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Salih Myopathy

Synonym: Early-Onset Myopathy with Fatal Cardiomyopathy

, PhD, , MSc, , PhD, , MD, PhD, and , MB BS, MPCH, MD, Dr Med Sci, FRCPCH.

Author Information
, PhD
Equipe Génétique des Anomalies du Développement
IFR Santé-STIC
Université de Bourgogne
Dijon, France
, MSc
Tampere Neuromuscular Research Unit
The Folkhälsan Institute of Genetics and the Department of Medical Genetics
Haartman Institute
University of Helsinki
Helsinki, Finland
, PhD
The Folkhälsan Institute of Genetics and the Department of Medical Genetics
Haartman Institute
University of Helsinki
Helsinki, Finland
, MD, PhD
Tampere Neuromuscular Research Unit
The Folkhälsan Institute of Genetics and the Department of Medical Genetics
Haartman Institute
University of Helsinki
Helsinki, Finland
, MB BS, MPCH, MD, Dr Med Sci, FRCPCH
Division of Pediatric Neurology
College of Medicine
King Saud University
Riyadh, Saudi Arabia

Initial Posting: .

Summary

Disease 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 age 20 months and four years. In the first decade of life, global motor performances are stable or tend to improve. Moderate joint and neck contractures and spinal rigidity may start in the first decade but become more obvious in the second decade. Scoliosis develops after age 11 years. Cardiac dysfunction starts 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. Diagnosis is based on clinical findings, marginally to moderately increased serum creatine kinase levels, characteristic skeletal muscle histology, and biallelic small frameshift deletions in the exons Mex1 and Mex3 of TTN, the only gene in which mutations 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 aid 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: Every six months from age five years: cardiac function and rhythm. Annually: respiratory function. As needed: orthopedic complications (foot deformity, joint contractures, and spinal deformity) by clinical examination and x-ray as needed.

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 mutant allele) 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 diagnosis for pregnancies at increased risk are possible if the disease-causing mutations in the family have been identified.

Diagnosis

Clinical Diagnosis

Salih myopathy is characterized clinically by the following:

  • 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

Testing

Biochemical and electrophysiologic studies

  • Serum creatine kinase (CK) is marginally to moderately increased (1.5-7x normal).
  • Electromyography (EMG) shows myopathic features (low-amplitude polyphasic potentials of short duration).
  • Nerve conduction studies (NCS) are normal.

Muscle biopsy. The following findings help distinguish Salih myopathy from congenital muscular dystrophy (CMD) and other congenital myopathies.

  • Histology of skeletal muscle reveals a pattern compatible with congenital myopathy (Figure 1): 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 2) highlights the “minicore-like” lesions seen on histology and reveals multiple foci of sarcomere disruption and mitochondria depletion.
Figure 1

Figure

Figure 1. 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 (more...)

Figure 2

Figure

Figure 2. 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 (more...)

Heart muscle biopsies (taken from two 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.

Electrocardiography (ECG) 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 3). With the onset of dilated cardiomyopathy (between ages 5 and 16 years), major rhythm disturbances become evident on ECG 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.

Figure 3

Figure

Figure 3. 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 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 (LVEF) followed by reduction of the right ventricle ejection fraction.

Respiratory function tests show a moderate restrictive pattern without clinical symptoms.

Molecular Genetic Testing

Gene. Salih myopathy is caused by biallelic mutation in the TTN exons (designated Mex1 and Mex3) that encode part of the C-terminal domain of titin.

Note: The part of the TTN protein that spans the sarcomere M-line is encoded by six exons that have been termed Mex1-Mex6 for ‘M-line exons 1 through 6’; these correspond to the last six exons, numbers 358 to 363.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Salih Myopathy

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
TTNSequence analysis of select exons 4Exons Mex1 and Mex3 5~100%
Sequence analysis of all 363 exons Sequence variants 6~100%
Deletion/duplication analysis 7Exonic or whole-gene deletionsUnknown, none reported

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Exons sequenced may vary by laboratory.

5. The two mutations reported to date are in these exons; see Molecular Genetics.

6. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To confirm/establish the diagnosis in a proband

Clinical findings that should be present to warrant consideration of skeletal muscle biopsy and molecular genetic testing include:

  • Delayed motor milestones but normal cognitive development;
  • Muscle weakness of limb-girdle distribution, myopathic face, variable degree of ptosis, and relative calf muscle hypertrophy;
  • Dilated cardiomyopathy in association with muscle weakness of limb-girdle distribution.

