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Laing Distal Myopathy

Synonym: Laing Early-Onset Distal Myopathy

, PhD, , BSc (Hons), and , PhD.

Author Information
, PhD
Associate Professor, Department of Neurology
Royal Perth Hospital
Perth, Western Australia
, BSc (Hons)
Centre for Medical Research
University of Western Australia
West Australian Institute for Medical Research
Nedlands, Western Australia
, PhD
Professor, NH&MRC Principal Research Fellow
Centre for Medical Research
University of Western Australia
West Australian Institute for Medical Research
Nedlands, Western Australia

Initial Posting: ; Last Update: June 17, 2010.

Summary

Disease 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 all affected individuals and mild facial weakness is often present. After distal weakness has been present for more than ten years, mild proximal weakness is observed. Life expectancy is normal.

Diagnosis/testing. Diagnosis relies on clinical findings and molecular genetic testing. Serum creatine kinase concentration is usually normal; muscle histology is not diagnostic. MYH7 is the only gene in which mutation is known to cause Laing distal myopathy.

Management. Treatment of manifestations: Physiotherapy to prevent or treat tightening of the tendo Achillis 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; electrocardiogram and echocardiogram performed at the time of initial evaluation should be repeated if symptoms of cardiac insufficiency occur.

Genetic counseling. Laing distal myopathy is inherited in an autosomal dominant manner. More than 90% of affected individuals have an affected parent: de novo mutations account for fewer than 10% of cases. Each child of an affected individual has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk is possible for families in which the disease-causing mutation has been identified.

Diagnosis

Clinical Diagnosis

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

  • Initial weakness of the great toe and ankle dorsiflexors, eventually leading to a high-stepping gait and secondary tightening of the tendo Achillis
  • Subsequent weakness of the finger extensors (within months to years) 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

    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. No affected individuals have been confined to a wheelchair for mobility.
  • Age of onset ranging from the first year of life to the late teens, but most commonly before age five years.
  • Family history consistent with autosomal dominant inheritance

Note: Identification of mutations within MYH7 is the gold standard for diagnosis of Laing distal myopathy (see Molecular Genetic Testing).

Testing

Serum creatine kinase concentration, usually normal, may in rare cases be as high as eight times the upper limit of normal.

Nerve conduction studies are normal.

Electromyographic findings are nonspecific, with occasional fibrillation potentials but no prolonged or large motor unit potentials [Zimprich et al 2000].

Muscle biopsy is not diagnostic. Myopathic features inconsistently identified include the following:

  • Excessive variation in fiber size, with small type I fibers in some and small type II fibers in others
  • Inconsistent fiber predominance and excessive central nucleation
  • Mild necrosis and regeneration; fatty replacement in "end-stage" muscles
  • Rimmed vacuoles and filamentous inclusions are seen rarely, in contrast to other distal myopathies
  • On immunohistochemical staining for slow and fast myosin in two individuals, coexpression of both isoforms in some muscle fibers, possibly indicating a switch from fiber type I to fiber type II [Lamont et al 2006]

Molecular Genetic Testing

Gene. MYH7, encoding the protein myosin heavy chain, cardiac muscle beta isoform, is the only gene known to be associated with Laing distal myopathy.

Clinical testing

  • Sequence analysis/mutation scanning of the MYH7 coding region and associated splice junctions. Specific MYH7 mutations identified to date include missense mutations to proline, deletions of an amino acid, or charge reversal from Glu to Lys in exons 32-38 [Meredith et al 2004, Udd 2009]. MYH7 mutations have been identified in approximately 50% of individuals with early-onset distal myopathy [Author, personal observation].

Table 1. Summary of Molecular Genetic Testing Used in Laing Distal Myopathy

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
MYH7Sequence analysis / mutation scanning 2Sequence variants 3, 4~95% 5

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

4. See Molecular Genetics.

5. Sequence analysis of the exons identifies all mutations known to date; no gross deletions or deep intronic mutations have as yet been identified in this gene.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. The current protocol for searching for mutations causing Laing distal myopathy in persons with characteristic clinical findings is to sequence exons 30-40 of MYH7 from genomic DNA. This should detect the majority of mutations associated with this phenotype, though Darin et al [2007] identified a p.Thr441Met mutation in exon 14 associated with a Laing distal myopathy phenotype and additional cardiomyopathy.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Laing distal myopathy is characterized by muscle weakness and atrophy [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].

Weakness follows a typical sequence in all affected children, initially affecting dorsiflexion of the ankle and great toe, leading to a high-stepping gait and secondary tightening of the tendo Achillis (see Figure 1).

Figure 1

Figure

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

Weakness of finger extensors develops shortly thereafter or over several years. The third and fourth fingers seem to be more severely affected than the other fingers (see Figure 2). Weakness of the finger extensors is often accompanied by a postural and action tremor of the hands.

Figure 2

Figure

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

Figure

Figure 3. Mild scapular winging and weakness develops later.

