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Laing Distal Myopathy

Synonym: Laing Early-Onset Distal Myopathy

, MBBS, PhD and , PhD.

Author Information

Initial Posting: ; Last Update: March 12, 2015.

Estimated reading time: 17 minutes

Summary

Clinical characteristics.

Laing distal myopathy is characterized by early-onset weakness (usually before age 5 years) that initially involves the dorsiflexors of the ankles and great toes and then the finger extensors, especially those of the third and fourth fingers. Weakness of the neck flexors is seen in most affected individuals and mild facial weakness is often present. After distal weakness has been present for more than ten years, mild proximal weakness may be observed. Life expectancy is normal.

Diagnosis/testing.

Diagnosis relies on clinical findings and the identification of a heterozygous pathogenic variant in MYH7.

Management.

Treatment of manifestations: Physiotherapy to prevent or treat tightening of the tendo Achilles is helpful. In more advanced cases, lightweight splinting of the ankle (e.g., with an ankle-foot orthosis) can be useful.

Surveillance: Annual neurologic examination; regular evaluation for scoliosis/kyphoscoliosis (especially during rapid growth); repeat electrocardiogram and echocardiogram if symptoms of cardiac insufficiency occur; respiratory assessment if symptoms suggest sleep apnea / sleep-related respiratory insufficiency.

Genetic counseling.

Laing distal myopathy is inherited in an autosomal dominant manner. Approximately 65%-70% of affected individuals have an affected parent; de novo mutation of MYH7 accounts for 30%-35% of cases. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible for families in which the pathogenic variant has been identified.

Diagnosis

Suggestive Findings

Laing distal myopathy is suggested in individuals with the following findings [Hedera et al 2003, Lamont et al 2006, Lamont et al 2014]:

  • Initial weakness of the great toe and ankle dorsiflexors, eventually leading to a high-stepping gait and secondary tightening of the tendo Achilles. Onset is usually before age five years, but rarely may be later (≤4th decade).
  • Subsequent weakness of the finger extensors (onset from months to 3 decades after lower-limb weakness) often accompanied by an action tremor of the hands
  • Mild involvement of the facial musculature, particularly of the orbicularis oculi and oris muscles
  • Early weakness of neck flexion in most families. Of note, in one family, weakness did not occur until the sixth decade.
  • Very slow progression of weakness with gradual involvement of the proximal leg and trunk muscles. Rarely a wheelchair is required for mobility.
  • Spinal complications (kyphoscoliosis, spinal rigidity, spinal extensor muscle contractures) in one third of patients
  • Cardiac complications (hypertrophic cardiomyopathy with onset from birth to 3rd decade of life, dilated cardiomyopathy with onset from birth to 2nd decade of life) in one third of patients
  • Family history consistent with autosomal dominant inheritance. Of note, one third of affected individuals have a de novo pathogenic variant [Lamont et al 2014].
  • Serum creatine kinase concentration that is usually normal, but may in rare cases be as high as eight times the upper limit of normal
  • Nerve conduction studies normal
  • Electromyographic findings that are nonspecific, with occasional fibrillation potentials but no prolonged or large motor unit potentials [Zimprich et al 2000]

Establishing the Diagnosis

The diagnosis of Laing distal myopathy is established in a proband with a heterozygous pathogenic variant in MYH7, encoding the protein myosin heavy chain, cardiac muscle beta isoform (see Table 1).

Molecular testing approaches can include the following:

  • Single-gene testing. Sequence analysis of MYH7 exons 32-39 from genomic DNA should detect the majority of pathogenic variants associated with this phenotype; however, Darin et al [2007] identified the pathogenic variant p.Thr441Met in exon 14 associated with a Laing distal myopathy and cardiomyopathy.
  • A multigene panel that includes MYH7 and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Laing Distal Myopathy

Gene 1MethodProportion of Probands with a Pathogenic Variant Detectable by Method
MYH7Sequence analysis 2~100% 3
Deletion/duplication analysis 4None reported 5
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

Sequence analysis of the exons identifies all pathogenic variants known to date

4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

No gross deletions or deep intronic pathogenic variants have as yet been identified in this gene.

Clinical Characteristics

Clinical Description

Laing distal myopathy is characterized by muscle weakness and atrophy beginning in the lower legs [Lamont et al 2006].