Skeletal muscle biopsy is an integral part of the diagnostic evaluation because of the marked clinical overlap within and between congenital myopathies and congenital muscular dystrophy (CMD). Muscle biopsy sections should be examined for histology, histochemistry, immunohistochemistry, and electron microscopy.

Note: Cardiac muscle biopsy is currently not indicated following the recognition of the disease.

Molecular genetic testing. If clinical findings and skeletal muscle biopsy suggest Salih myopathy, perform molecular genetic testing:

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

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

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 age 20 months and four years. In the first decade of life, global motor performances are stable or tend to improve. During this period skeletal muscle involvement mainly manifests as difficulty in running, climbing stairs, and rising up from the sitting position. Those who survive childhood remain ambulant, with or without support, and maintain normal cognitive function.

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

Cardiac dysfunction starts between age five and 16 years, progresses rapidly, and leads 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.

In contrast to individuals with heterozygous mutations in TTN associated with Udd distal myopathy, the parents of individuals with Salih myopathy are heterozygous carriers of a TTN mutation and remain asymptomatic with no cardiac or muscle disorder (Figure 4).

Figure 4

Figure

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. Actual prevalence figures are unknown.

Differential Diagnosis

Features of Salih myopathy distinguish it from other early-onset muscle disorders:

Spinal muscular atrophy (SMA), characterized by progressive symmetric muscle weakness resulting from degeneration and loss of anterior horn cells in the spinal cord and brain stem, is a common cause of muscle weakness in the neonatal period or early infancy [Salih 2012a]. Shared features of SMA and Salih myopathy:

  • Early onset of muscle weakness (age 6-12 months) (SMA II)
  • Weakness resulting in frequent falling and difficulty in walking up and down stairs (SMA III)
  • Normal intelligence

Features of SMA that distinguish it from Salih myopathy:

  • Onset after age 12 months (SMA III)
  • Frequent finger trembling
  • Sparing of facial muscles
  • Serum CK: normal
  • ECG: frequent background tremors (reflecting the spontaneous motor unit activity) but absence of cardiac involvement [Salih 2012b]
  • EMG: neurogenic features (polyphasic waves, positive sharp waves and fibrillations) as opposed to myopathic EMG features seen in Salih myopathy.
  • Skeletal muscle histology: group atrophy of type 1 and type 2 muscle fibers (in contrast with type 1 fiber predominance seen in Salih myopathy)

Duchenne muscular dystrophy (DMD) usually manifests in early childhood with delayed milestones. Subclinical or clinical cardiac involvement presents in the majority of affected individuals. Features of DMD that distinguish it from Salih myopathy:

  • Serum CK: high (>10-300 times normal)
  • ECG: characteristic pattern
  • Skeletal muscle histology: established dystrophic morphology seen early in childhood
  • Immunohistochemical staining of skeletal muscle: negative for dystrophin

Sarcoglycanopathies are common in North Africa and the Arabian Peninsula, where Salih myopathy originated [Salih 2010]. Overlapping features of the sarcoglycanopathies and Salih myopathy:

Features of the sarcoglycanopathies that distinguish them from Salih myopathy:

  • Serum CK: high (10-70 times normal)
  • ECG: tall R wave in V1 and V2 (in contrast to Salih myopathy where deep S waves are seen in the right precordial leads associated with reduced R/S ratio [Figure 3])
  • Echocardiogram: left ventricular dysfunction associated with regional wall motion abnormalities, (e.g., inferior wall and posterior septum hypokinesia) (in contrast to Salih myopathy, in which the contractile dysfunction and dilatation, initially restricted to the left ventricle, subsequently affects all chambers [Carmignac et al 2007])
  • Skeletal muscle histology: dystrophic early in the course of the disease
  • Immunohistochemical staining of skeletal muscle: negative staining for one or more of the sarcoglycans α (adhalin), β, γ, and δ

Other forms of limb-girdle muscular dystrophy (LGMD)

LGMD2I, caused by mutations in the fukutin-related protein gene (FKRP) [Nigro et al 2011], shows phenotypic overlap with Salih myopathy:

  • Onset within the first year [Boyden et al 2010]
  • In some, development of cardiomyopathy within the first year of life [Margeta et al 2009]
  • Presence of muscle weakness and calf muscle hypertrophy
  • Skeletal muscle histology: in some, mild myopathic features (however, significantly reduced signal with α-dystroglycan on immunostaining)

Features of LGMD2I that distinguish it from Salih myopathy:

  • Absence of ptosis
  • Serum CK: elevated
  • ECG: dysmorphic notched P-waves, complete or incomplete right bundle branch block (BBB) or incomplete left BBB, and Q waves in lateral leads [Hermans et al 2010]

LGMD2J, which is allelic to Salih myopathy and is caused by homozygous mutation of the C terminus of TTN, has later onset (1st to early 4th decade). In about half of all reported cases, weakness ultimately involved the distal muscles. Joint contractures have not been associated with LGMD2J [Pénisson-Besnier et al 2010] and cardiac abnormalities have not been described [Hermans et al 2010].

