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Udd Distal Myopathy

Synonyms: Tibial Muscular Dystrophy, Udd Myopathy

, MSc, , MD, PhD, Prof, and , PhD, Doc.

Author Information
, MSc
Neuromuscular Research Unit
University of Tampere
Tampere, Finland
, MD, PhD, Prof
Neuromuscular Research Unit
Tampere University Hospital
Vaasa Central Hospital
Finland
, PhD, Doc
Folkhälsan Institute of Genetics
Department of Medical Genetics, Haartman Institute
University of Helsinki
Helsinki, Finland

Initial Posting: ; Last Revision: August 8, 2013.

Summary

Disease characteristics. Udd distal myopathy is characterized by 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 tibial muscles. The long toe extensors become clinically involved after ten to 20 years, leading to foot drop and clumsiness when walking. In the mildest form, Udd distal myopathy can remain unnoticed even in the elderly.

Diagnosis/testing. EMG shows profound myopathic changes in the anterior tibial muscle. CT or MRI confirm fatty degeneration of the anterior tibial muscles and also show large patchy lesions in other clinically unaffected muscles. TTN, encoding the protein titin (TTN), is the only gene in which mutations are known to cause Udd distal myopathy. All reported affected Finnish families have a founder mutation termed FINmaj, a unique 11-bp deletion/insertion mutation that changes four amino-acid residues in exon Mex6. A number of other mutations have been identified in exons Mex5 and Mex6 in families from different populations.

Management. Treatment of manifestations: Orthoses for foot drop early in the disease course; tibial posterior tendon transposition to replace lost function of the anterior tibial muscle and long toe extensor muscles when foot drop is severe.

Surveillance: Neurologic examination every one to four years to evaluate disease progression and need for rehabilitation and orthotic treatment.

Agents/circumstances to avoid: Heavy muscle force training of weak muscles.

Genetic counseling. Udd distal myopathy is inherited in an autosomal dominant manner. Most individuals diagnosed with Udd distal myopathy have an affected parent. Each child of an individual with Udd distal myopathy has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation has been identified in the family.

Diagnosis

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

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
TTNTargeted mutation analysisFinnish founder mutation (FINmaj) 4 100% of the founder mutation
Sequence analysis of select exonsSequence variants in exons 358-363 (Mex1-Mex6) 4, 5Unknown 6
Sequence analysisSequence variants 5Close to 100% 6
Deletion/duplication analysis 7Exon or whole-gene deletion/duplicationUnknown, none reported

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

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

4. 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.

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. A number of other mutations in exons Mex5 and Mex6 in TTN have been found to date in several different families from several countries [Hackman et al 2002, Van den Bergh et al 2003, Hackman et al 2008, Pollazzon et al 2010, Unpublished data].

7. 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.

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.

Clinical Description

Natural History

The first symptoms of Udd distal myopathy are weakness of ankle dorsiflexion and inability to walk on the heels after age 25 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

Most affected individuals of Finnish heritage tested have the same mutation (FINmaj); recently, other mutations have also been identified [unpublished data]. Ninety-two percent 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 some variations when compared to the Finnish phenotype. Compound heterozygotes with atypical phenotypes have recently been identified [unpublished data].

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.

Differential Diagnosis

Disorders in the differential diagnosis of Udd distal myopathy are listed in Table 2.

Table 2. Distal Myopathies

Disease NameMean Age at OnsetInitial Muscle Group InvolvedSerum Creatine Kinase ConcentrationMuscle BiopsyGene (Locus) 1
Autosomal Dominant
Welander distal myopathy>40 yrsDistal upper limbs (index finger and wrist extensors)Normal or slightly increasedRimmed vacuolesTIA1
Udd distal myopathy>35Anterior compartment in legs± rimmed vacuolesTTN
Markesbery-Griggs late-onset distal myopathy>40Vacuolar and myofibrillar myopathyLDB3
Distal myotilinopathy>40Posterior > anterior in legsSlightly increasedVacuolar and myofibrillarMYOT
Laing early-onset distal myopathy (MPD1)<20Anterior compartment in legs and neck flexorsModerately 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
KLHL9-related distal myopathy 8-16 Ankle dorsiflexion1.5-14 timesMyopathicKLHL9
Distal ABD-filaminopathyEarly adulthoodDistal upper limbsNormal or slightly increasedScattered, grouped atrophic fibersFLNC
DesminopathyJuvenile / early adulthoodDistal lower limbs, Moderately elevatedConsistent with myofibrillar myopathyDES
Alpha-B crystallinopathy32-68Distal limbs1.5-2.5 timesRimmed vacuolar pathologyCRYAB
VCP-related distal myopathy20-25Distal limbs (frontotemporal dementia common)Slightly elevatedRimmed vacuolesVCP
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
NEB-related distal myopathy ChildhoodAnkle dorsiflexion, weakness of hand and finger extensorsnormal or slightly increasedScattered, grouped atrophic fibers without nemaline rodsNEB
Distal anoctaminopathy20-55Asymmetric calf involvement>10 timesNonspecific dystrophic myopathologyANO5

Udd & Griggs [2001], Udd [2012]

1. Locus given only if the gene is not known

Welander distal myopathy may sometimes have onset in the anterior compartment muscles of the lower legs, instead of the usual onset in the index finger and wrist 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. Hackman et al [2012] reported a missense mutation (c.1362G>A [p.Gly384Lys]) in TIA1 in numerous families from Finland, Sweden, and Great Britain, suggesting a common genetic founder effect.

