NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Hereditary Myopathy with Early Respiratory Failure

Synonyms: HMERF, MFM-Titinopathy, Myofibrillar Myopathy with Early Respiratory Failure

, MD, CM, FRCPC, PhD and , BMedSci, MBBS, PhD, FRCPath, FRCP, FMedSci.

Author Information

Initial Posting: ; Last Update: March 19, 2020.

Estimated reading time: 20 minutes

Summary

Clinical characteristics.

Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life. The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. Most affected individuals require walking aids within a few years of onset; some progress to wheelchair dependence and require nocturnal noninvasive ventilatory support about ten years after onset. The phenotype varies even among individuals within the same family: some remain ambulant until their 70s whereas others may require ventilator support in their 40s.

Diagnosis/testing.

The diagnosis of HMERF is established in a proband with typical clinical findings and/or a heterozygous pathogenic variant in the region of TTN that encodes the 119th fibronectin-3 domain of titin on molecular genetic testing.

Management.

Treatment of manifestations: Management is supportive. For distal leg weakness, use of ankle-foot orthoses can optimize independent ambulation early in the disease course; later in the disease course other mobility aids (canes, walkers, or wheelchairs) may be required. Noninvasive ventilation with bilevel positive airway pressure (BiPAP) or continuous positive airway pressure (CPAP) may be indicated for nocturnal hypoventilation initially, followed by mechanical ventilatory support as needed. Influenza vaccination, occupational therapy, and social service support are important.

Surveillance: Reassessment of muscle strength and clinical status annually by a neurologist; pulmonary function testing every six to 12 months, or guided by individual findings.

Pregnancy management: Although the onset of symptoms usually occurs after the age of childbearing, a pregnant woman with early manifestations of HMERF or at risk for HMERF should be considered high-risk because of the associated respiratory muscle weakness and the increased physiologic demands of pregnancy. Consultation with a high-risk maternal-fetal medicine specialist is recommended when possible.

Genetic counseling.

HMERF is inherited in an autosomal dominant manner with variable expressivity. Most individuals diagnosed with HMERF have an affected parent; to date, de novo pathogenic variants have not been reported in any individuals with genetically confirmed HMERF. Each child of an individual with HMERF has a 50% chance of inheriting the pathogenic variant. If the pathogenic variant has been identified in an affected family member, predictive testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.

Diagnosis

Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy with typical onset in adulthood. The diagnosis of this rare disorder is not supported by any formal diagnostic criteria at this time.

Suggestive Findings

Diagnosis of hereditary myopathy with early respiratory failure (HMERF) should be suspected in individuals with the following:

  • Adult-onset muscle disease with onset typically between ages 30 and 50 years (range 22-71 years)
    • The first symptoms usually relate to weakness of the distal leg muscles and may include foot drop or frequent falls.
    • Weakness may also involve the proximal muscles of the lower extremities, proximal and/or distal muscles of the upper extremities, and axial muscles.
    • Affected individuals may appear quite muscular even when weakness is present [Pfeffer et al 2014a].
      In particular, hypertrophy of the calf muscles is frequently reported [Ohlsson et al 2012]; however, atrophy of the calf muscles has also been reported [Pfeffer et al 2012] and may reflect a more advanced disease stage at the time of examination.
    • Serum creatine kinase is usually mildly elevated (range: normal to 1,000 units/L).
  • Evidence of respiratory muscle weakness early in the disease course
    Note: Since affected individuals may not report symptoms, they need to be specifically asked about orthopnea, dyspnea on exertion, and excessive daytime sleepiness.
  • Family history consistent with autosomal dominant inheritance

Note: Muscle MRI findings and muscle pathology studies can identify supportive evidence but may not be specific to this disorder (see Clinical Description).

Establishing the Diagnosis

The diagnosis of HMERF is established in a proband with typical clinical findings and/or a heterozygous* pathogenic variant in TTN identified by molecular genetic testing (see Table 1).

