Clinical characteristics.

Salih myopathy is characterized by muscle weakness (manifesting during the neonatal period or in very 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 of Salih myopathy is established in a proband with corresponding clinical phenotype and biallelic pathogenic truncating variants in exons 359, 360, and 361 of TTN identified by molecular genetic testing.

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. Education regarding correct posture for lying prone and sitting and Garchois brace when needed for scoliosis. Annual influenza vaccine and available immunizations for respiratory illnesses; aggressive treatment for lower respiratory tract infections. Treat heart failure and cardiac arrhythmia as soon as they are evident. Educate parents/caregivers on symptoms of cardiac manifestations; CPR training for parents/caregivers. Cardiac transplantation may be considered for progressive dilated cardiomyopathy and heart failure refractory to medical therapy. Appropriate technical support in educational settings; social work and family support as needed.

Surveillance: Clinical examination and radiographs as needed for orthopedic complications (e.g., foot deformity, joint contractures, spinal deformity). Annual evaluation of respiratory function beginning at age ten years. EKG, 24-hour Holter EKG, and echocardiogram every six months beginning at age five years. Assess family needs at each visit.

Agents/circumstances to avoid: Ibuprofen in those with evidence of cardiomyopathy and congestive heart failure.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from monitoring of motor development and cardiac function so that treatment can be instituted promptly.

Genetic counseling.

Salih myopathy is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TTN truncating variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial TTN pathogenic variants. Once the TTN pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

Salih myopathy should be suspected in individuals with the following clinical, laboratory, electrophysiologic, imaging, and histopathology findings and family history, although none of the following findings is specific for Salih myopathy and the phenotype overlaps with other autosomal recessive congenital titinopathies.

Clinical

• Muscle weakness manifesting during the neonatal period or in very 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 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 (see 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 in individual with Salih myopathy 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 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 (see 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.
• Immunohistochemistry of skeletal muscle shows normal expression of dystrophin, laminin α2 (merosin), integrin α7, α- and β-dystroglycan, desmin, emerin, and the sarcoglycans α, β, γ, and δ.
• Electron microscopy of skeletal muscle (see 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 muscle biopsy in an individual with Salih myopathy shows (A) increased fiber size variability, abundant centrally (more...)

Figure 3.

Longitudinal electron microscopy section of skeletal muscle taken at age ten years in an individual with Salih myopathy reveals focal disruptions of sarcomeric structures (arrows), Z-disk abnormalities including focal loss of dark Z-disk material, and (more...)

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of Salih myopathy is established in a proband with compatible clinical findings and biallelic truncating pathogenic (or likely pathogenic) variants in specific TTN exons (359, 360, and 361) identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic TTN variants of uncertain significance (or of one known TTN pathogenic variant and one TTN variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Salih myopathy is characterized by early-onset muscle weakness, delayed gross motor development, development of moderate joint and neck contractures and spinal rigidity, cardiomyopathy, and heart rhythm disturbances leading to early demise. Cognition is normal.

Muscle weakness manifests during the neonatal period or in very early infancy. Weakness occurs in a limb-girdle distribution with myopathic face and variable degree of ptosis. Gross motor development is delayed. 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. Relative calf muscle hypertrophy occurs. Those who survive childhood remain ambulant, with or without support.

Additional musculoskeletal manifestations. Moderate joint and neck contractures and spinal rigidity may appear in the first decade but become more obvious in the second decade. Scoliosis develops after age 11 years.

Respiratory function tests rarely show a moderate restrictive pattern manifesting in adulthood and is overshadowed by the development of dilated cardiomyopathy, which contributes to the morbidity and mortality.

Cardiac manifestations. Development of dilated cardiomyopathy usually occurs between ages five and 16 years. Left axis deviation (left anterior fascicular block) can be seen as early as age four years on electrocardiogram (EKG; Figure 1). 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.

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.

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.

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.

Cognition. Normal.

Prognosis. Cardiac dysfunction usually progresses rapidly. Heart rhythm disturbances are the major cause of sudden death, and their frequency and severity suggest primary involvement of the conduction system.