Progression is extremely slow and no affected adults have needed a wheelchair for mobility, even those in their seventh decade.

Cardiac problems are not generally described in affected individuals. However, a father and son in one family developed a dilated cardiomyopathy for which no other cause was found [Hedera et al 2003] and certain specific mutations, notably the glutamate to lysine charge reversal mutations, do show an associated, in some cases severe cardiomyopathy [Udd 2009].

Pathology. The muscle pathology in Laing distal myopathy is highly variable [Lamont et al 2006]. Type 1 slow muscle fibers (in which MYH7 is expressed) may be atrophic; there may be type 1 or type 2 fiber predominance; rimmed vacuoles, common in other distal myopathies, are rare [Lamont et al 2006].

Sural nerve biopsy in an older individual showed hypomyelination of large nerve fibers without onion bulb formation, and no degenerating or regenerating fibers [Voit et al 2001]. No other nerve biopsies have been reported.

Genotype-Phenotype Correlations

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

Laing distal myopathy. All mutations known to be associated with Laing distal myopathy occur within exons 32-38 as missense mutations to proline, deletion of an amino acid, or a charge reversal mutation 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 mutations p.Glu1801Lys and p.Glu1856Lys [Udd 2009] are associated with a Laing distal myopathy phenotype combined with cardiomyopathy. Similarly, the p.Glu1883Lys recessive myosin storage myopathy mutation is also associated with cardiomyopathy [Tajsharghi et al 2007]. There thus appears to be a class of Glu>Lys charge reversal mutations associated with a skeletal muscle disease (either Laing distal myopathy or myosin storage myopathy) and cardiomyopathy. Some of the mutations are recurrent, notably the p.Lys1617del and the p.Lys1729del mutations [Meredith et al 2004, Lamont et al 2006, Udd 2009].

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

Penetrance

Penetrance appears to be 100%; however, few large families have been studied (though a very large family in Spain is mentioned in the report of the ENMC Workshop on distal myopathies [Udd 2009]). Therefore, penetrance is still not fully delineated.

Anticipation

Anticipation does not occur in this disorder.

Nomenclature

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

Prevalence

Laing distal myopathy is rare; the prevalence is unknown. Three separate families have been identified in Western Australia (population 2 million), so the disorder is not that rare. In addition, more and more families with the disease in many countries around the world are being identified [Author, personal observation].

It is not known whether the disease is any more prevalent in certain populations.

Differential Diagnosis

Congenital myopathy. The early onset of Laing distal myopathy means that any of the milder congenital myopathies may be a differential diagnosis, such as central core disease (CCD) or centronuclear myopathy. 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, whereas it does not in individuals with Laing distal myopathy.

Distal myopathies. The other major group in the differential diagnosis is distal myopathy (see Table 2).

  • Udd distal myopathy is characterized by weakness of ankle dorsiflexion and inability to walk on the heels after the age of 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, leading to foot drop and clumsiness when walking. Udd distal myopathy is caused by mutations in TTN, the gene encoding titin [Hackman et al 2002].
  • Nonaka early-adult-onset distal myopathy with rimmed vacuoles usually begins in the second or third decade in the anterior compartment of the legs and in the toe extensors. Foot drop and a steppage gait are present with progression to loss of ambulation after 12 to 15 years. This is the same condition as quadriceps-sparing myopathy and is caused by mutation of GNE [Nishino et al 2002].
  • Markesbery-Griggs late-onset distal myopathy is characterized by weakness of ankle dorsiflexion usually beginning in the late 40s, followed later by slow progression to the finger and wrist extensor muscles and to the intrinsic muscles of the hand. Eventually the proximal leg muscles become involved. This disease is caused by a mutation in ZASP (LDB3) [Griggs et al 2007].
  • MPD3, a dominant distal myopathy, was described in Finland in a single family in which some affected individuals had onset in the upper limbs and others in the lower limbs; later, both upper and lower limbs are involved [Haravuori et al 2004].
  • Miyoshi early-adult-onset myopathy begins in the posterior compartment of the legs, manifests as difficulty climbing stairs and walking on toes and progresses to other distal and proximal muscles as with LGMD2B (see Dysferlinopathy). The serum CK concentration is usually more than 50 times normal.
  • Welander distal myopathy may sometimes have onset in the anterior compartment muscles of the lower legs, instead of the usual onset in the hand and finger extensors [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.

