Congenital Myopathies: General Approach

Literature and regulatory information updated: 6 October 2026.

Histological and genetic classification (nemaline, core, centronuclear/myotubular, congenital fibre type disproportion), new CMYO nomenclature, genetics-first diagnosis, standard of care and investigational therapies; includes STAC3-related congenital myopathy 13 (Bailey-Bloch congenital myopathy or Native American myopathy).

0. Initial Reference Table

The following table identifies the entities that this article integrates as subsections.

1. Introduction

Congenital myopathies are hereditary early-onset muscle diseases, usually stable or slowly progressive, defined for half a century by muscle biopsy appearance. The designation groups entities sharing neonatal or infantile hypotonia, predominantly axial and proximal weakness, facial weakness and, in severe forms, respiratory and bulbar compromise, but differing in genes, transmission and prognosis [3, 6]. For geneticists, interest rests on three characteristics: genetic heterogeneity, since the same histological lesion may involve several genes; allelic heterogeneity, since one gene may produce different lesions and phenotypes; and genotype-dependent associated risks, such as malignant hyperthermia susceptibility or X-linked myotubular myopathy liver disease [5, 6, 10].

The history of this group begins with morphological descriptions. In 1956, Shy and Magee published “A new congenital non-progressive myopathy” in Brain, the report that gave rise to central core disease [23]. In 1963, Shy, Engel, Somers and Wanko described “nemaline myopathy” in the same journal, a name derived from the threadlike appearance of the structures observed in the fibres [24]. In 1966, Spiro, Shy and Gonatas published “Myotubular myopathy. Persistence of fetal muscle in an adolescent boy”, introducing the term myotubular because of the resemblance of the fibres to fetal myotubes [25]. Congenital fibre-type disproportion and forms with multiminicores completed the classical classification, which the 2012 international consensus organised into myopathies with protein accumulation, with cores, with cores and rods, with centralised nuclei, and with small type 1 fibres as the sole abnormality [5].

The molecular era began in the early 1990s with the identification of RYR1 variants in dominant central core disease and TPM3 variants in nemaline myopathy [1]. In 1996, Laporte and colleagues identified MTM1, the gene responsible for X-linked myotubular myopathy, and showed that it encoded a member of a new phosphatase family conserved from yeast [26]. By the mid-2000s, approximately two dozen genes had been identified, and massively parallel sequencing accelerated discovery: at the time of the 277th ENMC workshop, the World Muscle Society gene table listed 41 genes associated with 59 congenital muscle diseases, and the ClinGen congenital myopathy expert panel had assessed 52 gene–disease associations [1].

These developments made purely histological classification insufficient. Biopsy is no longer mandatory in many patients, the same RYR1 variant can produce different appearances within families or at different ages, and some entities are genotype-defined (TTN, SELENON) rather than lesion-defined [1, 6]. In June 2024, the 277th ENMC workshop, published in 2026, approved a consensus definition, CMYO acronym and nomenclature integrating inheritance, gene, “congenital myopathy” and principal histology, e.g. “autosomal recessive RYR1 congenital myopathy with cores” (AR RYR1-CMYO with cores) [1]. It also recommended genetics-first diagnosis and announced revision of the 2012 standard of care by a dedicated working group [1].

Congenital myopathy 13 occupies in this article the place of an entity with its own description. Its history ran opposite to that of most: it was defined in 1987 by the anaesthetic event that revealed it, in a female infant from the Lumbee tribe of North Carolina, described as a clinical entity in 1988 and 2008, mapped to 12q13.13-q14.1 in 2008 and assigned to STAC3 in 2013, through a zebrafish locomotion screen [27–31]. The original name, Native American myopathy, no longer describes the distribution of the disease: the same founder variant has been identified in patients of African, Afro-Caribbean, Comorian, Middle Eastern, Turkish, Russian, Puerto Rican and South American ancestry, and in southern Africa it is a frequent cause of congenital hypotonia, so GeneReviews and the CMYO nomenclature prefer the names STAC3 disorder and congenital myopathy 13 [1, 17, 20].

This article addresses the group through a general approach. The broader approach to hereditary myopathies and dystrophies, including comparison between dystrophy guidelines and the congenital myopathy consensus, malignant hyperthermia susceptibility, contracture testing and dantrolene dosage are not developed here; RYR1-related myopathy and nemaline myopathy are described only to the extent necessary for diagnostic guidance and counselling.

