002/1097-4598(200012)23:12<1876::aid-mus13>3.0.co;2-a]