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

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
MYH7	Sequence analysis / mutation scanning 2	Sequence variants 3, 4	~95% 5	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Familial hypertrophic cardiomyopathy 1 (CMH1) (OMIM 160760). MYH7 mutations causing familial hypertrophic cardiomyopathy are spread along almost the entire length of the molecule, including both the head and the tail, overlapping the mutations causing Laing distal myopathy and myosin storage myopathy (see Familial Hypertrophic Cardiomyopathy).

Myosin storage myopathy (MSM, or hyaline body myopathy) (OMIM 608358). Myosin storage myopathy is genetically heterogeneous: autosomal recessive myosin storage myopathy has been linked to another chromosomal locus [Onengüt et al 2004].

MSM that is caused by mutations of MYH7 is usually either congenital or early-onset and either non-progressive or very slowly progressive. The weakness tends to be more proximal than distal. Five published MYH7 mutations have now been identified in MSM (p.Leu1779Pro, p.Leu1793Pro, p.Arg1845Trp, p.Glu1883Lys, p.His1901Leu). These mutations are in the tail of the myosin molecule, including the region of titin binding and the assembly competent domain [Tajsharghi et al 2003, Bohlega et al 2004, Dye et al 2006, Chai et al 2007, Tajsharghi et al 2007].

• The p.Leu1793Pro mutation has been linked with either myosin storage myopathy or pure cardiomyopathy in a mother and daughter in the same family [Uro-Coste et al 2009].
• The p.Arg1845Trp mutation is a recurrent mutation, described multiple times in unrelated affected individuals [Laing et al 2005, Shingde et al 2006, Pegoraro et al 2007].
• The p.Glu1883Lys mutation is unusual in that it is associated with recessive myosin storage myopathy and cardiomyopathy [Tajsharghi et al 2007].

Scapuloperoneal myopathy. Pegoraro et al [2007] identified p.Arg1845Trp, the mutation most commonly associated with myosin storage myopathy, in two of 17 persons with a clinical diagnosis of scapuloperoneal myopathy.

Hypertrophic distal myopathy and cardiomyopathy. One individual in a family with the p.Val606Met mutation had hypertrophic cardiomyopathy and hypertrophic distal myopathy, including gross hypertrophy of the tibialis anterior muscle, which is normally atrophic in Laing distal myopathy [Overeem et al 2007].

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

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

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

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:

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

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.

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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must have been identified in the family before prenatal testing can be performed.

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 available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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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