2. Molecular Genetics and Pathophysiology

2.1. From histology to gene: the new nomenclature

Histology–gene relationships are complex for four reasons: most congenital myopathies involve multiple possible genes; one gene's variants produce different lesions (ACTA1, for example, may cause nemaline myopathy, intranuclear rods, actin accumulation, fibre disproportion, caps and zebra bodies); one variant can look different within a family or across ages, demonstrated for RYR1 and reproduced in mice; and lesions evolve with age [6]. In the Swedish population study, the commonest histology was congenital myopathy with non-specific changes, birth incidence 4.1 per 100,000, and four in five genetically undiagnosed patients had non-specific histology [7].

ENMC nomenclature includes, in order, inheritance (where multiple modes exist), gene, “congenital myopathy” (CMYO) and principal histology. It applies only with a confirmed known-gene diagnosis or compatible, even non-specific, histology; without either, “probable CMYO” is temporarily acceptable [1]. A parallel classification was also proposed (congenital myopathy; gene; inheritance; principal finding), e.g. “congenital myopathy, genetically unresolved, nemaline”; motor function, weakness distribution and comorbidities do not form the label, and patient representatives rejected severity scales [1].

AD, autosomal dominant; AR, autosomal recessive. Examples from table 1 of the 277th ENMC workshop [1].

2.2. Pathophysiological mechanisms

The genes responsible for congenital myopathies encode proteins involved in calcium homeostasis and excitation–contraction coupling, the assembly and interaction of thin and thick filaments, and other processes such as membrane trafficking [7, 32]. Ryanodine receptor type 1, encoded by RYR1, is the calcium-release channel of the sarcoplasmic reticulum: variants that make it hypersensitive cause malignant hyperthermia susceptibility, whereas in myopathies the defect is reduced calcium release or calcium leak and, in recessive forms, reduced protein quantity [33]. In myotubular myopathy, loss of myotubularin, a lipid phosphatase that removes phosphate from position 3 of phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-bisphosphate, disorganises the triad (T tubule and terminal sarcoplasmic reticulum) and impairs stimulus-dependent calcium release; similar changes in the coupling apparatus have been observed in autosomal centronuclear forms, suggesting a common mechanism [4]. Dynamin 2 (DNM2), amphiphysin 2 (BIN1) and myotubularin participate in the same membrane-remodelling pathway; in the dominant DNM2 form, variants act through excessive or altered activity, which explains why reduction of dynamin 2 was explored as a therapeutic strategy [4, 33].

Thin filament myopathies (ACTA1, NEB, TPM2, TPM3, TNNT1, CFL2, LMOD3) impair force generation and sarcomere organisation; nemaline bodies derive from the Z-line, with similar lattice organisation and α-actinin content [6, 34]. Nebulin, 600 to 800 kDa, runs along the thin filament, anchors and stabilises F-actin and determines filament length [33]. KBTBD13, KLHL40 and KLHL41 participate in sarcomeric ubiquitination and protein turnover [35]. Selenoprotein N (SELENON) is an endoplasmic reticulum redox-control protein; deficiency causes oxidative stress vulnerability demonstrated in patient fibroblasts and myotubes [33]. Titin (TTN), the largest known protein, confers myofilament elasticity and participates in cardiac diastolic relaxation, explaining frequent cardiomyopathy in recessive congenital titinopathies [36].

2.3. Principal genes, inheritance and histological correlations

In Beggs laboratory's cohort (1,110 patients, 918 families), 70% had genetic diagnoses; 84% of solved cases involved nine genes, with the remaining 105 diagnosed families spread over 53 genes [1]. The table summarises key genes; each proportion concerns its specified histological entity rather than all congenital myopathies.

Other genes complete the spectrum: TNNT1 (Amish form), CFL2, KLHL41, LMOD3, MYPN, MYH2 (ophthalmoplegia), MEGF10 (diaphragmatic weakness, areflexia, dysphagia), HACD1 (childhood improvement), JPH1, CCDC78, MAP3K20, PYROXD1, CNTN1 and MYO18B (Klippel–Feil association) [33]. In Sweden, MYH2 (3.9 per 100,000 births) and RYR1 (2.0 per 100,000) were commonest, but MYH2 frequency reflected two families with 20 and 6 affected members, precluding population extrapolation [7].