Note: All HMERF-associated TTN pathogenic variants are located in the 119th fibronectin-3 domain of titin, which corresponds to the following (see Molecular Genetics):

* Rare individuals have been reported to be homozygous for the TTN pathogenic variant p.Pro30091Leu; such individuals have been born to parents who are both heterozygous and clinically asymptomatic or subclinically symptomatic (i.e., muscle abnormality demonstrable on imaging) [Palmio et al 2014]

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of HMERF is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with atypical findings in whom the diagnosis of HMERF has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of HMERF molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of TTN detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, gene-targeted deletion/duplication analysis can be considered; to date, however, no large deletions or complex rearrangements involving TTN have been associated with HMERF.
  • A multigene panel that includes TTN and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of HMERF is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Hereditary Myopathy with Early Respiratory Failure (HMERF)

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
TTNSequence analysis 3100% 4
Gene-targeted deletion/duplication analysis 5None reported 4
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

To date, all pathogenic variants associated with HMERF are located in the TTN 119th fibronectin domain, which is encoded by exon 285 of transcript NM_001256850​.1 [Ohlsson et al 2012, Pfeffer et al 2012, Izumi et al 2013, Toro et al 2013, Palmio et al 2014, Pfeffer et al 2014a, Pfeffer et al 2014b, Uruha et al 2015, Yue et al 2015, Palmio et al 2019]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life [Edström et al 1990, Pfeffer et al 2012].

Presentation

The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles.

Muscle Findings

Muscle weakness can have variability in its distribution and severity, but in general the lower extremities are more affected than the upper extremities. Usually, the earliest and most severely affected muscle is tibialis anterior (ankle dorsiflexion). However, early and predominant hip girdle weakness is also described [Pfeffer et al 2012].

Muscle MRI can be useful earlier in the disease course and is thought to be highly specific, with distinctive early involvement of the semitendinosus muscle [Birchall et al 2005]. Later in the disease course, numerous muscles become affected and this pattern may be nonspecific [Pfeffer et al 2012].

Muscle pathology can demonstrate findings that are considered to be specific to this disorder, but because of the patchy nature of abnormalities in myofibrillar myopathies, these findings are not present in all affected individuals [Selcen 2011].

The specific findings described with this disorder include the presence of "cheetah-print" aggregates [Pfeffer et al 2014a] and "necklace" inclusions [Uruha et al 2015].

Otherwise, features of myofibrillar myopathy such as eosinophilic cytoplasmic inclusions on hematoxylin and eosin staining and cytoplasmic bodies on electron microscopy may be present, but are not specific for HMERF. Other nonspecific myopathic findings may be present.

Respiratory Findings

A distinctive feature of this condition is the early diaphragmatic weakness that often occurs while individuals are still ambulant, which is typical of only a few other rare diseases (see Differential Diagnosis) or may be atypically present in other rare myopathies [Pfeffer & Povitz 2016]. Exertional dyspnea and/or orthopnea are the typical presenting symptoms, and pulmonary function testing demonstrates restrictive impairment. Patients develop progressive reduction in vital capacity and forced expiratory volumes, and often progress to require nocturnal noninvasive ventilatory support [Pfeffer et al 2012].

Progression

Most individuals require walking aids within a few years of onset, most commonly ankle-foot orthoses. Some will progress to wheelchair dependence and require nocturnal noninvasive ventilatory support about ten years after onset.

Weakness of respiratory muscles also progresses with time. Affected individuals become increasingly vulnerable to pulmonary infections as respiratory function deteriorates.

Of note, the phenotype varies even among individuals within the same family [Pfeffer et al 2012]: some affected individuals remain ambulant until their 70s whereas others may require ventilator support in their 40s.

Life Expectancy

Presumably life expectancy is decreased in this disorder, but because of the rarity of the condition, studies have not formally addressed this question. From the experience of the authors, individuals with this condition are more susceptible to pulmonary complications (due to the respiratory muscle weakness), which may result in early morbidity and mortality [Pfeffer et al 2014b].

Genotype-Phenotype Correlations

Although clinical variability is observed with HMERF-related TTN variants, no relationship between the pathogenic variant and phenotype is evident.

Penetrance

Penetrance appears to depend on the pathogenic variant.

For the common p.Cys30071Arg variant, penetrance appears to be complete, although individuals with very late-onset disease have been described (as late as age 71 years); therefore, it is possible that some affected individuals may die from other causes before the disease becomes manifest.

The p.Pro30091Leu variant appears to have reduced penetrance [Pfeffer et al 2014a] in at least one family, where only one of two heterozygous family members developed the disease.

Because the other pathogenic variants have only been described in a few individuals to date [Izumi et al 2013, Toro et al 2013, Palmio et al 2014, Uruha et al 2015, Yue et al 2015, Palmio et al 2019], data are insufficient to draw conclusions regarding their penetrance; however, current observations suggest complete penetrance.

