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Hereditary Myopathy with Early Respiratory Failure

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

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

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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. The disease course 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 suspected based on clinical findings, usually mildly elevated serum creatine kinase (CK), and a typical (but not specific) pattern of fatty infiltration of the semitendinosus muscle and anterior compartment muscles of the lower leg noted on MRI. The diagnosis is established by the presence of a pathogenic variant in the region of TTN that encodes the 119th fibronectin-3 domain of titin.

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. Occupational therapy and social service support are important.

Surveillance: Pulmonary function testing at intervals of six to 12 months, or guided by patient findings; reassessment of muscle strength and clinical status annually by a neurologist.

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. Most individuals diagnosed with HMERF have an affected parent; however, the proportion of cases caused by a de novo pathogenic variant is unknown. 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, prenatal testing for pregnancies at increased risk is possible.

Diagnosis

Suggestive Findings

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

  • 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.
  • Evidence of respiratory muscle weakness early in the disease course. 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

On physical examination:

  • Muscle weakness is generally most pronounced on testing of ankle dorsiflexion. In general the lower extremities are weaker than the upper extremities.
  • 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.
  • Contractures in the tibialis anterior and/or at the elbow have been reported [Pfeffer et al 2014a].
  • Spinal rigidity and nasal speech have been reported on occasion [Tasca et al 2010, Pfeffer et al 2014a].
  • Respiratory muscle weakness is difficult to identify on physical examination but may be suggested if patients become dyspneic when supine or if axial muscle weakness (e.g., neck flexor or abdominal muscle weakness) is present. In individuals who do not have respiratory symptoms, pulmonary function testing can identify respiratory muscle weakness, which is manifest as a restrictive defect (decreased vital capacity with no evidence of obstruction) and a decrease of vital capacity by 20% or more in the supine position compared with standing.

Of note, the phenotype is variable: affected individuals have presented with predominantly distal weakness, or proximal weakness, or respiratory muscle weakness alone, or combinations of the three [Pfeffer et al 2012].

Investigations should include serum creatine kinase (CK) which is usually mildly elevated and ranges from normal up to 1000 units/L.

Of note, the following additional investigations (including muscle MRI findings and muscle pathology) can help support the diagnosis.

MRI of the leg muscles may reveal a typical (but not specific) pattern of fatty infiltration invariably involving the semitendinosus muscle and anterior compartment muscles of the lower leg. This MRI finding is also reported in other muscle diseases including other myofibrillar myopathies [Wattjes et al 2010] (see Differential Diagnosis).

Muscle biopsy can identify supportive findings in many affected individuals; however, the findings are usually nonspecific, probably relating to sampling and the focal nature of pathologic changes.

  • Supportive histopathologic findings include:
    • Multiple eosinophilic cytoplasmic inclusions within a small percentage of muscle fibers that do not stain with SDH or NADH assays but do stain avidly with trichrome assays [Pfeffer et al 2012];
    • Blue-rimmed vacuoles within muscle fibers;
    • Increased fiber size variability (≤20-fold).
  • Immunohistochemical assays reveal abnormal accumulations of myofibrillar byproducts, such as for myotilin, desmin, p62, and VCP [Pfeffer et al 2014a].
  • Ultrastructural examination reveals Z-disc streaming and electron-dense fibrillar inclusions [Edström et al 1990, Ohlsson et al 2012].

Establishing the Diagnosis

The diagnosis of HMERF is established in a proband with the following [Ohlsson et al 2012, Pfeffer et al 2012, Izumi et al 2013, Palmio et al 2014, Toro et al 2013, Pfeffer et al 2014a, Pfeffer et al 2014c]:

See Table 1.

Table 1.

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

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
TTNSequence analysis 2 of the TTN region encoding the 119th fibronectin 3 domain100% 3
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.

2.

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.

3.

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].

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.

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

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

Presumably life expectancy is decreased in this disorder, but because of the rarity of the condition, studies have not formally addressed this question.

Genotype-Phenotype Correlations

No relationship between the pathogenic variant and phenotype is evident, except for the p.Pro30091Leu variant which appears to behave differently from the other pathogenic variants:

The most common pathogenic variant, p.Cys30071Arg, is associated with a highly variable phenotype.

The factors mediating phenotypic variability are unknown.

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 71years); 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 [Palmio et al 2014, Pfeffer et al 2014a] with more severe disease manifestations when the variant is present in the homozygous state [Palmio et al 2014].

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], data are insufficient to draw conclusions regarding their penetrance; however, preliminary 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 the very 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 per 100,000 [Norwood et al 2009].