2.4. Allelic diseases and phenotypic overlap

Several congenital myopathy genes produce distinct phenotypes, requiring contextual variant interpretation. Beyond myopathies, RYR1 causes malignant hyperthermia susceptibility, King–Denborough syndrome and exertional rhabdomyolysis; ENMC proposed that predominant malignant hyperthermia susceptibility be considered a pharmacogenetic phenotype rather than congenital myopathy [1]. DNM2 also causes axonal Charcot–Marie–Tooth (CMT2M), dominant intermediate DI-CMTB and lethal congenital contracture syndrome type 5 [33]. TTN causes dilated cardiomyopathy (truncating variants), Udd tibial distal myopathy (last exon), hereditary myopathy with early respiratory failure and limb-girdle dystrophy R10 [33]. TPM2 and less often TNNI2 and TNNT3 cause distal arthrogryposis; some actin-contact TPM2 and TPM3 variants cause hypercontractility with trismus rather than hypotonia [6, 33]. MYH7 is a major hypertrophic cardiomyopathy and Laing distal myopathy cause [36]. Large heterozygous NEB deletions (52 to 97 exons), identified in 12 families, caused predominantly distal dominant myopathy, the first statistically significant genotype–phenotype correlation for this gene [42].

2.5. Recurrent and founder variants with standardised nomenclature

2.6. Congenital myopathy 13: STAC3 and coupling at the triad

The STAC3 gene encodes an adaptor protein exclusive to skeletal muscle that localises to the triad, the junction between the transverse tubule and the terminal cisternae of the sarcoplasmic reticulum, and that is indispensable for transducing depolarisation into calcium release [17, 31]. The protein binds the dihydropyridine receptor, the CaV1.1 calcium channel encoded by CACNA1S, and is required for the voltage change detected by this sensor to open the RyR1 ryanodine channel; in addition, it increases surface expression of CaV1.1, determines the slow activation kinetics of its current and inhibits voltage-dependent inactivation [17, 20]. STAC3 thus joins RYR1 and CACNA1S as one of the three genes that control calcium release at the triad and in which variants can confer malignant hyperthermia susceptibility, which explains the coexistence, in the same disease, of a myopathy due to insufficient calcium release and a drug-triggered hypermetabolic response [17, 33].

Identification of the gene followed mapping of the locus. Stamm and colleagues applied homozygosity mapping to five Lumbee families and delimited a common 5.6 Mb homozygous region at 12q13.13-q14.1, between marker D12S398 and rs3842936, after excluding pathogenic variants in ITGA7, PIP5K2C, PDE1B and MLC1SA [16, 30]. Horstick and colleagues reached the gene through a zebrafish locomotion genetic screen, whose mutation was mapped to stac3, and sequenced the STAC3 coding region in five families with Native American myopathy (five affected and thirteen unaffected individuals): all affected individuals were homozygous for the missense variant p.(Trp284Ser) and all obligate carriers were heterozygous, with the variant not detected in three unaffected Lumbee, in thirteen European controls or in the 1000 Genomes Project database [16, 31]. In zebrafish, introduction of the variant reduced calcium transients and excitation-contraction coupling, and expression of normal human STAC3 rescued the phenotype [31].

The descriptions above were confirmed in VariantValidator against the MANE Select transcript NM_145064.3, which corresponds to the NM_145064.2 used in GeneReviews; the founder variant has the genomic description NC_000012.12:g.57244322C>G in GRCh38 [18]. The variants NM_145064.3:c.93del p.(Lys32ArgfsTer78) and NM_145064.3:c.834_836del p.(Asp279del) were likewise confirmed, with the genomic descriptions NC_000012.12:g.57249283del and NC_000012.12:g.57244340_57244342del [18]. Historical nomenclature deserves attention: the OMIM entry describes the founder variant as W284S in the molecular genetics section, but refers to it as “W84S” when summarising the Zaharieva series; this second form corresponds neither to the residue described in the original article nor to the description confirmed in VariantValidator, NM_145064.3:c.851G>C p.(Trp284Ser) [16, 52]. No deletions or duplications of whole exons or of the entire gene have been identified in patients with a confirmed molecular diagnosis, so sequencing detects all pathogenic variants described to date and copy number analysis has a documented yield of zero [17].