Onset is usually before age five years. In a few children onset has been so early as to delay walking. In two families, weakness was not recognized until the teenage years [Zimprich et al 2000, Hedera et al 2003, Lamont et al 2006]. In one family with 20 affected members, onset of lower-limb weakness occurred between early childhood and the fourth decade [Lamont et al 2014].

Weakness follows a typical sequence: initially dorsiflexion of the ankle and great toe is affected and leads to a high-stepping gait, dropped big toe, and secondary tightening of the tendo Achilles (see Figure 1).

Figure 1. . Early development of anterior compartment weakness has led to marked tightening of the tendo Achilles bilaterally, with the affected individual unable to place his heels on the ground.

Figure 1.

Early development of anterior compartment weakness has led to marked tightening of the tendo Achilles bilaterally, with the affected individual unable to place his heels on the ground.

Weakness of finger extensors develops between months and several decades after the onset of leg weakness [Lamont et al 2014]. The third and fourth fingers appear to be more severely affected than the other fingers (see Figure 2), although any of the fingers can be affected. The thumb is spared. Weakness of the finger extensors is often accompanied by a postural and action tremor of the hands.

Figure 2. . Individual with Laing distal myopathy attempting to extend her second to fifth fingers.

Figure 2.

Individual with Laing distal myopathy attempting to extend her second to fifth fingers. Note marked weakness of third and fourth finger extension.

Mild facial weakness is often present, leading to inability to bury the eyelashes completely when closing the eyes tightly, and inability to keep the lips pursed against resistance. One affected individual has a mild Bell's phenomenon.

Weakness of neck flexion, seen in all affected individuals, is usually early in onset, though weakness of neck flexion did not manifest in one family until the sixth decade. In most affected individuals and sites, the weakness is symmetric.

After distal weakness has been present for more than ten years, mild proximal weakness occurs, with a slight Trendelenburg gait and mild scapular winging (see Figure 3). Axial musculature may be mildly weak as well, manifesting as, for example, inability to do a sit-up.

Figure 3. . Mild scapular winging and weakness develops later.

Figure 3.

Mild scapular winging and weakness develops later.

Progression is usually extremely slow; however, in one person the weakness became generalized and a wheelchair was required for mobility by age 15 years [Lamont et al 2014].

Spinal manifestations, which can include kyphoscoliosis and spinal rigidity, occur in one third of patients and can vary within a family.

Cardiac problems are common. In their review of 88 affected individuals from 22 families, Lamont et al [2014] reported cardiac involvement ranging from hypertrophic cardiomyopathy with onset from birth to the third decade of life, to dilated cardiomyopathy with onset from birth to the second decade of life. In an earlier report, a father and son in one family developed a dilated cardiomyopathy for which no other cause was found [Hedera et al 2003].

Pathology. The muscle pathology in Laing distal myopathy is highly variable [Lamont et al 2006, Lamont et al 2014].

The most common myopathic feature is excessive variation in fiber size, with either type 1 or type 2 fibers involved. Fiber type predominance is common. In one large family, ten of 14 muscle biopsies showed abnormally small type 1 fibers with type 1 predominance, fulfilling criteria for congenital fiber-type disproportion [Muelas et al 2010].

Another common finding is core pathology of either central cores or multiminicores [Cullup et al 2012, Lamont et al 2014].

Other findings can include:

  • Excessive central nucleation and mild necrosis and regeneration;
  • Fatty replacement in "end-stage" muscles.

Of note, in contrast to other distal myopathies, rimmed vacuoles and filamentous inclusions are rarely seen.

Immunohistochemical staining for slow and fast myosin in two individuals revealed co-expression of both isoforms in some muscle fibers, possibly indicating a switch from fiber type 1 to fiber type 2 [Lamont et al 2006].

Genotype-Phenotype Correlations

No genotype-phenotype correlations for MYH7 have been identified to date.

Laing distal myopathy. Most pathogenic variants known to be associated with Laing distal myopathy occur within exons 32-39. They include missense pathogenic variants to proline, arginine, or valine; deletion of an amino acid; or a charge reversal pathogenic variant from glutamate to lysine in the tail of the encoded protein (myosin heavy chain, cardiac muscle beta isoform protein), including the region of the binding site for M protein and myomesin [Meredith et al 2004, Udd 2009].

The charge reversal pathogenic variants p.Glu1801Lys, p.Glu1856Lys, and p.Glu1914Lys are associated with a Laing distal myopathy phenotype combined with cardiomyopathy [Udd 2009, Lamont et al 2014]. More recently it has been shown that missense pathogenic variants to proline (p.Arg1608Pro) and amino acid deletions (p.Leu1793del, p.Lys1617del) can also be associated with a combined phenotype.