Heterozygotes. In contrast to individuals with heterozygous pathogenic variants in TTN associated with hereditary myopathy with early respiratory failure (HMERF) and Udd distal myopathy, heterozygous parents of individuals with Salih myopathy usually remain asymptomatic without muscle disorder (see Figure 4). However, individuals heterozygous for TTN truncating variants with high cardiac PSI are considered at risk for cardiomyopathy. Note: PSI (proportion spliced in) is the proportion of TTN transcripts in which a given exon is spliced into an expressed transcript based on RNA sequencing data from human left ventricular tissue [Tharp et al 2019].

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 exact genotype-phenotype correlations are known. There are individuals with biallelic TTN truncating variants in exons 359, 360, and 361 without a fatal cardiomyopathy.

Nomenclature

Salih myopathy was initially referred to as Salih congenital muscular dystrophy [Salih et al 1998, Subahi 2001].

Although the designation "early-onset titinopathy with fatal cardiomyopathy" is sometimes used synonymously with the designation Salih myopathy, Salih myopathy is one of several titinopathies characterized by early onset and fatal cardiomyopathy.

Prevalence

Salih myopathy is thought to be rare. It was originally described in consanguineous families of Arab descent originating from Sudan and Morocco. Subsequently, the disease has been identified in many populations [Chauveau et al 2014, Salih et al 2021, El Kadiri et al 2022, Salih 2023]. 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 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in pediatric neurology, physical therapy, occupational therapy, orthopedics, cardiology, and pulmonology (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

Avoid ibuprofen (Brufen^®) in affected individuals with congestive heart failure and those with evidence of cardiomyopathy. An individual who had reduced left ventricular ejection fraction developed edema following its administration [SA Subahi & MA Salih, unpublished observation].

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from monitoring of 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, as 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 caused by biallelic truncating pathogenic variants in specific TTN exons (359, 360, and 361) and inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a TTN truncating variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a TTN pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• The heterozygous parents of individuals with Salih myopathy are usually asymptomatic without muscle disorder; however, individuals heterozygous for a TTN truncating variant who have high cardiac PSI are at risk for cardiomyopathy (see Clinical Description, Heterozygotes).

Sibs of a proband

• If both parents are known to be heterozygous for a TTN truncating variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial TTN pathogenic variants.
• The heterozygous sibs of an individual with Salih myopathy are usually asymptomatic without muscle disorder; however, individuals heterozygous for a TTN truncating variant who have high cardiac PSI are at risk for cardiomyopathy (see Clinical Description, Heterozygotes).

Offspring of a proband. The offspring of an individual with Salih myopathy are obligate heterozygotes for a TTN truncating variant.

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

Heterozygote Detection

Heterozygote 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 sibs for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk 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 heterozygous or are at risk of being heterozygous.
• It is appropriate to offer TTN molecular genetic testing for reproductive partners of individuals known to be heterozygous for a TTN pathogenic variant, particularly if consanguinity is likely.

Prenatal and Preimplantation Genetic Testing

Once the causative TTN truncating variants have been identified in an affected family member, prenatal and preimplantation genetic testing for Salih myopathy are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

TTN encodes titin, the biggest single polypeptide in humans, found in numerous isoforms of varying size. 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.

To date, biallelic pathogenic variants reported to cause Salih myopathy are small frameshift deletions in TTN exons 359, 360, and 361 [Carmignac et al 2007]. The predicted truncated titin proteins resulting from these frameshift variants are incorporated into ultrastructurally normal sarcomeres [Carmignac et al 2007].

Mechanism of disease causation. Loss of function

TTN-specific laboratory technical considerations. 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].

TTN variants should be annotated using the sequence LRG_391, covering TTN transcript variant IC (NM_001267550.1), and the corresponding exon numbering (as also adopted by the Leiden Open Variant Database and by CardioDB).

Acknowledgments

The authors would like to thank Ana Ferreiro, MD, PhD, Virginie Carmignac, PhD, and Saad Subahi, MD, who have contributed to the understanding of this disorder. Thanks are also due to Loida M Sese for secretarial work, and Sayed Taha and Vir Salvador for medical illustration.

Author History

Virginie Carmignac, PhD (2012-2025)
Maria Francesca Di Feo, MD (2025-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

• 3 April 2025 (sw) Comprehensive update posted live
• 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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