Markesbery et al. (1974) reported a late adult-onset, autosomal dominant form of distal myopathy with onset in the anterior compartment of the legs rather than in the hands, which is the presenting feature of Welander myopathy (604454). In ... Markesbery et al. (1974) reported a late adult-onset, autosomal dominant form of distal myopathy with onset in the anterior compartment of the legs rather than in the hands, which is the presenting feature of Welander myopathy (604454). In addition, they reported the occurrence of cardiomyopathy. Edstrom et al. (1980) thought that the family of Markesbery et al. (1974) had a distinct disorder because the affected members showed cardiomyopathy (which was never found in Welander myopathy) and had different histopathologic findings (compare Edstrom, 1975 and Markesbery et al., 1977). Udd (1992) reported a large consanguineous Finnish pedigree with 2 separate muscle disease phenotypes: mild late-onset distal myopathy inherited in an autosomal dominant pattern and severe limb-girdle muscular dystrophy (see LGMD2J) inherited in an autosomal recessive pattern. Segregation analysis showed that the corrected proportion of affected persons with the severe proximal type was 0.246 and the proportion of affected persons with the distal myopathy was 0.58. The findings were compatible with the hypothesis that the severe LGMD phenotype was the homozygous manifestation of a dominant gene that in the heterozygous state caused the milder distal myopathy. Udd et al. (1992), who referred to the distal myopathy as 'tibial muscular dystrophy,' reported follow-up on the large affected Finnish pedigree. Partanen et al. (1994) studied a family with very late-onset (fifth or sixth decade) or asymptomatic hereditary myopathy of the anterior tibial muscle. The muscles of the upper extremity were spared. The anterior tibial muscles had a characteristic myopathic alteration with rimmed vacuoles. Twelve persons, both male and female, were affected, and male-to-male transmission was demonstrated. Partanen et al. (1994) noted the similarity of their cases to those of Markesbery et al. (1974) in that there was late adult onset in the anterior compartment of the legs. However, Partanen et al. (1994) thought that the patients reported by Markesbery et al. (1974) had a far wider involvement and earlier onset of disease. Partanen et al. (1994) distinguished 6 types of distal myopathy: (1) Welander myopathy; (2) a late-onset autosomal dominant form with onset in the anterior compartment of the legs; (3) an early adult-onset recessive or sporadic form with onset in the anterior compartment of the legs with vacuolar myopathy on biopsy (Sunohara et al., 1989); (4) an early adult-onset recessive distal myopathy of the posterior compartment of the legs (Miyoshi et al., 1986; 254130); (5) an autosomal recessive vacuolar myopathy sparing the quadriceps (Sadeh et al., 1993; 600737); and (6) a late-onset autosomal dominant tibial dystrophy as described by Udd et al. (1991, 1992) and Udd (1992). Udd et al. (1993) investigated 66 Finnish patients with late adult-onset tibial muscular dystrophy. Symptoms appeared after the age of 35 years with reduced ankle dorsiflexion, and progression was slow without marked disability. Facial muscles, upper extremities, and proximal muscles were usually spared. Pedigree data suggested autosomal dominant inheritance. The clinical studies suggested homogeneity in the various families affected with this rather frequent disorder in Finns. Van den Bergh et al. (2003) reported a Belgian family with tibial muscular dystrophy. The proband had onset of gait difficulties in his late 40s, and clinical examination showed steppage gait and weakness and atrophy of the anterior compartment muscles of the lower legs without proximal weakness or sensory loss. CT scan of the lower leg muscles showed marked atrophy and low density, suggestive of fatty degeneration. Family investigation revealed that the proband's father, a paternal uncle, and one of his daughters had mild tibialis anterior weakness and atrophy, although all were asymptomatic. In affected members of the family, Van den Bergh et al. (2003) identified a heterozygous mutation in the Mex6 exon of the titin gene (188840.0006). The authors noted that the family showed incomplete disease penetrance. - Pathologic Findings In 12 affected members of a large Finnish pedigree with distal myopathy, Udd et al. (1992) found that muscle biopsy did not show vacuolar degeneration, which was in contrast to most adult-onset distal myopathies. Histopathologic changes correlating with the muscular dystrophy were extensive in tibial anterior muscles in patients with distal myopathy and in all muscles of those family members who had a severe limb-girdle muscular dystrophy phenotype. Among 66 Finnish patients with TMD, Udd et al. (1993) found that muscle biopsies showed nonspecific dystrophic changes in clinically affected muscles and severe adipose replacement in the anterior tibial muscles. Asymptomatic muscles had mild myopathic changes only. Vacuolar degeneration was detected in a minority of patients. Electromyography showed profound myopathic changes in the anterior tibial muscle, but extensor brevis muscles were well preserved. Computed tomography or magnetic resonance imaging of muscles disclosed marked involvement of tibial extensor muscles and focal patches of fatty degeneration in various asymptomatic muscles. In tibial muscular dystrophy, some biopsies showed rimmed vacuoles and others did not. Udd (1997) concluded that the presence or absence of rimmed vacuoles was not indicative of heterogeneity because there was intrafamilial variation and families with or without rimmed vacuoles were shown to be genealogically linked.