Table 2. Distal Myopathies

Disease NameMean Age at Onset (Years)Initial Muscle Group InvolvedSerum Creatine Kinase ConcentrationMuscle BiopsyGene Symbol (Locus) 1
Autosomal dominant
Welander distal myopathy>40Distal upper limbs (finger and wrist extensors)Normal or slightly increasedRimmed vacuoles(2p13)
Udd distal myopathy>35Anterior compartment in legs± Rimmed vacuolesTTN
Markesbery-Griggs late-onset distal myopathy>40Vacuolar and myofibrillar myopathyZASP (LDB3)
Distal myotilinopathy>40Posterior > anterior in legsSlightly increasedVacuolar and myofibrillarMYOT
Laing early-onset distal myopathy (MPD1)<20Anterior compartment in legs and neck flexorsNormal to (rarely) moderately increasedType 1 fiber atrophy in tibial anterior muscles; disproportion in proximal musclesMYH7
Distal myopathy with vocal cord and pharyngeal signs (MPD2)35-60Asymmetric lower leg and hands; dysphonia1-8 timesRimmed vacuolesMATR3
Distal myopathy with pes cavus and areflexia15-50Anterior and posterior lower leg; dysphonia and dysphagia2-6 timesDystrophic, rimmed vacuoles(19p13)
New Finnish distal myopathy (MPD3)>30Hands or anterior lower leg1-4 timesDystrophic; rimmed vacuoles; eosinophilic inclusions(8p22-q11 and 12q13-q22)
Autosomal recessive
Nonaka early-adult-onset distal myopathy15-20Anterior compartment in legs<10 timesRimmed vacuolesGNE
Miyoshi early-adult-onset myopathy Posterior compartment in legs>10 timesMyopathic changesDYSF

Udd & Griggs [2001]

1. Locus given only if the gene is not known

Note: Of the distal myopathies presented in Table 2, those most likely to be considered in the differential diagnosis for Laing distal myopathy include Udd distal myopathy (tibial muscular dystrophy), Nonaka distal myopathy, Markesbury-Griggs distal myopathy, and MPD3 [Mastaglia et al 2005]. The major feature differentiating Laing distal myopathy from these entities is age of onset (see Table 2). Another distinguishing feature is the weakness of neck flexion, which although mild, does present early in most individuals with Laing distal myopathy.

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).

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 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 Achillis (Figure 1) and the pattern of muscle weakness.
  • Although it does not appear that cardiac manifestations are a prominent feature in most cases, an electrocardiogram and echocardiogram should be performed as a baseline.

Treatment of Manifestations

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

Surveillance

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

Electrocardiogram and echocardiogram should be repeated if symptoms of cardiac insufficiency occur.

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 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

  • More than 90% of individuals diagnosed with Laing distal myopathy have an affected parent.
  • A proband with Laing distal myopathy may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations is less than 10%. Four individuals who have Laing distal myopathy as the result of a new dominant mutation have been identified [Meredith et al 2004, Udd 2009].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include full history and examination looking for weakness and secondary contractures. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although more than 90% of individuals diagnosed with Laing distal myopathy have an affected parent, the family history 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.

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 the 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 mutation.

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 mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo mutation. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

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)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
    Email: info@muscular-dystrophy.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

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
MYH714q11​.2Myosin-7MYH7 homepage - Leiden Muscular Dystrophy pagesMYH7

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) 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

Normal allelic variants. MYH7 comprises 40 exons.

Exonic normal allelic variants (exons 30-40):

  • p.Ser1491Cys
  • p.Thr1522Thr
  • p.Val1691Met
  • p.Ala1702Ala
  • p.Glu1799Glu
  • p.Arg1846Gly
  • p.Lys1919Asn

Non-coding normal allelic variants (exons 30-40):

  • Intron 31: +112G>C
  • Intron 32: +37A>C
  • Intron 38: +31G>A
  • Intron 39: –63G>A
  • 3'UTR G>A +112

Pathologic allelic variants. All MYH7 pathologic allelic variants identified to date are in exons 32-38.

  • p.Arg1500Pro (exon 32)
  • p.Glu1508del (exon 33)
  • p.Ala1603Pro (exon 34)
  • p.Lys1617del (exon 34)
  • p.Ala1663Pro (exon 35)
  • p.Leu1706Pro (exon 35)
  • p.Lys1729del (exon 36)
  • p.Glu1801Lys (exon 37)
  • p.Glu1856Lys (exon 38)

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

Abnormal gene product. All published mutations causing Laing distal myopathy are missense mutations to proline, deletion of an amino acid, or conversion of glutamate to lysine within exons 32-38. The missense mutations to proline and amino-acid deletions 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 mutant protein, Armel & Leinwand [2010] demonstrated reduced thermodynamic stability and reduced thick filament stability.

Similarly, the most frequently found mutation in myosin storage myopathy, p.Arg1845Trp, is predicted by silico analysis to cause disruption of the ability of the myosin tail to form a coiled coil [Laing et al 2005], and myosin storage myopathy mutations overlap the position of Laing distal myopathy mutations. Armel & Leinwand [2009] show that the myosin storage myopathy mutations may either reduce thermodynamic stability or affect thick filament assembly.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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Chapter Notes

Acknowledgments

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

Revision History

  • 17 June 2010 (me) Comprehensive update posted live
  • 17 October 2006 (me) Review posted to live Web site
  • 6 September 2006 (nl) Original submission
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