Nomenclature

Hereditary myopathy with early respiratory failure (HMERF) has previously been termed:

The authors prefer the term "myofibrillar myopathy-titinopathy" [Pfeffer et al 2014a] because of the clinical, MRI, and pathologic similarities of HMERF with the myofibrillar myopathies. For pragmatic purposes this term is useful because future cases of HMERF are most likely to be identified among persons with myofibrillar myopathy.

Prevalence

The prevalence of HMERF is not known, but it is most likely under-recognized because of its broad phenotypic spectrum and relatively recent discovery of its underlying genetic etiology.

Two studies have indicated that about 5% of persons with an undiagnosed myofibrillar myopathy have a TTN pathogenic variant and a phenotype consistent with HMERF [Toro et al 2013, Pfeffer et al 2014a]. This suggests that HMERF is a fairly common subtype of myofibrillar myopathy, which itself is rare. Of note, the estimated prevalence of desminopathy in the northeastern United Kingdom (accounting for 3% of myofibrillar myopathy in that population [Pfeffer et al 2014a]) is 0.17:100,000 [Norwood et al 2009].

Differential Diagnosis

Table 2.

Disorders to Consider in the Differential Diagnosis of Hereditary Myopathy with Early Respiratory Failure

DisorderGene(s)MOIClinical Features of Differential Disorder
Overlapping w/HMERFDistinguishing from HMERF
Amyotrophic lateral sclerosis>30 genes 1AD
AR
XL
Presents w/respiratory failure in ~3% of cases 2
  • Presence of combined upper & lower motor neuron signs
  • Early atrophy of hand muscles
  • Characteristic neurophysiologic abnormalities
Facioscapulohumeral muscular dystrophy (FSHD)DNMT3B
SMCHD1 3
AD
  • Typically presents w/weakness of facial & proximal arm muscles (esp shoulder & hip girdle)
  • Highly variable disease severity
  • Absence of early respiratory failure
  • Presence of facial weakness
Late-onset Pompe disease (late-onset glycogen storage disease type II)GAAAR
  • Proximal muscle weakness
  • Respiratory insufficiency
  • Early diaphragmatic weakness while still ambulant
  • Pathologic findings
  • Muscle MRI abnormalities
Limb-girdle muscular dystrophy type 2
(LGMD2; OMIM PS253600)
~29 genes 4AR
  • Weakness & wasting restricted to limb musculature (proximal > distal)
  • Subtypes LGMD2I (FKRP) & the sarcogylcanopathies (LGMD2C-LGMD2F) affect the respiratory muscles early in disease course. 5
LGMD2I is distinguished by presence of degenerating/ regenerating muscle fibers on muscle biopsy.
Myofibrillar myopathy
(MFM) (OMIM PS601419)
BAG3
CRYAB
DES
FLNC
KY
LDB3
MYOT
PYROXD1
AD
AR
  • Significant overlap in clinical, MRI, & pathologic features w/HMERF; some individuals w/HMERF meet diagnostic criteria for MFM on muscle biopsy. 6
  • Slowly progressive weakness that can involve both proximal & distal muscles
  • Distal muscle weakness present in ~80% of individuals
  • Respiratory muscle weakness can occur esp in DES-, CRYAB-, or BAG3-related MFM. 7
Some pathology findings may be specific to HMERF (necklace inclusions, cheetah-skin aggregates).
Myotonic dystrophy type 1
(DM1)
DMPK 8AD
  • Highly variable muscle disease
  • May present w/distal muscle weakness & respiratory muscle involvement
  • Distribution of muscle weakness, usually incl face or eyelids
  • Variable multisystem features incl: myotonia; cataracts; cognitive deficits; cardiac arrhythmia; endocrine & GI dysfunction
Oculopharyn-godistal myopathy 1 (OMIM 164310)LRP12AD
AR
Early diaphragmatic weakness while still ambulantOcular, facial, & pharyngeal weakness
Myasthenia gravisN/AN/AMay present w/respiratory failure & skeletal muscle weakness 9
  • Fatigability
  • Bulbar muscles often affected
  • Electrodecremental response demonstrated on nerve conduction studies
  • Jittery motor unit potentials on single-fiber electromyography
  • Most affected individuals are seropositive for AchR or MuSK antibodies.

