Salih Myopathy

Clinical characteristics.

Salih myopathy is characterized by muscle weakness (manifest during the neonatal period or in early infancy) and delayed motor development; children acquire independent walking between ages 20 months and four years. In the first decade of life, global motor performance is stable or tends to improve. Moderate joint and neck contractures and spinal rigidity may manifest in the first decade but become more obvious in the second decade. Scoliosis develops after age 11 years. Cardiac dysfunction manifests between ages five and 16 years, progresses rapidly, and leads to death between ages eight and 20 years, usually from heart rhythm disturbances.

Diagnosis/testing.

The diagnosis is established in a proband by identification of biallelic pathogenic variants in the first three M-line-encoding exons (Mex1, Mex2, and Mex3) of TTN, the only gene in which pathogenic variants are known to cause Salih myopathy.

Management.

Treatment of manifestations: Care, best provided by a multidisciplinary team, includes stretching exercises and physical therapy; assistive mechanical devices for sitting and ambulation as needed; and appropriate technical support in educational settings. Treat heart failure and cardiac arrhythmia as soon as they are evident. Cardiac transplantation may be considered for progressive dilated cardiomyopathy and heart failure refractory to medical therapy.

Prevention of secondary complications: Annual influenza vaccine and other respiratory infection-related immunizations are advised. Aggressive treatment of lower-respiratory tract infections.

Surveillance: Electrocardiogram (EKG), 24-hour Holter EKG, and echocardiogram every six months beginning at age five years. Annual evaluation of respiratory function beginning at age 10 years. Clinical examination and x-ray as needed for orthopedic complications (e.g., foot deformity, joint contractures, spinal deformity).

Agents/circumstances to avoid: Ibuprofen in those with congestive heart failure.

Genetic counseling.

Salih myopathy is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant) and are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variants in the family have been identified.

Suggestive Findings

Salih myopathy should be suspected in individuals with the following clinical, laboratory, electrophysiologic, imaging, and histopathology findings.

Clinical

• Muscle weakness manifesting during the neonatal period or in early infancy
• Delayed motor milestones but normal cognitive development
• Muscle weakness of limb-girdle distribution, myopathic face, variable degree of ptosis, and relative calf muscle hypertrophy
• Development of dilated cardiomyopathy between ages five and 16 years
• Major heart rhythm disturbances leading to sudden death before age 20 years

Laboratory. Serum creatine kinase (CK) is marginally to moderately increased (1.5-7x normal).

Electrophysiologic

• Electrocardiography. Left axis deviation (left anterior fascicular block) can be seen as early as age four years (Figure 1). With the onset of dilated cardiomyopathy, rhythm disturbances can include polymorphic premature ventricular complexes, bigeminism and trigeminism, couplets, triplets, atrioventricular heart block, atrioventricular nodal reentrant tachycardia, premature atrial complexes, premature ventricular complexes, and ventricular tachycardia.
• Electromyography shows myopathic features (low-amplitude polyphasic potentials of short duration).
• Nerve conduction studies are normal.

Figure 1.

Electrocardiogram at age four years showing left axis deviation (left anterior fascicular block)

Echocardiogram reveals, at the onset of cardiomyopathy, reduced function of the left ventricle and dilatation and global hypokinesia without wall hypertrophy. Later, dilatation involves the left atrium and ventricle, subsequently affecting all chambers.

Skeletal muscle biopsy. The following findings help distinguish Salih myopathy from congenital muscular dystrophy (CMD) and other congenital myopathies. Muscle biopsy sections should be examined for histology, histochemistry, immunohistochemistry, and electron microscopy:

• Histology of skeletal muscle reveals a pattern compatible with congenital myopathy (Figure 2): mild variation in fiber size, abundant centrally located nuclei, no increase in connective tissue before age six years, and mild endomysial fibrosis after age six years.
  Oxidative stains reveal multiple small lesions of reduced or absent oxidative activity with poorly defined boundaries.
  Myofibrillar ATpase staining shows remarkable type 1 fiber predominance (>90%). In one individual, massive muscle fiber loss was seen in a second biopsy taken at age ten years [Carmignac et al 2007].
• Immunohistochemistry of skeletal muscle shows normal expression of dystrophin, laminin α2 chain (merosin), integrin α7, α- and β-dystroglycan, desmin, emerin, and the sarcoglycans α (adhalin), β, γ, and δ.
• Electron microscopy of skeletal muscle (Figure 3) highlights the "minicore-like" lesions seen on histology and reveals multiple foci of sarcomere disruption and mitochondria depletion.

Figure 2.

Skeletal muscle histology of two children with Salih myopathy taken at age four years (A and D) and 14 years (B and C). A and D. The early biopsy shows (A) increased fiber size variability, abundant centrally located nuclei (CNLs) but no endomyseal fibrosis (more...)

Figure 3.

Longitudinal electron microscopy section of skeletal muscle taken at age ten years reveals focal disruptions of sarcomeric structures (arrows), Z-disk abnormalities including focal loss of dark Z-disk material, and early dissolution of I-band filaments (more...)