Myosin storage myopathy. The pathogenic variants known to be associated with myosin storage myopathy cluster within exons 37-39.

Penetrance

Penetrance appears to be at least 85%.

Muelas et al [2010] reported a large Spanish family in which the age of onset ranged from birth to the sixth decade; 15% of family members were reported to be asymptomatic. (Note, however, that individual ages at the time of reporting were not clearly stated.)

In one apparent instance of de novo mutation, the supposedly unaffected father was found to be a somatic mosaic; however, when examined, he did have mild weakness [Lamont et al 2014].

Nomenclature

The following alternate terms for Laing distal myopathy are no longer in use or are too nonspecific to be used:

  • Early-onset chromosome 14-linked distal myopathy (Laing)
  • Autosomal dominant distal muscular dystrophy
  • Infantile autosomal dominant distal myopathy
  • Autosomal dominant distal myopathy (a nonspecific term that could apply to other distal myopathies such as tibial muscular dystrophy)
  • Gowers myopathy

Prevalence

The prevalence of Laing distal myopathy is unknown. It is thought to be the most common distal myopathy worldwide [B Udd, personal communication] and has been reported in most populations [Chai et al 2007, Park et al 2013, Lamont et al 2014]. The frequency of de novo pathogenic variants would also suggest a relatively high prevalence.

Laing distal myopathy does not appear to be more prevalent in any specific populations [Author, personal observation].

Differential Diagnosis

Mutation of MYH7 accounts for approximately 50% of early-onset distal myopathy [Author, personal observation].

Other disorders to consider in the differential diagnosis of Laing distal myopathy are discussed below.

Congenital Myopathy

The early onset of Laing distal myopathy means that any of the milder congenital myopathies may be a differential diagnosis. These include central core disease (CCD; OMIM 117000), distal nebulin myopathy (OMIM 256030), or centronuclear myopathy – including X-linked centronuclear myopathy (XLCNM; also known as myotubular myopathy [MTM]), and autosomal dominant centronuclear myopathy (OMIM 160150).

Sometimes clinical manifestations can give a clue. For instance, the weakness in CCD is more proximal than distal, affecting the hip girdle in particular. In centronuclear myopathy, ptosis and restriction of eye movements are common. However, the overlap in phenotype between the milder congenital myopathies and Laing distal myopathy can be considerable. In these situations, muscle biopsy should show characteristic structural changes in the congenital myopathies, such as central cores in CCD, or nemaline bodies in distal nebulin myopathy. The presence of cardiomyopathy points to a MYH7 pathogenic variant being the cause. Use of a multigene panel including MYH7 and the other genes listed in the differential diagnosis in Table 2 is now the most cost-effective method of obtaining a molecular diagnosis of Laing distal myopathy.

Distal Myopathies

The other major group in the differential diagnosis of Laing distal myopathy is distal myopathy (see Table 2). The distal myopathies most likely to be considered in the differential diagnosis for Laing distal myopathy include Udd distal myopathy (tibial muscular dystrophy), Nonaka distal myopathy, and myofibrillar myopathy [Mastaglia et al 2005]. The major features differentiating Laing distal myopathy from these entities are age of onset and weakness of neck flexion, which – although mild – does present early in most individuals with Laing distal myopathy.

Table 2.

Distal Myopathies

Disease Name 1GeneMode of InheritanceMean Age at OnsetInitial Muscle Group Involved 2Serum CK
Laing distal myopathyMYH7AD<5 yrsAnkle and great toe extensorsUsually normal; rarely 8x normal
Udd distal myopathy (tibial muscular dystrophy)TTNAD>35 yrsAnterior compartment legsNormal
Nonaka/GNE related myopathiesGNEAR>20 yrsAnkle dorsiflexion, toe extension<10x normal
Myofibrillar myopathies (OMIM PS601419)DES
MYOT
LDB3
FLNC
BAG3
CRYAB
AD or ARMostly adulthood, rarely teensIf presentation is distal, ankle dorsiflexion plantarflexion, +/- finger wrist extensionNormal to 4x normal
Miyoshi myopathyDYS1ARLate teens, early adulthoodCalf muscles20-150x normal
Welander distal myopathy (OMIM 604454)TIA1AD>40 yrsFinger extensorsNormal
Distal anoctaminopathyANO5AR>20 yrsAnkle plantar flexion5x normal
1.