Because of the map location of TMD on 2q31, the gene encoding the giant skeletal muscle protein titin (188840) was a strong positional as well as functional candidate for the site of causative mutations. Hackman et al. (2002) ... Because of the map location of TMD on 2q31, the gene encoding the giant skeletal muscle protein titin (188840) was a strong positional as well as functional candidate for the site of causative mutations. Hackman et al. (2002) demonstrated a heterozygous 11-bp deletion/insertion in the last exon (exon 363) of the TTN gene (188840.0004) as the cause of TMD in 81 Finnish patients from 12 unrelated families. One of the families with the 11-bp deletion was the large Finnish family reported by Udd et al. (1992). A different mutation in the TTN gene, a missense mutation that was also located in the last exon (188840.0005), was identified in an affected French family.
Udd distal myopathy is characterized by the following:...
DiagnosisClinical DiagnosisUdd 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 TestingSerum 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 TestingGene. 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 MyopathyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency 1Test AvailabilityTTNTargeted mutation analysisFinnish founder mutation (FINmaj) 2 100% of the founder mutationClinical Sequence analysis of select exonsSequence variants in exons 358-363 (Mex1-Mex6) 2, 3Unknown 4 Sequence analysisSequence variants 3Close to 100% 4Deletion / duplication analysis 5Exon or whole gene deletion/duplicationUnknown, none reported1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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 detected4. 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.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a probandFor 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.Genetically Related (Allelic) DisordersHeterozygous 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).
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]. ...
Natural HistoryThe 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.
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]. ...
Genotype-Phenotype CorrelationsAll 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].
Disorders in the differential diagnosis of Udd distal myopathy are listed in Table 2....
Differential DiagnosisDisorders in the differential diagnosis of Udd distal myopathy are listed in Table 2.Table 2. Distal MyopathiesView in own windowDisease NameMean Age at OnsetInitial Muscle Group InvolvedSerum Creatine Kinase ConcentrationMuscle BiopsyGene Symbol (Locus) 1Autosomal DominantWelander distal myopathy>40 yrsDistal 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 myopathyLDB3 Distal myotilinopathy>40Posterior > anterior in legsSlightly increasedVacuolar and myofibrillarMYOTLaing early-onset distal myopathy (MPD1)<20Anterior compartment in legs and neck flexorsModerately increasedType 1 fiber atrophy in tibial anterior muscles; disproportion in proximal musclesMYH7Distal myopathy with vocal cord and pharyngeal signs (MPD2)35-60Asymmetric lower leg and hands; dysphonia1-8 timesRimmed vacuolesMATR3KLHL9-related distal myopathy 8-16 Ankle dorsiflexion1.5-14 timesMyopathicKLHL9Distal ABD-filaminopathyEarly adulthoodDistal upper limbsNormal or slightly increasedScattered, grouped atrophic fibersFLNCDesminopathyJuvenile / early adulthoodDistal lower limbs, Moderately elevatedConsistent with myofibrillar myopathyDESAlpha-B crystallinopathy32-68Distal limbs1.5-2.5 timesRimmed vacuolar pathologyCRYABVCP-related distal myopathy20-25Distal limbs (frontotemporal dementia common)Slightly elevatedRimmed vacuolesVCPDistal 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 RecessiveNonaka 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 rodsNEBDistal anoctaminopathy20-55Asymmetric calf involvement>10 timesNonspecific dystrophic myopathologyANO5Udd & Griggs [2001], Udd [2012]1. Locus given only if the gene is not knownWelander 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. 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.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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of muscle involvement in an individual diagnosed with Udd distal myopathy, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 ManifestationsUsually 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. SurveillanceDisease progression and the need for rehabilitation and orthotic treatment should be evaluated by neurologic examination every one to four years.Agents/Circumstances to AvoidHeavy muscle force training of weak muscles should be avoided.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTTN2q31.2TitinFinnish Disease Database ARVD/C Genetic Variants Database TTN homepage - Leiden Muscular Dystrophy pagesTTNData 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) View in own window 188840TITIN; TTN 600334TIBIAL MUSCULAR DYSTROPHY, TARDIVENormal allelic variants. 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. Pathologic 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 all affected Finnish families [Hackman et al 2002]. The mutation is described as 293,269_293,279indel11 (referred sequence: GenBank AJ277892.2).Other identified disease-causing mutations:293,356T>C, in exon Mex6 identified in a family of French heritage [Hackman et al 2002] 293,329T>A, in exon Mex6 identified in a family of Belgian heritage [Van den Bergh et al 2003] 293,379C>T STOP-codon in exon Mex6 in French families [Hackman et al 2008] 293,378delA in exon Mex6 in Spanish families [Hackman et al 2008, Negrao et al 2010] 293,326A>C, in exon Mex6 identified in an Italian family [Pollazzon et al 2010]292,998delT in exon Mex5 in a French family [Hackman et al 2008]293381_293386delAGATGG, in exon Mex6 identified in a family of Swiss heritageNormal 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. 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.