AD = autosomal dominant; AR = autosomal recessive; GI = gastrointestinal; HMERF = hereditary myopathy with early respiratory failure; MOI = mode of inheritance; XL = X-linked

1.

See Amyotrophic Lateral Sclerosis: Phenotypic Series to view genes associated with this phenotype in OMIM.

2.
3.

The diagnosis of FSHD1 is established in a proband with characteristic clinical features by identification of a heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a chromosome 4 permissive haplotype. The diagnosis of FSHD2 is established in a proband by identification of hypomethylation of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a chromosome 4 permissive haplotype. Hypomethylation of the D4Z4 repeat array can be due to a heterozygous pathogenic variant in SMCHD1 or DNMT3B.

4.

See Muscular dystrophy, limb-girdle, autosomal recessive for a list of genes associated with this phenotype in OMIM.

5.
6.
7.
8.

DM1 is caused by expansion of a CTG trinucleotide repeat in the noncoding region of DMPK.

9.

Other similar clinical presentations may occur atypically with other disorders and may be considered on a case-by-case basis. The individual should be evaluated in the context of coexisting medical conditions, medication use, and/or toxic exposures. Reversible or treatable medical conditions such as endocrine disorders, autoimmune disease, or nutritional deficiencies should be considered when appropriate. An example of a toxic exposure is a single case report of colchicine use causing isolated respiratory muscle weakness that resolved on discontinuation of treatment [Tanios et al 2004].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hereditary myopathy with early respiratory failure (HMERF), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with HMERF

System/ConcernEvaluationComment
NeuromuscularNeuromuscular assessment by neurologist w/expertise in inherited muscle disorders
PTAssess lower limb function & general mobility.
OTAssess for need for home &/or office adaptations & mobility aids.
RespiratoryAssess pulmonary function & need for nocturnal ventilator support
Miscellaneous/
Other
Consultation w/clinical geneticist &/or genetic counselorTo incl genetic counseling
Social services consultationAssist w/workplace adaptations &/or access to social/disability benefits.

OT = occupational therapy; PT = physical therapy

Treatment of Manifestations

At present no disease-modifying therapy exists. Management is supportive. Because of the rarity of this disorder, no formal treatment guidelines have been developed, although general recommendations based on clinical experience are provided in Table 4.

Table 4.

Treatment of Manifestations in Individuals with HMERF

Manifestation/ConcernTreatmentConsiderations/Other
Distal leg weaknessAnkle-foot orthosesTo optimize independent ambulation
Other mobility aids such as canes, walkers, or wheelchairsMay be required later in disease course
InactivityExercises & activities suggested by PT consultationTo prevent continued loss of physical function
Nocturnal hypoventilationNoninvasive ventilation w/BiPAP or CPAP
Respiratory failureMechanical ventilatory support as needed
↑ susceptibility to respiratory tract infectionsInfluenza vaccination
Gradually progressive nature of this diseaseOT & social services support

BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; OT = occupational therapy; PT = physical therapy

Surveillance

No specific guidelines are in place for surveillance of this disorder; general recommendations are provided in Table 5.

Table 5.

Recommended Surveillance for Individuals with HMERF

System/ConcernEvaluationFrequency
NeuromuscularReassessment of muscle strength & clinical status w/a neurologist who can coordinate any additional required servicesAnnually
RespiratoryPulmonary function testingEvery 6-12 mos or guided by individual findings

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Information is insufficient to determine if particular issues in HMERF relate to pregnancy. In general, onset of symptoms occurs after the age of childbearing. However, a pregnant woman with early manifestations of HMERF or at risk for HMERF should be considered at high risk because of the associated respiratory muscle weakness and the increased physiologic demands of pregnancy. Consultation with a high-risk maternal-fetal medicine specialist is recommended when possible.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for 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

Hereditary myopathy with early respiratory failure (HMERF) is inherited in an autosomal dominant manner with variable expressivity.

Note: The TTN pathogenic variant, p.Pro30091Leu, is associated with extremely variable expressivity. Individuals heterozygous for p.Pro30091Leu may have mild clinical manifestations or only subclinical manifestations (i.e., muscle abnormality demonstrable on imaging) while individuals homozygous for the variant are reported to have more severe (and earlier onset) disease manifestations [Palmio et al 2014]. For this reason, the terms "semirecessive" and "semidominant" have been proposed to describe the mode of inheritance associated with the p.Pro30091Leu pathogenic variant [Palmio et al 2014, Tasca & Udd 2018].