Listed from most similar to Laing distal myopathy to least similar

2.

Information on histologic findings is included in the discussion that follows.

Distal myopathies less likely to be considered in the differential diagnosis are Miyoshi distal myopathy (predominantly affecting the posterior compartment of the leg and much more rapidly progressive) and Welander distal myopathy (predominantly affecting the hands).

  • Udd distal myopathy (tibial muscular dystrophy) is characterized by weakness of ankle dorsiflexion after age 35 years. Disease progression is slow and muscle weakness remains confined to the anterior tibial muscles. The long-toe extensors become clinically involved after ten to 20 years. Muscle biopsy reveals mild dystrophic or myopathic changes with or without rimmed vacuoles.
  • Nonaka early-adult-onset distal myopathy (see GNE-related myopathy) usually begins in the anterior compartment of the legs and in the toe extensors in the second or third decade, progressing to loss of ambulation after 12 to 15 years. Muscle biopsy reveals rimmed vacuoles.
  • Myofibrillar myopathies (OMIM PS601419) are a genetically heterogeneous group of disorders with the common finding of disintegration of the sarcomeric Z-discs and the myofibrils, which leads to abnormal ectopic accumulation of multiple proteins involved in the structure of the Z-disc, including desmin, dystrophin, and myotilin. Muscle biopsy reveals hyaline spheroid and granular structures containing numerous deposited proteins. Most myofibrillar myopathies are characterized by onset of proximal weakness, but all can have onset of distal weakness, most often in the legs.
  • Miyoshi early-adult-onset myopathy begins in late teenage years or early adulthood and initially affects the calves. It progresses to other distal and proximal muscles. Twenty years after onset it is indistinguishable from its allelic condition, limb-girdle-muscular dystrophy 2B (LGMD2B) (see Dysferlinopathy). The serum CK concentration is 20- to 150-fold normal values – much higher than that in other distal myopathies [Udd 2014]. Muscle biopsy reveals muscular dystrophy and inflammation.
  • Welander distal myopathy (OMIM 604454) typically begins in the hand and finger extensors, but may sometimes begin in the anterior compartment muscles of the lower legs [von Tell et al 2002]. Typically, affected individuals experience weakness of the extensor of the index finger after age 40 years, followed by slow progression to the other finger extensors and to the anterior and posterior leg muscles [Hackman et al 2013]. Muscle biopsy reveals rimmed vacuoles.
  • Distal anoctaminopathy leads to weakness of ankle plantar flexion, often asymmetrically, after age 20 years. This condition is allelic to limb-girdle-muscular dystrophy 2L (LGMD2L). Muscle biopsy reveals scattered fiber necrosis.

Charcot-Marie-Tooth Hereditary Neuropathy also commonly features foot drop and thus may be considered in the differential diagnosis. Evidence of sensory involvement, namely reduction in pinprick appreciation in the toes, is usually seen in Charcot-Marie-Tooth neuropathy.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Laing distal myopathy, the following evaluations are recommended:

  • A full neurologic history and examination at presentation, with particular reference to early gross motor milestones. The examination should particularly note tightening of the tendo Achilles (Figure 1) and the pattern of muscle weakness.
  • As severe cardiac manifestations are a feature in one third of individuals with Laing distal myopathy, an electrocardiogram and echocardiogram should be performed as a baseline.
  • Electromyography/nerve conduction studies
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Physiotherapy assessment with particular reference to preventing or treating tightening of the tendo Achilles is very useful. In persons with more advanced disease, lightweight splinting of the ankle (e.g., with an ankle-foot orthosis) may be recommended.

The cardiomyopathy may respond to ACE inhibitors or other medication. Cardiac consultation is recommended.

Kyphoscoliosis may be treated with surgical stabilization of the spine. There is no treatment for spinal rigidity.

Surveillance

After establishing the diagnosis (see Evaluations Following Initial Diagnosis) and instituting the indicated therapies (see Treatment of Manifestations), annual review is recommended.

Additional recommendations include:

  • Spinal review for evidence of scoliosis and/or kyphoscoliosis, especially during the years of rapid growth in adolescence;
  • Repeat electrocardiogram and echocardiogram if symptoms of cardiac insufficiency occur;
  • Respiratory function and assessment if symptoms suggest either sleep apnea or sleep-related respiratory insufficiency.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Laing distal myopathy is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Approximately 65%-70% of individuals diagnosed with Laing distal myopathy have an affected parent.
  • De novo pathogenic variants in MYH7 account for 30%-35% of individuals with Laing distal myopathy.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include full history, examination looking for weakness and secondary contractures, and molecular genetic testing if the pathogenic MYH7 variant has been identified.
  • The family history of some individuals diagnosed with Laing distal myopathy may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations and molecular genetic testing has been performed on the parents of the proband.
  • Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected. One such family has been reported [Lamont et al 2014].