Congenital muscular dystrophy (CMD). Muscle weakness in CMD typically begins at birth or in early infancy. Affected children present with delay or arrest of gross motor development. Subtypes of CMD known to be associated with cardiac involvement include the following:

Dystroglycanopathies. Dilated cardiomyopathy has been reported in persons with mutations of FKRP and in persons with Fukuyama CMD. These disorders are distinguished from Salih myopathy by the presence of:

  • Intellectual disability / epilepsy
  • Variable eye malformations
  • Brain MRI: central nervous system malformations

Laminin α2 deficiency (also known as MDC1A) results from biallelic mutation of LAMA2 and is characterized by congenital hypotonia and delayed or arrested motor milestones, progressive diffuse joint contractures, spinal rigidity, and normal cognitive abilities in the majority of affected individuals. Approximately one third of persons with laminin α2 deficiency develop left ventricular dysfunction [Wang et al 2010]. Similarities to Salih myopathy:

Differentiating features of laminin α2 deficiency:

  • Brain MRI: diffuse white matter signal abnormalities
  • Immunohistochemical staining of skeletal muscle: total or partial merosin deficiency

See LAMA2-Related Muscular Dystrophy.

LMNA-related CMD (L-CMD) is characterized by infantile hypotonia and weakness of axial-cervical muscles. Cardiac involvement is frequent; affected individuals develop dilated cardiomyopathy [Quijano-Roy et al 2008]. Sudden death, probably secondary to severe ventricular arrhythmia, has been reported in several individuals. L-CMD is distinguished from Salih myopathy by the absence of the following:

  • Facial weakness
  • Ptosis
  • Muscle pseudohypertrophy

Other congenital myopathies

The congenital myopathies are characterized by hypotonia, delayed motor development, proximal weakness, poor muscle bulk, elongated myopathic facies (in many individuals), scoliosis, and foot deformities. Because of the marked clinical overlap among and between congenital myopathies and CMD, the diagnosis rests on muscle histology that shows morphologic changes resulting from disintegration of the sarcomeric Z-disk and myofibrils. Muscle biopsy findings help guide molecular genetic testing.

Classic multiminicore disease (MmD) is caused by SEPN1 mutations [Ferreiro et al 2002a]. The phenotype of MmD caused by RYR1 mutations is usually milder than that caused by mutations in SEPN1, and is also associated with hand involvement [Ferreiro et al 2002b].

Classic MmD has considerable overlap with Salih myopathy:

  • Neonatal hypotonia and early-onset delayed motor development
  • Weakness maximally involving the trunk and neck flexors; pelvic and shoulder girdle muscles to a lesser degree
  • Individuals usually ambulatory
  • Facial muscle weakness ranging from absent to severe
  • Serum CK: may be slightly elevated
  • Skeletal muscle histology: shows common features with Salih myopathy
  • H&E staining: variability in fiber size, increased number of internal nuclei, and normal or mildly increased fat and connective tissue
  • Myofibrillar ATPase staining: frequently shows type 1 fiber predominance, whereas oxidative stains reveal minicores (multiple focal lesions of sarcomere disruption and/or reduced or absent oxidative activity) (see Figure 1)
  • Electron microscopy: appearance of the cores ranging from focal areas of Z-line streaming and reduced or absent mitochondria to severe focal disorganization of myofibrillar structure [Ferreiro et al 2000]

Features of MmD that distinguish it from Salih myopathy:

  • Major respiratory involvement requiring respiratory support
  • Cardiac involvement (right ventricular failure, cardiomyopathy) secondary to respiratory impairment

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with Salih myopathy, the following are recommended:

  • Neurologic examination
  • Assessment of strength and joint mobility by physical and occupational therapists
  • Assessment of cardiac function with particular attention to possible cardiomyopathy and/or arrhythmia, which are often fatal complications
  • Comprehensive respiratory evaluation including assessment of respiratory rate and pulmonary function
  • Spinal x-rays to evaluate for presence of scoliosis in the second decade
  • Medical genetics consultation

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.