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with HMERF are heterozygous for a TTN pathogenic variant inherited from an affected parent.
  • To date, de novo pathogenic variants have not been reported in any individuals with genetically confirmed HMERF.
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include germline mosaicism in a parent or a de novo pathogenic variant in the proband. Neither germline mosaicism nor de novo mutation has been reported; therefore, it is unknown whether germline mosaicism or de novo pathogenic variants occur in this disorder.
  • The family history of some individuals diagnosed with HMERF may appear to the negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, a milder phenotype, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluation and/or molecular genetic testing has been performed on the parents of the proband.

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 and/or is known to have the TTN pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Note: The HMERF phenotype may vary among individuals within the same family.
  • If the proband has a known TTN pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
  • If the parents have not been tested for the TTN pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for HMERF because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
  • If both parents are heterozygous for the p.Pro30091Leu TTN pathogenic variant, sibs have a 50% chance of inheriting one pathogenic variant and having mild or subclinical manifestations of HMERF and a 25% chance of inheriting two pathogenic variants and having severe disease manifestations.

Offspring of a proband

Other family members. The risk to other family members depends on the clinical/genetic status of the proband's parents: if a parent is affected or has a pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

  • Predictive testing for at-risk relatives is possible once the TTN pathogenic variant has been identified in an affected family member.
  • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals age <18 years)

  • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
  • For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of HMERF it is appropriate to consider testing of symptomatic individuals regardless of age.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the TTN pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

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. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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.

  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    BP59
    Evry cedex 91002
    France
    Phone: +33 01 69 47 28 28
    Email: dmc@afm.genethon.fr
  • Muscular Dystrophy Association - Canada
    2345 Yonge Street
    Suite 900
    Toronto Ontario M4P 2E5
    Canada
    Phone: 866-687-2538 (toll-free); 416-488-0030
    Fax: 416-488-7523
    Email: info@muscle.ca
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy UK
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
    Email: info@musculardystrophyuk.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.

Hereditary Myopathy with Early Respiratory Failure: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
TTN2q31​.2TitinTTN homepage - Leiden Muscular Dystrophy pagesTTNTTN

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Hereditary Myopathy with Early Respiratory Failure (View All in OMIM)

188840TITIN; TTN
603689MYOPATHY, MYOFIBRILLAR, 9, WITH EARLY RESPIRATORY FAILURE; MFM9

Molecular Pathogenesis

Titin is the molecular scaffold protein that spans half of the sarcomere. Pathogenic variants in different domains of titin can result in different disorders affecting muscle tissue, with combinations of cardiomyopathy, proximal myopathy, distal myopathy, and respiratory failure, the presentation of which can range from congenital to very late onset.

Pathogenic variants causing HMERF are all located within the 119th fibronectin 3 domain of titin (see exon designations below). The function of this domain and disease mechanism of HMERF are unknown. Genetic constructs expressing the FN119 domain with HMERF-associated variants demonstrated reduced solubility compared to normal [Hedberg et al 2014], suggesting that myofibrillar aggregates may cause disease pathogenesis and the myopathologic resemblance to myofibrillar myopathy.

Mechanism of disease causation. The mechanism of disease causation is presumably gain of function, similar to the mechanism causing other myofibrillar myopathies; however, this has not to date been formally studied or proven for HMERF.

TTN-specific laboratory technical considerations. All HMERF-associated pathogenic variants reside in a single TTN exon, which contains non-repetitive sequence.

The FN119 domain exon corresponds to the following:

Table 6.

Notable TTN Pathogenic Variants

Reference SequencesDNA Nucleotide Change (Alias 1)Predicted Protein ChangeComment [Reference]
NM_001256850​.1
NP_001243779​.1 2
c.90211T>C
(g.274375T>C)
p.Cys30071ArgThe most common pathogenic variant assoc w/HMERF; identified in the majority of cases. There appears to have been an ancient founder effect linking families in England, Scandinavia, Europe, & Canada [Ohlsson et al 2012, Pfeffer et al 2012, Palmio et al 2014, Pfeffer et al 2014a, Pfeffer et al 2014b].
c.90272C>T
(g.274436C>T)
p.Pro30091LeuVariant known to be assoc w/either dominant or recessive inheritance, w/highly variable expressivity [Palmio et al 2014, Pfeffer et al 2014a]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