Markesbery-Griggs late-onset distal myopathy (zaspopathy) is characterized by weakness of ankle dorsiflexion usually beginning in the late 40s, followed later by slow progression to the calf muscles, the finger and wrist extensor muscles, and the intrinsic muscles of the hand. Eventually the proximal leg muscles become involved. Cardiomyopathy may occur at late stages. Mutations in LDB3 (ZASP) are causative [Griggs et al 2007].

Distal myotilinopathy is characterized by onset of ankle weakness after age 40 years or even very late in the 60s. In contrast to the late onset, progression is not very slow and can lead to wheelchair dependence even ten to 15 years after onset, including weakness and atrophy of proximal and upper limb muscles [Pénisson-Besnier et al 2006].

Laing distal myopathy (MPD1) is characterized by early-onset weakness (usually before age five 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. After distal weakness has been present for more than ten years, mild proximal weakness is observed. Life expectancy is normal. Mutations in MYH7 (the only gene in which mutations are known to cause Laing distal myopathy) are identified in approximately 50% of individuals with early-onset distal myopathy. Recently, a cohort of more than 60 affected individuals was reported in Spain [Muelas et al 2010, Muelas et al 2012].

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 (see Inclusion Body Myopathy 2).

Miyoshi early-adult-onset myopathy begins in the posterior compartment of the legs, manifest as difficulty climbing stairs and walking on toes and progressing to other distal and proximal muscles as with LGMD2B (see Dysferlinopathy). The serum CK concentration is usually more than 50 times normal.

MPD3, a dominant distal myopathy, was described in Finland in a single family, in which some affected individuals had onset in the thenar eminence and hypothenar eminence of the hands and others in the anterior compartment muscles of lower limbs; later, both upper and lower limbs are involved [Haravuori et al 2004].

In facioscapulohumeral muscular dystrophy (FSHD) and some congenital myopathies, the initial symptom can be a selective defect in the tibialis anterior muscle as with Udd distal myopathy. FSHD typically presents before age 20 years with weakness of the facial muscles and the stabilizers of the scapula or the dorsiflexors of the foot. Severity is highly variable. Weakness is slowly progressive and about 20% of affected individuals eventually require a wheelchair. Life expectancy is not shortened. Inheritance is autosomal dominant.

Distal anoctaminopathy, which may present with similarities to Miyoshi myopathy, is characterized by early-adult onset distal myopathy with asymmetric calf involvement, starting with pain and hypertrophy and turning into weakness and atrophy. Affected individuals have very high CK levels and nonspecific dystrophic myopathology with scattered fiber necrosis. The evolution is slow and individuals remain ambulant into late adulthood. Mutations in ANO5, distributed throughout the gene, are causative [Penttilä et al 2012, Udd 2012].

Vocal cord and pharyngeal dysfunction with distal myopathy caused by mutations in MATR3 is a disorder reported in only two families.

19p13 distal myopathy is a disorder reported in two Italian families [Servidei et al 1999, Sangiuolo et al 2000, Di Blasi et al 2004].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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.

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

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 reported.
  • 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 pathogenic variant, the risk depends on the genetic status of the proband's parents.
    • If a parent of the proband is affected or has a pathogenic variant, the risk to the sibs is 50%.
    • If the pathogenic variant 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 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 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.

Prenatal Testing

If the pathogenic variant 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.

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 an option for some families in which the pathogenic variant 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 - 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. Udd Distal Myopathy: Genes and Databases

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 Udd Distal Myopathy (View All in OMIM)

188840TITIN; TTN
600334TIBIAL MUSCULAR DYSTROPHY, TARDIVE

Gene structure. TTN has 363 exons [NM_001267550.1] and approximately 294,000 base pairs (bp), with mRNA of more than 100,000 bp. TTN variants (SNPs) and several splicing variants have been found. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. In Mex6, the last exon of TTN, a unique 11-bp deletion/insertion termed FINmaj that changes four amino-acid residues without interrupting the reading frame is observed in most affected Finnish families [Hackman et al 2002]. The mutation is described as 293,269_293,279indel11 (referred sequence: GenBank AJ277892.2).

Other identified pathogenic variants in TTN:

Normal gene product. Titin is the biggest single polypeptide found in humans. The entire coding region codes for up to 38,138 amino acids (4200 kd). According to UniProt several different isoforms expressed in different striated muscles exist and the size of the full-length protein may be up to 38138 residues. Titin is expressed as several different isoforms, caused by alternative splicing, in different skeletal muscles and cardiac muscle. The titin protein is the third myofilament in the sarcomere along with myosin and actin filaments. Titin spans more than one half the length of a sarcomere in heart and skeletal muscle. Structurally different parts of the protein perform distinct functions (mechanical, developmental, and regulatory). Titin binds and interacts with a large number of other sarcomeric proteins.