Establishing the Diagnosis

The diagnosis of Salih myopathy is established in a proband by identification of biallelic pathogenic variants in M-line-encoding exons Mex1, Mex2, and Mex3* of TTN on molecular genetic testing (see Table 1).

*Note: The last six exons of TTN (359 to 364 in the LRG [NG_011618.3] numbering that numbers the exons sequentially along the chromosome; C-terminal domain) encode the part of titin that spans the sarcomere M-line; these exons are called Mex1-Mex6 for "M-line-encoding exons 1 through 6." For mapping of these exons to other transcripts, see Molecular Genetics.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, 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 Salih myopathy 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 a phenotype indistinguishable from many other inherited disorders with myopathy and/or cardiomyopathy are more likely to be diagnosed using genomic testing (see Option 2).

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by myopathy, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; 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 Salih Myopathy

Clinical Description

Salih myopathy is characterized by muscle weakness manifest during the neonatal period or in early infancy, and delayed motor development. Children acquire independent walking between ages 20 months and four years. In the first decade of life, global motor performance is stable or tends to improve. During this period skeletal muscle involvement mainly manifests as difficulty in running, climbing stairs, and rising from a sitting position. Those who survive childhood remain ambulant, with or without support, and maintain normal cognitive function.

Musculoskeletal. Moderate joint and neck contractures and spinal rigidity may appear in the first decade but become more obvious in the second decade. Respiratory function tests show a moderate restrictive pattern. Scoliosis develops after age 11 years.

Cardiac dysfunction manifests between ages five and 16 years and progresses rapidly, leading to death between ages eight and 20 years. Heart rhythm disturbances are the major cause of sudden death and their frequency and severity suggest primary involvement of the conduction system.

Electrocardiography (EKG) is very helpful in signaling the occurrence of cardiac involvement. Left axis deviation (left anterior fascicular block) can be seen as early as age four years (Figure 1). With the onset of dilated cardiomyopathy (between ages 5 and 16 years), major rhythm disturbances become evident on EKG and Holter monitoring, including polymorphic premature ventricular complexes, bigeminism and trigeminism, couplets, triplets, atrioventricular heart block, atrioventricular nodal reentrant tachycardia, premature atrial complexes, premature ventricular complexes, and ventricular tachycardia.

Echocardiogram reveals, at the onset of cardiomyopathy, reduced function of the left ventricle and dilatation and global hypokinesia without wall hypertrophy. Later, dilatation involves the left atrium and ventricle, subsequently affecting all chambers and leading to congestive heart failure.

Radionuclide angiography using MUGA (multi-gated acquisition) scan reveals the deteriorating ventricular function with reduction of the left ventricular ejection fraction followed by reduction of the right ventricle ejection fraction.

Heart muscle biopsies (taken from 2 individuals) showed increased interstitial fibrosis compatible with dilated cardiomyopathy [Carmignac et al 2007]. Oxidative staining was normal without focal oxidative defects or significant disarray of the cardiomyocyte structure, in contrast to the classic observation in hypertrophic cardiomyopathy.

Heterozygotes. In contrast to individuals with heterozygous pathogenic variants in TTN associated with Udd distal myopathy, the heterozygous parents of individuals with Salih myopathy remain asymptomatic with no cardiac or muscle disorder (Figure 4).

Figure 4.

Mid-calf muscle MRI of parents of a proband at age (A) 55 years and (B) 44 years were normal and showed no fatty degeneration of the anterior tibial muscles.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known.

Nomenclature

Salih myopathy was initially referred to as Salih congenital muscular dystrophy [Salih et al 1998, Subahi 2001]. Subsequently, it was renamed Salih myopathy [Fukuzawa et al 2008, Pernigo et al 2010].

Prevalence

Salih myopathy is thought to be rare. It has been described in consanguineous families of Arab descent originating from Sudan and Morocco. The actual prevalence is unknown.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Salih myopathy, 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 of Salih Myopathy

Treatment of Manifestations

Treatment involves prompt management of disease manifestations using a multidisciplinary approach that includes specialists in pediatric neurology, physiotherapy, occupational therapy, orthopedics, cardiology, and pulmonology.

Stretching exercises and physical therapy help prevent contractures and promote mobility. Assistive mechanical devices including orthotics, canes, and walkers can be used as needed.

Individuals with Salih myopathy have normal cognition: technical support should be provided in the school environment. Stimulation and emotional support can improve school performance and sense of social involvement.

Parents and/or caregivers should be made aware of the symptoms of heart failure, arrhythmia (including presyncope and syncope), and thromboembolic disease, and of the need to urgently seek medical care when any of these symptoms appear.

Training of caregivers in cardiopulmonary resuscitation may be suggested once the symptoms of cardiomyopathy start.

Adequate posture should be maintained when lying prone and sitting. Garchois brace (made of plexidur, a rigid but light and heat-deformable material) is used to reduce the degree of deformity and slow the progression of scoliosis [Wang et al 2010].

Cardiac transplantation should be considered for progressive dilated cardiomyopathy and heart failure refractory to medical therapy.

Prevention of Secondary Complications

Annual influenza vaccine and other respiratory infection-related immunizations are advised.