Previously used reference sequences: AJ277892.2, Q8WZ42.4

References

Literature Cited

  • Birchall D, von der Hagen M, Bates D, Bushby KM, Chinnery PF. Subclinical semitendinosus and obturator externus involvement defines an autosomal dominant myopathy with early respiratory failure. Neuromuscul Disord. 2005;15:595–600. [PubMed: 16084088]
  • Chinnery PF, Johnson MA, Walls TJ, Gibson GJ, Fawcett PR, Jamieson S, Fulthorpe JJ, Cullen M, Hudgson P. Bushby KM. A novel autosomal dominant distal myopathy with early respiratory failure: clinico-pathologic characteristics and exclusion of linkage to candidate genetic loci. Ann Neurol. 2001;49:443–52. [PubMed: 11310621]
  • Edström L, Thornell LE, Albo J, Landin S, Samuelsson M. Myopathy with respiratory failure and typical myofibrillar lesions. J Neurol Sci. 1990;96:211–28. [PubMed: 2376753]
  • Gautier G, Verschueren A, Monnier A, Attarian S, Salort-Campana E, Pouget J. ALS with respiratory onset: Clinical features and effects of non-invasive ventilation on the prognosis. Amyotroph Lateral Scler. 2010;11:379–82. [PubMed: 20001486]
  • Hedberg C, Toledo AG, Gustafsson CM, Larson G, Oldfors A, Macao B. Hereditary myopathy with early respiratory failure is associated with misfolding of the titin fibronectin III 119 subdomain. Neuromuscul Disord. 2014;24:373–9. [PubMed: 24636144]
  • Izumi R, Niihori T, Aoki Y, Suzuki N, Kato M, Warita H, Takahashi T, Tateyama M, Nagashima T, Funayama R, Abe K, Nakayama K, Aoki M, Matsubara Y. Exome sequencing identifies a novel TTN mutation in a family with hereditary myopathy with early respiratory failure. J Hum Genet. 2013;58:259–66. [PubMed: 23446887]
  • Jerusalem F, Ludin H, Bischoff A, Hartmann G. Cytoplasmic body neuromyopathy presenting as respiratory failure and weight loss. J Neurol Sci. 1979;41:1–9. [PubMed: 220387]
  • Kinoshita M, Satoyoshi E, Suzuki Y. Atypical myopathy with myofibrillar aggregates. Arch Neurol. 1975;32:417–20. [PubMed: 165803]
  • Norwood FL, Harling C, Chinnery PF, Eagle M, Bushby K, Straub V. Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population. Brain. 2009;132:3175–86. [PMC free article: PMC4038491] [PubMed: 19767415]
  • 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]
  • 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]
  • Palmio J, Leonard-Louis S, Sacconi S, Savarese M, Penttilä S, Semmler AL, Kress W, Mozaffar T, Lai T, Stojkovic T, Berardo A, Reisin R, Attarian S, Urtizberea A, Cobo AM, Maggi L, Kurbatov S, Nikitin S, Milisenda JC, Fatehi F, Raimondi M, Silveira F, Hackman P, Claeys KG, Udd B. Expanding the importance of HMERF titinopathy: new mutations and clinical aspects. J Neurol. 2019;266:680–90. [PMC free article: PMC6394805] [PubMed: 30666435]
  • Pfeffer G, Barresi R, Wilson IJ, Hardy SA, Griffin H, Hudson J, Elliott HR, Ramesh AV, Radunovic A, Winer JB, Vaidya S, Raman A, Busby M, Farrugia ME, Ming A, Everett C, Emsley HC, Horvath R, Straub V, Bushby K, Lochmüller H, Chinnery PF, Sarkozy A. Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure. J Neurol Neurosurg Psychiatry. 2014a;85:331–8. [PMC free article: PMC6558248] [PubMed: 23486992]
  • 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]
  • Pfeffer G, Joseph JT, Innes AM, Frizzell JB, Wilson IJ, Brownell AK, Chinnery PF. Titinopathy in a Canadian family sharing the British founder haplotype. Can J Neurol Sci. 2014b;41:90–4. [PMC free article: PMC6558278] [PubMed: 24384345]
  • Pfeffer G, Povitz M. Respiratory management of patients with neuromuscular disease: current perspectives. Degener Neurol Neuromuscul Dis. 2016;6:111–8. [PMC free article: PMC6053085] [PubMed: 30050373]