The mechanism was characterised in human material in the Zaharieva series, with primary myoblasts obtained from two patients; the cells of one of them did not differentiate into multinucleated myotubes, so functional assessment was performed only in the myotubes of the patient with compound heterozygosity p.(Trp284Ser)/c.997-1G>T [52]. Resting cytosolic calcium concentration, measured with the ratiometric fluorescent indicator fura-2, and the size of intracellular calcium stores did not differ from controls [52]. Nor was there a shift in sensitivity to activating stimuli: the median effective concentration of 4-chloro-m-cresol, a direct RyR1 agonist, was 363.7 ± 44 µM in controls and 384.2 ± 30 µM in the patient's myotubes, and that of potassium chloride, which acts through membrane depolarisation, was 10.6 ± 0.6 mM in controls and 12.7 ± 1.2 mM in the patient [52]. What was altered was the amplitude of the response: the potassium chloride-induced calcium peak fell to approximately 10% of that observed in controls, and the 4-chloro-m-cresol-induced peak also decreased significantly, demonstrating deficient excitation-contraction coupling and suggesting that release mediated by direct RyR1 activation is not intact, unlike what has been described in Stac3-null mouse myotubes [52]. The localisation of CaV1.1 and RyR1 in differentiated myotubes and in patients' muscle sections was normal, with preserved colocalisation in fibres; western blot analysis showed no change in the content of STAC3, CaV1.1 or the auxiliary β1a subunit of the dihydropyridine receptor in three patients; and co-immunoprecipitation with anti-CaV1.1 antibody pulled down STAC3 protein to the same extent in patients and controls [52]. The disease mechanism is therefore neither defective trafficking of CaV1.1 to the sarcolemma nor loss of the stable interaction between STAC3 and CaV1.1, which occurs through the C1 domain rather than the SH3 domains; the proposed explanation is loss of interaction of the variant with the II-III loop of CaV1.1, a region critical for functional coupling with RyR1 [52]. These data have a direct anaesthetic consequence: the absence of a shift in median effective concentration and normal resting calcium distinguish this mechanism from that of “classical” malignant hyperthermia due to dominant RYR1 variants, in which the characteristic cellular phenotype is precisely increased sensitivity to agonists [52].

No genotype-phenotype correlations have been established, and the only two available clues point in different directions [17]. The Russian patient, carrying a nonsense variant and a frameshift variant, NM_145064.3:c.93del p.(Lys32ArgfsTer78), had a milder phenotype than described in previous series, without short stature, palatal anomalies, multiple contractures or feeding difficulties; the authors attribute the difference to nonsense-mediated RNA decay and to preservation of two alternative coding isoforms not affected by the frameshift variant [54]. In the pulmonary series of five patients, all homozygous for the founder variant, respiratory function ranged from normal to the need for tracheostomy at 6 months, with no identifiable relationship between genotype and severity [57]. The Zaharieva series supports a trend and, at the same time, its limit: the patient with the most severe presentation in that cohort, with severe perinatal asphyxia and cardiac arrest, was compound heterozygous for the founder variant and for the splicing variant c.997-1G>T, and three patients with a more severe phenotype published earlier also had variants other than the founder variant, frameshift or splicing; but clinical variability is equally observed among patients homozygous for the founder variant and among members of the same family, so factors beyond variant type contribute to the phenotype [52, 53, 55]. STAC3 is not associated with any other germline phenotype [17].

Large, polymorphic genes complicate interpretation. Only approximately 7% of NEB coding variants observed in a population exome database are pathogenic; the gene has 183 exons and a triplicate repeat region that is poorly aligned by short reads, and a proportion of pathogenic variants are structural [33]. In TTN, many missense variants have no clinical impact, and several causal variants escape routine analyses because they do not affect the N2A isoform or are intronic or affect non-canonical splicing [1]. In RYR1, variants of uncertain significance are a frequent problem, and detection of a single variant in suspected recessive disease requires a search for the second allele [6].

