Hereditary Myopathy With Early Respiratory Failure
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 courseNote: 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):
- NM_001256850.1: exon 285
- NM_133378.4: exon 284
- NM_001267550.2: exon 335
* 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 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| TTN | Sequence analysis 3 | 100% 4 |
| Gene-targeted deletion/duplication analysis 5 | None reported 4 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 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:
- Myopathy with respiratory failure and myofibrillar aggregates [Kinoshita et al 1975, Edström et al 1990];
- Hereditary cytoplasmic body myopathy with early respiratory failure [Jerusalem et al 1979];
- Hereditary inclusion body myopathy with early respiratory failure [Chinnery et al 2001].
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
| Disorder | Gene(s) | MOI | Clinical Features of Differential Disorder | |
|---|---|---|---|---|
| Overlapping w/HMERF | Distinguishing from HMERF | |||
| Amyotrophic lateral sclerosis | >30 genes 1 | AD AR XL | Presents w/respiratory failure in ~3% of cases 2 |
|
| Facioscapulohumeral muscular dystrophy (FSHD) | DNMT3B SMCHD1 3 | AD |
|
|
| Late-onset Pompe disease (late-onset glycogen storage disease type II) | GAA | AR |
|
|
| Limb-girdle muscular dystrophy type 2 (LGMD2; OMIM PS253600) | ~29 genes 4 | AR |
| 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 |
| Some pathology findings may be specific to HMERF (necklace inclusions, cheetah-skin aggregates). |
| Myotonic dystrophy type 1 (DM1) | DMPK 8 | AD |
|
|
| Oculopharyn-godistal myopathy 1 (OMIM 164310) | LRP12 | AD AR | Early diaphragmatic weakness while still ambulant | Ocular, facial, & pharyngeal weakness |
| Myasthenia gravis | N/A | N/A | May present w/respiratory failure & skeletal muscle weakness 9 |
|
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.
Gautier et al [2010]
- 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.
Poppe et al [2004]
- 6.
Pfeffer et al [2014a]
- 7.
Selcen & Engel [2003], Walter et al [2007], Selcen et al [2009]
- 8.
DM1 is caused by expansion of a CTG trinucleotide repeat in the noncoding region of DMPK.
- 9.
Qureshi et al [2004]
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/Concern | Evaluation | Comment |
|---|---|---|
| Neuromuscular | Neuromuscular assessment by neurologist w/expertise in inherited muscle disorders | |
| PT | Assess lower limb function & general mobility. | |
| OT | Assess for need for home &/or office adaptations & mobility aids. | |
| Respiratory | Assess pulmonary function & need for nocturnal ventilator support | |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor | To incl genetic counseling |
| Social services consultation | Assist 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/Concern | Treatment | Considerations/Other |
|---|---|---|
| Distal leg weakness | Ankle-foot orthoses | To optimize independent ambulation |
| Other mobility aids such as canes, walkers, or wheelchairs | May be required later in disease course | |
| Inactivity | Exercises & activities suggested by PT consultation | To prevent continued loss of physical function |
| Nocturnal hypoventilation | Noninvasive ventilation w/BiPAP or CPAP | |
| Respiratory failure | Mechanical ventilatory support as needed | |
| ↑ susceptibility to respiratory tract infections | Influenza vaccination | |
| Gradually progressive nature of this disease | OT & 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/Concern | Evaluation | Frequency |
|---|---|---|
| Neuromuscular | Reassessment of muscle strength & clinical status w/a neurologist who can coordinate any additional required services | Annually |
| Respiratory | Pulmonary function testing | Every 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.