Attention to education by providing school technical aid is important since cognition is normal. Stimulation and emotional support can improve school performance and the 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

Monitor as follows:

  • Every six months: cardiac function (by ECG, 24-hour Holter-ECG recording and echocardiography) starting at age five years.
  • Yearly: respiratory function, using pulmonary function testing or spirometry.
  • As needed: orthopedic complications (foot deformity, joint contractures, and spinal deformity) by clinical examination and x-rays as needed.

Agents/Circumstances to Avoid

Ibuprofen (Brufen®):

  • Give with care in those with evidence of cardiomyopathy. A patient who had reduced LVEF developed edema following its administration [Subahi and 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 early.

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

Pregnancy Management

If a fetus is diagnosed prenatally to have 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 for access to information on clinical studies for a wide range of diseases and conditions.

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

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 mutant allele).
  • Heterozygotes (carriers) are asymptomatic. Note: In contrast to individuals with heterozygous pathogenic allelic variants in TTN associated with Udd distal myopathy, the parents of individuals with Salih myopathy are heterozygous carriers of a TTN pathogenic variant and 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.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

  • No individuals with Salih myopathy have reproduced.
  • Unless an individual with Salih myopathy has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in TTN.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.

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 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, are carriers, or are at risk of being carriers.

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

If the pathogenic variants have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the pathogenic variants have been identified.

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.

  • 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 Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
    Email: info@muscular-dystrophy.org
  • Congenital Muscle Disease International Registry (CMDIR)
    The CMD International Registry is a patient self-report registry with the goal to register the global congenital muscle disease population which includes congenital myopathy and congenital muscular dystrophy.
    1712 Pelican Avenue
    San Pedro CA 90732
    Phone: 800-363-2630
    Fax: 310-872-5374
    Email: counselor@cmdir.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. Salih Myopathy: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Salih Myopathy (View All in OMIM)

188840TITIN; TTN
611705MYOPATHY, EARLY-ONSET, WITH FATAL CARDIOMYOPATHY

Molecular Genetic Pathogenesis

To date, biallelic mutations 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 mutations (i.e. heterozygotes) are asymptomatic, presumably as a result of nonsense-mediated decay (NMD) of the mutant 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. TTN 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]. 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 Symbol.

Pathogenic allelic variants. To date, the biallelic mutations 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 2. Selected TTN Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.97820_97827delACCAAGTG
(g.289385_289392delACCAAGTG) 2
p.Gln32608HisfsTer9
(p.Q33535HRfs*7) 2
NM_133378​.4
NP_596869​.4
c.98867delA
g.289390_289397delA
(291297delA) 2
p.Lys32956ArgfsTer22
(Lys33883ArgfsTer20) 2

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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Reference sequence: AJ277892​.2

Normal gene product. Titin is the biggest single polypeptide in humans, found in numerous isoform size variants. The entire coding region predicts a protein of 38,138 amino acids (4200 kd). Titin is expressed as several different isoforms, caused by alternative splicing, in different skeletal muscles and 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 titins resulting from the frameshift mutations in Mex1 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.

References

Literature Cited

  1. Bang ML, Centner T, Fornoff F, Geach AJ, Gotthardt M, McNabb M, Witt CC, Labeit D, Gregorio CC, Granzier H, Labeit S. The complete gene sequence of titin, expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. Circ Res. 2001;89:1065–72. [PubMed: 11717165]
  2. Boyden SE, Salih MA, Duncan AR, White AJ, Estrella EA, Burgess SL, Seidahmed MZ, Al-Jarallah AS, Alkhalidi HM, Al-Maneea WM, Bennett RR, Alshemmari SH, Kunkel LM, Kang PB. Efficient identification of novel mutations in patients with limb girdle muscular dystrophy. Neurogenetics. 2010;11:449–55. [PMC free article: PMC2944962] [PubMed: 20623375]
  3. Carmignac V, Salih MAM, Quijano-Roy S, Marchand S, Marchand S, Al Rayess MM, Mukhtar MM, Ja U, Labeit S, Guicheney P. C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy. Ann Neurol. 2007;61:340–51. [PubMed: 17444505]
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Chapter Notes

Acknowledgments

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

Revision History

  • 12 January 2012 (me) Review posted live
  • 28 October 2011 (mas) Original submission
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