Differential Diagnosis

Late-onset glycogen storage disease type II (GSD II) is characterized by proximal muscle weakness and respiratory insufficiency. Inheritance is autosomal recessive. The diagnosis is confirmed by partial deficiency of the enzyme acid alpha-glucosidase (GAA) (activity 2%-40% of normal controls) and/or presence of biallelic pathogenic variants in GAA. Late-onset GSDII is differentiated from HMERF by its inheritance pattern, pathologic findings, muscle MRI abnormalities, results of GAA enzyme assay, and molecular genetic test results.

Myofibrillar myopathy (MFM) is characterized by slowly progressive weakness that can involve both proximal and distal muscles. Distal muscle weakness is present in about 80% of individuals. Respiratory muscle weakness can occur particularly in disease caused by mutation of DES (encoding desmin), CRYAB (encoding α B crystalline), and BAG3 (encoding BAG family molecular chaperone regulator 3) [Selcen & Engel 2003, Walter et al 2007, Selcen et al 2009].

MFM is most commonly inherited in an autosomal dominant manner. The diagnosis of MFM is based on clinical findings, electromyography (EMG), nerve conduction studies, and, most importantly, muscle histology. MFM has significant overlap in clinical, MRI and pathologic features with HMERF, and some individuals with HMERF meet diagnostic criteria for MFM on muscle biopsy [Pfeffer et al 2014a]. MFM is distinguished from HMERF on the basis of molecular genetic test results.

Limb-girdle muscular dystrophy (LGMD) is characterized by weakness and wasting restricted to the limb musculature (proximal greater than distal) and muscle degeneration/regeneration on muscle biopsy. Some subtypes of LGMD are known to affect the respiratory muscles early in the disease course, namely LGMD2I (caused by mutation of FKRP) [Poppe et al 2004] and the sarcogylcanopathies (LGMD2C-LGMD2F) [Politano et al 2001].

  • LGMD2I is distinguished from HMERF by its autosomal recessive inheritance and presence of degenerating/regenerating muscle fibers on muscle biopsy. Molecular genetic testing is diagnostic.
  • The sarcoglycanopathies also are inherited in an autosomal recessive manner, and have childhood onset that can resemble Duchenne muscular dystrophy. Molecular genetic testing and muscle biopsy are used to establish the diagnosis.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscle disease which typically presents with weakness of facial and proximal arm muscles, and particularly the shoulder and hip girdle. Disease severity is highly variable. FSHD is differentiated from HMERF by the absence of early respiratory failure, and the presence of facial weakness. The most common genetic lesion in FSHD is a contraction of the D4Z4 allele.

Myotonic dystrophy type 1 is a highly variable autosomal dominant muscle disease that may present with distal muscle weakness and respiratory muscle involvement. However, this disorder is differentiated from HMERF by the distribution of muscle weakness, which usually includes facial or eyelid muscles. The variable multisystem features of this disease (which include myotonia, cataracts, cognitive deficits, cardiac arrhythmia, endocrine dysfunction, and gastrointestinal dysfunction) also differentiate it from HMERF. Noncoding trinucleotide expansions of DMPK are diagnostic.

Amyotrophic lateral sclerosis presents with respiratory failure in about 3% of cases [Gautier et al 2010]. It is differentiated from HMERF by the presence of combined upper and lower motor neuron signs, early atrophy of the hand muscles, and characteristic neurophysiologic abnormalities.

Myasthenia gravis may present with respiratory failure with skeletal muscle weakness [Qureshi et al 2004]. It is differentiated from HMERF by the findings of fatiguability; bulbar muscles are often affected. Electrodecremental response is demonstrated on nerve conduction studies, and jittery motor unit potentials on single fiber electromyography. Most affected individuals are seropositive for AchR or MuSK antibodies.

Other similar clinical presentations may occur atypically with other disorders and may be considered on a case by case basis. The patient 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 which 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 following evaluations are recommended:

  • Neuromuscular neurology consultation, ideally at a center with expertise in inherited muscle disease to coordinate specialized testing
  • Respiratory medicine consultation to assess pulmonary function and coordinate nocturnal ventilator support if required
  • Physiotherapy consultation to assess lower limb function and general mobility
  • Occupational therapy consultation to recommend home and/or office adaptations and mobility aids
  • Social services consultation to assist with workplace adaptations and/or access to social/disability benefits
  • Clinical genetics consultation to help coordinate genetic investigations and provide genetic counseling consultation

Treatment of Manifestations

At present no disease-modifying therapy exists. Management is supportive.

For distal leg weakness, use of ankle-foot orthoses can optimize independent ambulation. Later in the disease course other mobility aids such as canes, walkers, or wheelchairs may be required.

Exercises and activities suggested by physiotherapy consultation may be helpful to prevent continued loss of physical function due to inactivity.

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.

Patients have increased susceptibility to respiratory tract infections and, therefore, influenza vaccination should be prioritized.

