Clinical Diagnosis

Udd distal myopathy is characterized by the following:

• Distal myopathy. Ankle dorsiflexion weakness manifesting in the fourth to seventh decade
• EMG. Profound myopathic changes in the anterior tibial muscle but preservation of the extensor brevis muscle
• CT or MRI. Fatty degeneration of anterior tibial muscles and large patchy lesions in other clinically unaffected muscles

Testing

Serum CK concentration is normal or slightly elevated.

Muscle biopsy shows progressive dystrophic changes in the tibialis anterior muscle with rimmed vacuoles at the early stages and replacement with adipose tissue at later stages of the disease.

Molecular Genetic Testing

Gene. The only gene in which mutations are known to cause Udd distal myopathy is TTN, encoding the protein titin (TTN).

Clinical testing

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

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency 1	Test Availability
TTN	Targeted mutation analysis	Finnish founder mutation (FINmaj) 2	100% of the founder mutation	Clinical
	Sequence analysis of select exons	Sequence variants in exons 358-363 (Mex1-Mex6) 2, 3	Unknown 4
	Sequence analysis	Sequence variants 3	Close to 100% 4
	Deletion / duplication analysis 5	Exon or whole gene deletion/duplication	Unknown, none reported

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. FINmaj is an 11-bp deletion/insertion observed in exon “Mex6" in all Finnish families with Udd distal myopathy [Hackman et al 2002]. Note: The part of the TTN protein that spans the sarcomere M-line is encoded by six exons that have been termed Mex1-Mex6 for ‘M-line exons 1 through 6’; in the gene, these correspond to exons 358 to 363 (reference sequence NM_001267550​.1). Thus, Mex6 is the last exon (363) of TTN.

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. Seven other mutations in exons Mex5 and Mex6 in TTN have been found to date in several different European families [Hackman et al 2002, Van den Bergh et al 2003, Hackman et al 2008, Pollazzon et al 2010, unpublished data].

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. See CMA.

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

• For a proband with Finnish ancestry, targeted mutation analysis for the common Finnish mutation
• For a proband of other background, sequencing of Mex1-Mex6

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 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).

Genetically Related (Allelic) Disorders

Heterozygous mutations in other parts of the very large TTN gene cause dilated cardiomyopathy (CMD1G) [Gerull et al 2002], hypertrophic cardiomyopathy (CMH9) [Satoh et al 1999], and hereditary myopathy with early respiratory failure (HMERF) [Lange et al 2005, Ohlsson et al 2012, Pfeffer et al 2012] (see Dilated Cardiomyopathy and Familial Hypertrophic Cardiomyopathy).

In the homozygous state, the Mex6 FINmaj mutation causes the much more severe and completely different limb-girdle muscular dystrophy 2J (LGMD2J) phenotype [Udd et al 2005, Pénisson-Besnier et al 2010] (see Limb-Girdle Muscular Dystrophy Overview).

Natural History

The first symptoms of Udd distal myopathy are weakness of ankle dorsiflexion and inability to walk on the heels after age 35 years. Disease progression is slow and muscle weakness remains confined to the anterior compartment muscles. The long toe extensors become clinically involved after ten to 20 years, leading to foot drop and clumsiness when walking. Nine percent of Finnish cases have shown aberrant phenotypes including proximal leg or posterior lower-leg muscle weakness even at onset [Udd et al 2005].

At age 75 years, one third of affected individuals show mild-to-moderate difficulty walking as a result of proximal leg muscle weakness; walking ability is otherwise preserved throughout life.

Life span is not reduced.

In the mildest form, Udd distal myopathy can remain unnoticed even in elderly individuals.

Genotype-Phenotype Correlations

All affected individuals of Finnish heritage tested have the same mutation (FINmaj) and 92% have the common phenotype; a minority with the identical mutation show a variety of phenotypes [Udd et al 2005].

Other European families with point mutations in the Mex6 exon of TTN have the common phenotype with no apparent differences when compared to the Finnish phenotype.

One family with a single-base deletion and frameshift mutation in the Mex5 exon of TTN shows a more severe phenotype with earlier onset and more proximal involvement [Hackman et al 2008].

Penetrance

Penetrance is close to 100% at age 65 years.

Prevalence

Prevalence in Finland is at least 9:100,000 individuals.

Evaluations Following Initial Diagnosis

To establish the extent of muscle involvement in an individual diagnosed with Udd distal myopathy, the following evaluations are recommended:

• CT and MRI identify affected muscles with high specificity.
• EMG can help identify involved muscles but is much less accurate and less convenient for the affected individual.
• Manual muscle force measurement can be used to help identify involved muscles but is even less specific than EMG.

Treatment of Manifestations

Usually no specific treatment is needed other than orthoses to counteract foot drop.

In individuals in their 40s and 50s with severe drop foot, tibial posterior tendon transposition can be performed to replace lost function of the anterior tibial muscle and long toe extensor muscles.

Surveillance

Disease progression and the need for rehabilitation and orthotic treatment should be evaluated by neurologic examination every one to four years.

Agents/Circumstances to Avoid

Heavy muscle force training of weak muscles should be avoided.

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

Udd distal myopathy is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with Udd distal myopathy have an affected parent.
• A proband with Udd distal myopathy may have the disorder as the result of a new gene mutation. To date, however, de novo mutations have not been observed.
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing if the mutation has been identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: The family history may appear to be negative because of failure to recognize the disorder in family members, death of the parent before the onset of symptoms, or very late onset of mild disease in the affected parent.