3. Clinical Spectrum and Manifestations by Organ System

3.1. Shared characteristics

Congenital myopathies share signs with widely variable severity. Delayed motor milestones are usual; the face is long and narrow with facial weakness and ptosis, dolichocephaly and high arched palate; intelligence is normal; weakness is generalised or mainly proximal and limb-girdle, sometimes distal, axial and respiratory; severe cases have respiratory and bulbar weakness [3]. Examination usually shows a hypotonic “frog-leg” posture with hyporeflexia, reduced muscle mass and intact sensation; lower facial weakness with open mouth and tented upper lip is often disproportionate to ptosis [6]. Polyhydramnios and reduced fetal movements may affect pregnancy [3, 6].

The course is generally static or slowly progressive. Many patients make motor progress after the neonatal period and maintain strength in adulthood, but these diseases are not entirely static: the 2012 consensus identifies walking, respiratory function and scoliosis as the three domains in which late deterioration may occur [5]. The ENMC adds that age-related decline in muscle mass and strength does not exclude the “non-progressive” nature of the definition, and that some individuals, particularly in later adulthood, deteriorate slowly [1].

3.2. Prenatal and neonatal presentation

The earliest presentations include fetal akinesia or hypokinesia, abnormal limb positions, arthrogryposis, pterygia, hydrops and polyhydramnios; at birth, respiratory failure is partly attributable to pulmonary hypoplasia and chest wall restriction, in addition to respiratory muscle weakness [1]. In fetal akinesia sequence, recessive RYR1 variants were detected in 8% of a cohort with lethal multiple pterygium syndrome or fetal akinesia sequence; up to half of severe presentations of nemaline myopathy are due to recessive ACTA1 variants, and recessive NEB and KLHL40 variants have been described in fetal akinesia [58]. More recent genomic series place recessive TTN variants as the most frequent cause of intrauterine presentations (approximately 10% of diagnoses, often with amyoplasia), followed by recessive loss-of-function variants in NEB and RYR1, dominant de novo variants in ACTA1 and recessive variants in CACNA1S, SCN4A and STAC3; approximately 50% of these cases remain without a molecular diagnosis [1].

In neonates, the forms most frequently presenting at birth are severe nemaline myopathy and myotubular myopathy, which may clinically resemble congenital myotonic dystrophy [59]. Very severe hypotonia without antigravity movements suggests nemaline myopathy (ACTA1, NEB or KLHL40), X-linked myotubular myopathy or severe RYR1-related forms [6].

3.3. Rod (nemaline) myopathies

Nemaline myopathy is characterised by weakness, hypotonia and reduced or absent reflexes, most pronounced in the face, neck flexors and proximal limb muscles [35]. The archived GeneReviews chapter (retired and retained only for historical reference) describes six clinical forms: severe congenital or neonatal (16%), Amish, intermediate congenital (20%), typical congenital (46%), childhood-onset (13%) and adult-onset (4%); severe neonatal respiratory failure and arthrogryposis are associated with death in the first year, independent walking before 18 months predicts survival, and most children with the typical form eventually walk [35]. In the series of 143 patients reported by Ryan and colleagues, respiratory failure was the main cause of death in 17 of the 23 infants with the severe congenital form, and respiratory compromise occurred in approximately 96% of intermediate forms and 37% of typical forms, according to the 2012 consensus [5].

Disproportionate axial and respiratory involvement is common to all variants and determines long-term prognosis; the course is generally stable, although some patients with ACTA1 variants have severe progression in late childhood, and primary dilated or hypertrophic cardiomyopathy has been described in several cases [36]. In a French cohort of 49 patients with NEB-related myopathy published in 2026, 23 had the typical form, with childhood onset and walking preserved beyond 11 years; 33 had respiratory failure, with a median age at initiation of ventilatory support of 16 years; 32 had facial weakness; and only 14 required nutritional support, all of whom also received respiratory assistance [60]. Nemaline myopathy type 6 (KBTBD13) is distinguished by slowness of movement: in a study of 24 adult patients, 96% reported weakness and slowness and 83% difficulty running since childhood [41]. The Amish form (TNNT1) presents with hypotonia, contractures and neonatal tremor, with pectus carinatum and death from respiratory failure usually in the second year of life [6].