Given the gradually progressive nature of this disease, occupational therapy and social services support are important.

Surveillance

The following are appropriate:

  • Pulmonary function testing at intervals of 6-12 months, or guided by patient findings
  • Reassessment of muscle strength and clinical status annually with a neurologist who can coordinate any additional required services

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 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.

From the point of view of the fetus the authors are unaware of any specific issues relating to HMERF, since this is an adult-onset disorder.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe 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

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

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with HMERF have an affected parent. However, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
  • The proportion of cases caused by de novo pathogenic variants is unknown; to date de novo pathogenic variants have not been reported in any individuals with genetically confirmed HMERF.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are 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 mutation occurs in this disorder.
  • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotype. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for HMERF because of the existence of two possibilities:
    • Reduced penetrance in a parent, or
    • Delayed onset of clinical manifestations in a parent
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte 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.

Offspring of a proband. Each child of an individual with HMERF has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the 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. Testing for a familial pathogenic variant in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of HMERF, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow up and evaluations.

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 or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the TTN pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis 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 (HMERF): 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 (HMERF) (View All in OMIM)

188840TITIN; TTN
603689HEREDITARY MYOPATHY WITH EARLY RESPIRATORY FAILURE; HMERF

Molecular Genetic Pathogenesis

The molecular pathogenesis is not fully understood; however, based on the muscle pathology changes, it is likely that pathogenic variants lead to abnormal aggregation of myofibrillar material, as in the other myofibrillar myopathies.

Gene structure. The gene has various reference sequences, although in the most commonly used reference sequence (AJ277892.2) the inferred complete gene is 294,540 base pairs, encoding 363 exons, which are subject to massive alternative splicing. For a detailed summary of gene and protein information, see Table A, Gene.

Variants of uncertain significance. Originally, HMERF was associated with the TTN variant p.Arg32450Trp in the region encoding the kinase domain of titin [Lange et al 2005]. This variant has been reclassified as a polymorphism found in healthy controls, and as such is a variant of uncertain significance (rs140319117). Relatives of the original families reported by Lange et al [2005] also had a variant g.274436C>T (p.Pro30091Leu) in the region encoding the 119th fibronectin-3 domain of titin, which is known to cause HMERF on its own [Hedberg et al 2014]. Screening studies searching for kinase domain variants in persons with HMERF have not identified any further individuals with kinase domain variants [Pfeffer et al 2014b, Toro et al 2013, Pfeffer et al 2014a]. It remains possible that the kinase domain variant could have a modifier effect on the phenotype, given that functional studies suggest that this mutant disturbs binding of nbr1 [Lange et al 2005]; future studies are needed to address this question. However, until further evidence is presented it should be assumed that all cases of HMERF are caused by pathogenic variants in the 119th fibronectin-3 domain of TTN.

Pathogenic variants. To date only missense variants have been associated with HMERF.

Table 2.

TTN Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide ChangePredicted Protein ChangeReference Sequences
Uncertain significanceg.294540C>T (rs140319117)p.Arg32450TrpAJ277892​.2
Q8WZ42​.4
Pathogenicg.274367C>Gp.Pro30068Arg
g.274375T>Cp.Cys30071Arg
g.274426T>Cp.Trp30088Arg
g.274427G>Tp.Trp30088Leu
g.274428G>Cp.Trp30088Cys
g.274436C>Tp.Pro30091Leu
g.274599C>Gp.Asn30145Lys
g.274613G>Ap.Gly30150Asp

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

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

Normal gene product. Titin is a giant sarcomeric protein that spans from the Z-disc to the M-line. It is massively alternatively spliced and its inferred complete sequence is 34,350 amino acids (Uniprot Q8WZ42). The domain which is mutated in HMERF is the 119th fibronectin-3 domain and is at amino acid residues 30,068-30,159. Titin has a total of 132 fibronectin type III domains.

Abnormal gene product. The mechanism by which dominant pathogenic variants in this particular domain of TTN cause late-onset disease affecting predominantly respiratory and lower-limb muscles is unknown.

References

Literature Cited

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Chapter Notes

Author Notes

Gerald Pfeffer is a clinical neurologist with a research interest in hereditary neuromuscular disorders. He is currently a PhD candidate in genetics at the Institute of Genetic Medicine in Newcastle, UK.

Patrick F Chinnery is a Consultant Neurologist at Newcastle upon Tyne Hospitals NHS Foundation Trust, and Professor of Neurogenetics at Newcastle University, where he is Director of the Institute of Genetic Medicine.

Acknowledgments

GP is the recipient of a Bisby Fellowship from the Canadian Institutes of Health Research. 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

  • 27 February 2014 (me) Review posted live
  • 5 December 2013 (gp) Original submission
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