Lower respiratory tract infections should be treated aggressively when they occur.

Surveillance

Table 4.

Recommended Surveillance for Individuals with Salih Myopathy

Agents/Circumstances to Avoid

Ibuprofen (Brufen^®):

• Give with care in those with evidence of cardiomyopathy. A patient who had reduced left ventricular ejection fraction developed edema following its administration [Subahi & Salih, unpublished observation].
• Avoid in those with congestive heart failure.

Evaluation of Relatives at Risk

Early diagnosis of at-risk sibs by clinical examination and/or molecular genetic testing is important in order to monitor motor development and cardiac function so that treatment can be instituted promptly.

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

Pregnancy Management

If a fetus is diagnosed prenatally with Salih myopathy, special considerations are needed at and following delivery since muscle weakness may manifest during the neonatal period.

Therapies Under Investigation

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

Mode of Inheritance

Salih myopathy is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers) of one Salih myopathy-related TTN pathogenic variant.
• Heterozygotes (carriers) are asymptomatic. Note: In contrast to individuals with heterozygous pathogenic variants in TTN associated with Udd distal myopathy, the parents of individuals with Salih myopathy remain asymptomatic with no cardiac or muscle disorder (Figure 4).

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Individuals with Salih myopathy are not known to have reproduced.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a TTN pathogenic variant.

Carrier Detection

Carrier testing for at-risk family members requires prior identification of the TTN pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic 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 carriers or are at risk of being carriers.

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 for Salih myopathy are possible.

Molecular Pathogenesis

To date, biallelic pathogenic variants reported to cause Salih myopathy are small frameshift deletions in TTN exons Mex1 and Mex3 in consanguineous families of Moroccan and Sudanese origin [Carmignac et al 2007]. Carriers of these frameshift variants (i.e., heterozygotes) are asymptomatic, presumably as a result of nonsense-mediated decay (NMD) of the mutated mRNA. Since homozygotes survive, the NMD cannot be complete. Some titin protein that lacks the last C-terminal domains is produced. Whether the total decrease of titin protein or the loss of C terminus is more important for the phenotype is not known.

Gene structure. The longest TTN transcript, NM_001267550.1, has 363 exons with a coding capacity of 113,414 bp. TTN has a large number of alternative splicing variants, which can result in confusion in exon and nucleotide numbering in the literature [Bang et al 2001, Guo et al 2010, Savarese et al 2018b]. Transcript variant (N2A) NM_133378.4 is a long transcript with 312 exons that encodes the isoform N2A, the predominant titin isoform in skeletal muscle. For a detailed summary of gene and protein information, see Table A, Gene.

The Mex1 – Mex6 domain exons correspond to the following exons:

• LRG_391 (NG_011618.3): exons 359-364
• NM_133378.4: exons 307-312
• NM_001267550.1: exons 358-363
• NM_001256850.1: exons 307-312

Pathogenic variants. To date, the biallelic variants reported to cause Salih myopathy are small frameshift deletions in TTN exons Mex1 and Mex3 in two consanguineous families of Moroccan and Sudanese origin [Carmignac et al 2007] (Table 2).

Table 5.

Selected TTN Pathogenic Variants

Normal gene product. Titin is the biggest single polypeptide in humans, found in numerous isoforms of varying size. The entire coding region predicts a protein of 38,138 amino acids (4,200 kd). Titin is expressed as several different isoforms, caused by alternative splicing, in different skeletal muscles and in cardiac muscle [Bang et al 2001, Guo et al 2010].

Titin functions as a template in sarcomere assembly and for maintenance of sarcomere integrity. The titin protein is the third myofilament in the sarcomere along with myosin and actin filaments. Titin spans more than one half the length of a sarcomere in heart and skeletal muscle. Structurally different parts of the protein perform distinct functions (mechanical, developmental, and regulatory) [Carmignac et al 2007]. Titin binds and interacts with a large number of other sarcomeric proteins.

Abnormal gene product. The predicted truncated titin proteins resulting from the frameshift variants in Mex1, Mex2, and Mex3 are incorporated into ultrastructurally normal sarcomeres in homozygous affected individuals [Carmignac et al 2007]. Therefore, absence of the last five (Mex2-Mex6) exons is compatible with life but causes this severe congenital disorder. Asymptomatic heterozygous carriers of these titin deletions presumably have sufficient full-length titin to result in normal sarcomere function.

Acknowledgments

The authors would like to thank Loida M Sese for secretarial work, and Sayed Taha and Vir Salvador for medical illustration.

Author History

Virginie Carmignac, PhD (2012-present)
Peter Hackman, PhD (2012-present)
Mustafa Salih, MB BS, MPCH, MD, Dr Med Sci, FRCPCH, FAAN (2012-present)
Marco Savarese, PhD (2019-present)
Tiina Suominen, MSc; University of Helsinki (2012-2019)
Bjarne Udd, MD, PhD (2012-present)

Revision History

• 11 April 2019 (sw) Comprehensive update posted live
• 12 January 2012 (me) Review posted live
• 28 October 2011 (mas) Original submission

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