Sibs of a proband

• The risk to the sibs of the proband of inheriting the disorder is 50% if the proband has the Finnish founder mutation FINmaj.
• If the proband has another mutation, the risk depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected or has a disease-causing mutation, the risk to the sibs is 50%.
  • If the disease-causing mutation cannot be detected in the DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
  • Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with Udd distal myopathy is at a 50% risk 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 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 approximately 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.

Requests for prenatal testing for adult-onset conditions such as Udd distal myopathy are not common. 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. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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).

Literature Cited

1. Di Blasi C, Moghadaszadeh B, Ciano C, Negri T, Giavazzi A, Cornelio F, Morandi L, Mora M. Abnormal lysosomal and ubiquitin-proteasome pathways in 19p13.3 distal myopathy. Ann Neurol. 2004;56:133–8. [PubMed: 15236412]
2. Gerull B, Gramlich M, Atherton J, McNabb M, Trombitas K, Sasse-Klaassen S, Seidman JG, Seidman C, Granzier H, Labeit S, Frenneaux M, Thierfelder L. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet. 2002;30:201–4. [PubMed: 11788824]
3. Griggs R, Vihola A, Hackman P, Talvinen K, Haravuori H, Faulkner G, Eymard B, Richard I, Selcen D, Engel A, Carpen O, Udd B. Zaspopathy in a large classic late-onset distal myopathy family. Brain. 2007;130:1477–84. [PubMed: 17337483]
4. Hackman P, Vihola A, Haravuori H, Marchand S, Sarparanta J, De Seze J, Labeit S, Witt C, Peltonen L, Richard I, Udd B. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet. 2002;71:492–500. [PMC free article: PMC379188] [PubMed: 12145747]
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6. Haravuori H, Siitonen HA, Mahjneh I, Hackman P, Lahti L, Somer H, Peltonen L, Kestila M, Udd B. Linkage to two separate loci in a family with a novel distal myopathy phenotype (MPD3). Neuromuscul Disord. 2004;14:183–7. [PubMed: 15036327]
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10. Negrao L, Udd B, Matos A, Rebelo O, Geraldo A, Marques C. The first Portuguese patient with distal myopathy caused by a homozygous mutation in the titin gene. Sinapse. 2010;10:15–18.
11. Ohlsson M, Hedberg C, Brådvik B, Lindberg C, Tajsharghi H, Danielsson O, Melberg A, Udd B, Martinsson T, Oldfors A. Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin. Brain. 2012;135(Pt 6):1682–94. [PubMed: 22577218]
12. Pénisson-Besnier I, Talvinen K, Dumez C, Vihola A, Dubas F, Fardeau M, Hackman P, Carpen O, Udd B. Myotilinopathy in a family with late onset myopathy. Neuromuscul Disord. 2006;16:427–31. [PubMed: 16793270]
13. Pénisson-Besnier I, Hackman P, Suominen T, Sarparanta J, Huovinen S, Richard-Crémieux I, Udd B. Myopathies caused by homozygous titin mutations: LGMD2J and variations of phenotype. J Neurol Neurosurg Psychiatry. 2010;81:1200–2. [PubMed: 20571043]
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15. Pollazzon M, Suominen T, Penttilä S, Malandrini A, Carluccio MA, Mondelli M, Marozza A, Federico A, Renieri A, Hackman P, Dotti MT, Udd B. The first Italian family with tibial muscular dystrophy (TMD) caused by a novel titin mutation. J Neurol. 2010;257:575–9. [PubMed: 19911250]
16. Sangiuolo F, Bruscia E, Capon F, Servidei S, Dallapiccola B, Novelli G. Fine mapping of a distinctive autosomal dominant vacuolar neuromyopathy using 11 novel microsatellite markers from chromosome band 19p13.3. Eur J Hum Genet. 2000;8:809–12. [PubMed: 11039585]
17. Satoh M, Takahashi M, Sakamoto T, Hiroe M, Marumo F, Kimura A. Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Biochem Biophys Res Commun. 1999;262:411–7. [PubMed: 10462489]
18. Servidei S, Capon F, Spinazzola A, Mirabella M, Semprini S, de Rosa G, Gennarelli M, Sangiuolo F, Ricci E, Mohrenweiser HW, Dallapiccola B, Tonali P, Novelli G. A distinctive autosomal dominant vacuolar neuromyopathy linked to 19p13. Neurology. 1999;53:830–7. [PubMed: 10489050]
19. Udd B, Griggs R. Distal myopathies. Curr Opin Neurol. 2001;14:561–6. [PubMed: 11562566]
20. Udd B. Distal myopathies--new genetic entities expand diagnostic challenge. Neuromuscul Disord. 2012;22:5–12. [PubMed: 22197426]
21. Udd B, Vihola A, Sarparanta J, Richard I, Hackman P. Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J. Neurology. 2005;64:636–42. [PubMed: 15728284]
22. Van den Bergh PY, Bouquiaux O, Verellen C, Marchand S, Richard I, Hackman P, Udd B. Tibial muscular dystrophy in a Belgian family. Ann Neurol. 2003;54:248–51. [PubMed: 12891679]
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Suggested Reading

1. Udd B. Molecular biology of distal muscular dystrophies-Sarcomeric proteins on top. Biochim Biophys Acta. 2007;1772:145–58. [PubMed: 17029922]

Revision History

• 23 August 2012 (me) Comprehensive update posted live
• 4 March 2010 (me) Comprehensive update posted to live Web site
• 3 April 2007 (me) Comprehensive update posted to live Web site
• 17 February 2005 (me) Review posted to live Web site
• 27 July 2004 (bu) Original submission