3.4. Central-nuclear myopathies

X-linked myotubular MTM1 disease is among the severest congenital myopathies. Approximately 80% of affected boys have classical severe disease, polyhydramnios, reduced fetal movements, neonatal hypotonia, weakness and respiratory failure; motor milestones are severely delayed, most never walk independently, facial and extraocular muscles are involved and almost all need 24-hour daily ventilation [4]. Infants have length above the 90th percentile with proportionally lower weight (60%), long fingers (43%), cryptorchidism (over 50%), contractures including clubfoot (30%) and areflexia (60%); approximately one-third are premature [4]. Moderate/mild forms (approximately 20%) allow ambulation and adult survival in many, and rare adult onset exists [4].

Non-muscular complications have gained prominence. Hepatic peliosis, blood-filled cysts capable of fatal bleeding, affects up to 5% per GeneReviews and 10% per a 2026 review; that review combines natural history, trials and cases showing episodic intrahepatic cholestasis, elevated bile acids, hyperbilirubinaemia, ultrasound abnormalities and steatosis, proposing liver disease in most severely affected patients [4, 10]. Other low-frequency manifestations include pyloric stenosis (approximately 5%), gastro-oesophageal reflux (10%), arrhythmias of uncertain severity (10%), gallstones (9%), renal stones (10%), elevated liver tests (20%), scoliosis in 75% in one series, ophthalmoplegia, ptosis and severe myopia [4]. Among 50 natural history patients, 86.7% were non-ambulant, 75% required over 16 hours daily ventilation and 43% had learning difficulties [61].

Heterozygous females are usually asymptomatic, but manifesting carriers are increasingly identified, from severe childhood weakness to mild, often asymmetrical adult weakness, with ptosis, ophthalmoparesis and potentially unnoticed respiratory decline [4, 62].

The autosomal centronuclear forms share weakness of the limb girdles, trunk and neck, frequent ptosis and ophthalmoparesis. The dominant DNM2 form ranges from congenital to adult-onset forms, with neck flexor weakness, external ophthalmoplegia and ptosis as early clues; the late-onset form associated with middle-domain variants has a progressive phase that compromises walking in the great majority of patients and is among the forms causing the least respiratory failure [5, 6]. The recessive BIN1 form has intermediate severity, while the dominant BIN1 form described in nine patients from five families is a progressive adult-onset myopathy without facial weakness [38]. Recessive RYR1 variants can also produce a centronuclear pattern, and SPEG is associated with both centronuclear myopathy and dilated cardiomyopathy [6, 36].

3.5. Core myopathies and fibre type disproportion

Central core disease, in most cases associated with dominant RYR1, ranges from mild to severe: most patients have mild symmetrical proximal weakness, variable facial and neck involvement, usually spared extraocular muscles, motor delay and independent walking, with generally normal life expectancy; severe forms combine profound hypotonia, spinal deformities, hip dislocation, contractures and respiratory failure [63]. Congenital hip dislocation is particularly suggestive of RYR1-related myopathy [5, 6]. Exertional myalgia, heat intolerance and predisposition to heatstroke also suggest RYR1 [5, 6]. RYR1-related myopathy and malignant hyperthermia susceptibility are part of the differential diagnosis.

Multiminicore disease was classically divided into the classical form (75%), a moderate form with hand involvement, an antenatal form with arthrogryposis and an ophthalmoplegic form (less than 10% each); the classical form combines neonatal hypotonia, motor delay, axial weakness, scoliosis and significant respiratory involvement, with secondary cardiac compromise [3, 64]. SELENON-related myopathy has a distinct phenotype: onset between birth and the second decade (mean 2.7 years in a series of 41 patients), marked axial weakness with a rigid spine, scoliosis in 86.1% from a mean age of 8.9 years, relatively preserved limb strength, respiratory failure in all patients from a mean age of 10.1 years and a need for ventilation while still walking in 81.7% in an international series of 132 patients [39, 65]. The same series described ophthalmoparesis in severe forms, loss of walking in 10%, consistent functional decline from the late third decade and reduced life expectancy even in mild forms [39]. The ENMC adds wasting of the medial thighs as a characteristic sign and a rigid spine in 88% of patients younger than 10 years [1].