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to sibs of a proband appears to be low.

Offspring of a proband. Each child of an individual with Laing distal myopathy has a 50% chance of inheriting the MYH7 pathogenic variant.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with Laing distal myopathy has the pathogenic variant or clinical evidence of the disorder, the MYH7 pathogenic variant likely occurred de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the MYH7 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for Laing distal myopathy are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Muscular Dystrophy Association - Canada
    2345 Yonge Street
    Suite 900
    Toronto Ontario M4P 2E5
    Canada
    Phone: 866-687-2538 (toll-free); 416-488-0030
    Fax: 416-488-7523
    Email: info@muscle.ca
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy UK
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
    Email: info@musculardystrophyuk.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Laing Distal Myopathy: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
MYH714q11​.2Myosin-7MYH7 homepage - Leiden Muscular Dystrophy pagesMYH7MYH7

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Laing Distal Myopathy (View All in OMIM)

160500MYOPATHY, DISTAL, 1; MPD1
160760MYOSIN, HEAVY CHAIN 7, CARDIAC MUSCLE, BETA; MYH7

Gene structure. MYH7 comprises 40 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. See Table 3 (pdf) for a list of benign variants.

Pathogenic variants. Specific MYH7 pathogenic variants identified to date include missense variants to proline, deletion or insertion of an amino acid, or charge reversal from Glu to Lys in exons 32-39 [Meredith et al 2004, Udd 2009, Lamont et al 2014]. Some pathogenic variants, notably p.Lys1617del and p.Lys1729del, are recurrent [Meredith et al 2004, Lamont et al 2006, Udd 2009, Lamont et al 2014].

Table 4.

MYH7 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeMYH7 ExonReference Sequences
c.1322C>T 1p.Thr441Met14NM_000257​.3
NP_000248​.2
c.4499G>Cp.Arg1500Pro32
c.4823G>Cp.Arg1608Pro 234
c.4850_4852delAGAp.Lys1617del34
c.5186_5188delp.Lys1729del36
c.5377_5379delp.Leu1793del 237
c.5401G>Ap.Glu1801Lys 237
c.5566G>Ap.Glu1856Lys 238
c.5740G>Ap.Glu1914Lys 239

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.
2.

See Table 5 (pdf) for a complete list of MYH7 pathogenic variants identified to date.

Normal gene product. The normal gene product is the myosin heavy chain of slow skeletal muscle fibers, which is also expressed in the heart.

Abnormal gene product. The pathogenic missense variants resulting in proline and amino-acid deletions or insertions should disrupt the ability of the myosin tail to form a coiled coil [Meredith et al 2004]. The effect of the glutamate to lysine mutations is uncertain. Using biophysical analysis of the p.Arg1500Pro mutated protein, Armel & Leinwand [2010] demonstrated reduced thermodynamic stability and reduced thick filament stability.

References

Literature Cited

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  • Chai J, Liu C, Lai P, Yee W. Myosin storage myopathy with a novel slow-skeletal myosin (MYH7) mutation in a Chinese patient. Neuromuscul Disord. 2007;17:838.
  • Cullup T, Lamont PJ, Cirak S, Damian MS, Wallefeld W, Gooding R, Tan SV, Sheehan J, Muntoni F, Abbs S, Sewry CA, Dubowitz V, Laing NG, Jungbluth H. Mutations in MYH7 cause multi-minicore disease with variable cardiac involvement. Neuromusc Disord. 2012;22:1096–104. [PubMed: 22784669]
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Chapter Notes

Acknowledgments

NGL is supported by Australian National Health and Medical Research Council Fellowship 403904.

Author History

Nigel G Laing, PhD (2006-present)
Phillipa Lamont, MBBS, PhD (2006-present)
William Wallefeld, BSc (Hons); University of Western Australia (2010-2015)

Revision History

  • 12 March 2015 (me) Comprehensive update posted live
  • 17 June 2010 (me) Comprehensive update posted live
  • 17 October 2006 (me) Review posted live
  • 6 September 2006 (nl) Original submission
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