  • Poppe M, Bourke J, Eagle M, Frosk P, Wrogemann K, Greenberg C, Muntoni F, Voit T, Straub V, Hilton-Jones D, Shirodaria C, Bushby K. Cardiac and respiratory failure in limb-girdle muscular dystrophy 2I. Ann Neurol. 2004;56:738–41. [PubMed: 15505776]
  • Qureshi AI, Choundry MA, Mohammad Y, Chua HC, Yahia AM, Ulatowski JA, Krendel DA, Leshner RT. Respiratory failure as a first presentation of myasthenia gravis. Med Sci Monit. 2004;10:CR684–9. [PubMed: 15567987]
  • Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
  • Selcen D. Myofibrillar myopathies. Neuromuscul Disord. 2011;21:161–71. [PMC free article: PMC3052736] [PubMed: 21256014]
  • Selcen D, Engel AG. Myofibrillar myopathy caused by novel dominant negative alpha B-crystallin mutations. Ann Neurol. 2003;54:804–10. [PubMed: 14681890]
  • Selcen D, Muntoni F, Burton BK, Pegoraro E, Sewry C, Bite AV, Engel AG. Mutation in BAG3 causes severe dominant childhood muscular dystrophy. Ann Neurol. 2009;65:83–9. [PMC free article: PMC2639628] [PubMed: 19085932]
  • Tanios MA, El Gamal H, Epstein SK, Hassoun PM. Severe respiratory muscle weakness related to long-term colchicine therapy. Respir Care. 2004;49:189–91. [PubMed: 14744269]
  • Tasca G, Udd B. Hereditary myopathy with early respiratory failure (HMERF): Still rare, but common enough. Neuromuscul Disord. 2018;28:268–76. [PubMed: 29361395]
  • Toro C, Olivé M, Dalakas MC, Sivakumar K, Bilbao JM, Tyndel F, Vidal N, Farrero E, Sambuughin N, Goldfarb LG. Exome sequencing identifies titin mutations causing hereditary myopathy with early respiratory failure (HMERF) in families of diverse ethnic origins. BMC Neurol. 2013;13:29. [PMC free article: PMC3610280] [PubMed: 23514108]
  • Uruha A, Hayashi YK, Oya Y, Mori-Yoshimura M, Kanai M, Murata M, Kawamura M, Ogata K, Matsumura T, Suzuki S, Takahashi Y, Kondo T, Kawarabayashi T, Ishii Y, Kokubun N, Yokoi S, Yasuda R, Kira J, Mitsuhashi S, Noguchi S, Nonaka I, Nishino I. Necklace cytoplasmic bodies in hereditary myopathy with early respiratory failure. J Neurol Neurosurg Psychiatry. 2015;86:483–9. [PubMed: 25253871]
  • Walter MC, Reilich P, Huebner A, Fischer D, Schröder R, Vorgerd M, Kress W, Born C, Schoser BG, Krause KH, Klutzny U, Bulst S, Frey JR, Lochmüller H. Scapuloperoneal syndrome type Kaeser and a wide phenotypic spectrum of adult-onset, dominant myopathies are associated with the desmin mutation R350P. Brain. 2007;130:1485–96. [PubMed: 17439987]
  • Yue D, Gao M, Zhu W, Luo S, Xi J, Wang B, Li Y, Cai S, Li J, Wang Y, Lu J, Zhao C. New disease allele and de novo mutation indicate mutational vulnerability of titin exon 343 in hereditary myopathy with early respiratory failure. Neuromuscul Disord. 2015;25:172–6. [PubMed: 25500009]

Chapter Notes

Acknowledgments

GP is an Assistant Professor and clinical neurologist at the University of Calgary and Department of Clinical Neurosciences. He is the recipient of funding from the Canada Foundation for Innovation, and Muscular Dystrophy Canada. PFC is an Honorary Consultant Neurologist at Newcastle upon Tyne Foundation Hospitals NHS Trust, a Wellcome Trust Senior Fellow in Clinical Science (084980/Z/08/Z), and a UK NIHR Senior Investigator.

PFC receives additional support from the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z), the Medical Research Council (UK) Centre for Translational Research in Neuromuscular Diseases, and EU FP7 TIRCON, and the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University.

Revision History

  • 19 March 2020 (ha) Comprehensive update posted live
  • 27 February 2014 (me) Review posted live
  • 5 December 2013 (gp) Original submission
Copyright © 1993-2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2020 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK185330PMID: 24575448

Views

Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...