Abnormal gene product. The FINmaj mutation does not alter the final size of the mRNA products; the abnormal protein is incorporated into the sarcomere. The frameshift mutations cause truncated mRNA products and in some cases nonsense mediated decay [unpublished data]. Mex6 mutations may cause conformational changes in titin and alter the interactions with other sarcomeric proteins and/or may cause proteolysis of C-terminal titin domains.

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

  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]
  5. Hackman P, Marchand S, Sarparanta J, Vihola A, Pénisson-Besnier I, Eymard B, Pardal-Fernández JM, Hammouda EH, Richard I, Illa I, Udd B. Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD). Neuromuscul Disord. 2008;18:922–8. [PubMed: 18948003]
  6. Hackman P, Sarparanta J, Lehtinen S, Vihola A, Evilä A, Jonson PH, Luque H, Kere J, Screen M, Chinnery PF, Ahlberg G, Edström L, Udd B. Ann Neurol. 2012 [PubMed: 23401021]
  7. 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]
  8. Lange S, Xiang F, Yakovenko A, Vihola A, Hackman P, Rostkova E, Kristensen J, Brandmeier B, Franzen G, Hedberg B, Gunnarsson LG, Hughes SM, Marchand S, Sejersen T, Richard I, Edstrom L, Ehler E, Udd B, Gautel M. The kinase domain of titin controls muscle gene expression and protein turnover. Science. 2005;308:1599–603. [PubMed: 15802564]
  9. Muelas N, Hackman P, Luque H, Garcés-Sánchez M, Inmaculada I, Suominen T, Sevilla T, Mayordomo F, Gómez L, Martí P, Millán JM, Udd B, Vílchez J. MYH7 gene tail mutation causing myopathic profiles beyond Laing distal myopathy. Neurology. 2010;75:732–41. [PubMed: 20733148]
  10. Muelas N, Hackman P, Luque H, Suominen T, Espinós C, Garcés-Sánchez M, Sevilla T, Azorín I, Millán J, Udd B, Vílchez J. Spanish MYH7 founder mutation of Italian ancestry causing a large cluster of Laing myopathy patients. Clin Genet. 2012;81:491–4. [PubMed: 21395566]
  11. 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.
  12. 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;135:1682–94. [PubMed: 22577218]
  13. Palmio J, Evilä A, Chapon F, Tasca G, Xiang F, Brådvik B, Eymard B, Echaniz-Laguna A, Laporte J, Kärppä M, Mahjneh I, Quinlivan R, Laforêt P, Damian M, Berardo A, Taratuto AL, Bueri JA, Tommiska J, Raivio T, Tuerk M, Gölitz P, Chevessier F, Sewry C, Norwood F, Hedberg C, Schröder R, Edström L, Oldfors A, Hackman P, Udd B. Hereditary myopathy with early respiratory failure: occurrence in various populations. J Neurol Neurosurg Psychiatry. 2014;85:345–53. [PubMed: 23606733]
  14. 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]
  15. 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]
  16. Penttilä S, Palmio J, Suominen T, Raheem O, Evilä A, Muelas N, Tasca G, Waddell L, Clarke N, Barboi A, Hackman P, Udd B. Eight new mutations and the expanding phenotype variability in muscular dystrophy caused by ANO5. Neurology. 2012;78:897–903. [PubMed: 22402862]
  17. Pfeffer G, Elliott HR, Griffin H, Barresi R, Miller J, Marsh J, Evilä A, Vihola A, Hackman P, Straub V, Dick DJ, Horvath R, Santibanez-Koref M, Udd B, Chinnery PF. Titin mutation segregates with hereditary myopathy with early respiratory failure. Brain. 2012;135:1695–713. [PMC free article: PMC3359754] [PubMed: 22577215]
  18. 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]
  19. 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]
  20. 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]
  21. 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]
  22. Udd B, Griggs R. Distal myopathies. Curr Opin Neurol. 2001;14:561–6. [PubMed: 11562566]
  23. Udd B. Distal myopathies--new genetic entities expand diagnostic challenge. Neuromuscul Disord. 2012;22:5–12. [PubMed: 22197426]
  24. 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]
  25. 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]
  26. von Tell D, Somer H, Udd B, Edstrom L, Borg K, Ahlberg G. Welander distal myopathy outside the Swedish population: phenotype and genotype. Neuromuscul Disord. 2002;12:544–7. [PubMed: 12117477]

Suggested Reading

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

Chapter Notes

Revision History

  • 8 August 2013 (cd/bu) Revision: mutations in TIA1 reported to cause Welander distal myopathy; distal anoctaminopathy added to differential diagnosis
  • 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
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Tests in GTR by Gene

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