Congenital fibre-type disproportion is characterised by hypotonia and generalised weakness at birth or in the first year; in more than 90% of patients, weakness is stable or improves, respiratory involvement occurs in approximately 30%, feeding difficulties in almost 30%, contractures in approximately 25% and spinal deformities in 25% or more; ophthalmoplegia, ptosis and facial or bulbar weakness with severe limb and respiratory weakness suggest a poorer prognosis [66].

3.6. Respiratory, cardiac and other systemic involvement

Respiratory compromise does not always parallel limb weakness. Its determinants include respiratory muscle weakness, particularly of the diaphragm, altered respiratory control, bulbar dysfunction, restrictive lung disease from impaired growth and sleep-disordered breathing [5]. Ventilatory respiratory failure from birth is typical of myotubular myopathy and severe ACTA1-related forms; moderate involvement occurs in recessive RYR1-related multiminicore disease, DNM2 forms with pleckstrin homology domain variants and BIN1 forms; compromise disproportionate to limb weakness is common with SELENON, NEB, ACTA1 and in some patients with TPM3 [5]. In a 1996 study cited by the consensus, 9% to 13% of patients with congenital myopathy had respiratory disease, 16% deteriorated in strength and respiratory function after acquiring walking, and mortality from respiratory or cardiac failure by 20 years was 14% [5]. In a Dutch cohort of 61 patients with centronuclear myopathy, 26% used home ventilation, 13 of the 16 only at night [67].

Primary cardiomyopathy is rare and had not been documented in genetically confirmed RYR1 or MTM1 cases at the time of the 2012 consensus, although it had been described rarely with ACTA1, DNM2 and TPM2; right ventricular dysfunction secondary to respiratory failure is possible, particularly with SELENON [5]. Cardiomyopathy independent of respiratory failure should prompt consideration of TTN and MYH7 and, more rarely, ACTA1 [6]. Among congenital titinopathies, cardiac involvement has been described in approximately 50%, predominantly dilated cardiomyopathy and systolic dysfunction, present at birth in approximately one-third [36]. SPEG and KBTBD13 have also been associated with cardiomyopathy [36, 48].

Orthopaedic involvement includes scoliosis (particularly with SELENON, NEB and RYR1), rigid spine, contractures, hip dislocation, fractures and low bone density; bulbar dysfunction causes swallowing difficulty, prolonged meals, chewing fatigue, dysarthria and a weak voice [1, 5]. Central nervous system involvement is rare: significant cognitive impairment should prompt a search for another cause or diagnostic reassessment, except when hypoxic–ischaemic encephalopathy has followed respiratory failure at birth [5].

3.7. Congenital myopathies in adulthood

In a French cohort of 142 adults with histologically and genetically defined congenital myopathy, RYR1 forms were the most represented (45%), followed by DNM2 forms (18%); 82% had prenatal, infantile or childhood onset, 15% had onset after 18 years (median 43 years), 15% used a wheelchair, and the poorest respiratory outcome occurred with SELENON [68]. In the same cohort, mild restrictive ventilatory impairment (forced vital capacity above 60% predicted) was present in 61 patients (71.8% of those assessed), moderate impairment (30% to 60%) in 16 (18.8%) and severe impairment (below 30%) in 4 (4.7%) [68]. The ENMC reports that neonatal or infantile onset is identifiable in more than 80% of patients, but that mild forms present to physicians in adolescence or adulthood after prolonged diagnostic delay, often with a retrospective history of motor delay and reduced athletic ability; it highlights three late presentations: KBTBD13-related nemaline myopathy, women with MTM1 variants (progressive weakness, sometimes with asymmetric facial weakness), and adults with malignant hyperthermia susceptibility-associated RYR1 variants who develop late cramps and myalgia [1].

3.8. Congenital myopathy 13: syndromic phenotype and natural history

Congenital myopathy 13 differs from other congenital myopathies in combining weakness with a constellation of craniofacial and skeletal anomalies, which historically brought it close to King-Denborough syndrome, Carey-Fineman-Ziter syndrome and Moebius syndrome [16, 55]. The initial description, by Bailey and Bloch in 1987, was of a 3-month-old female infant from the Lumbee tribe with cleft palate, micrognathia, talipes equinus and arthrogryposis, who developed malignant hyperthermia under halothane during gastrostomy placement for poor feeding [17, 27]. Stewart and colleagues described in 1988 six Lumbee children with congenital weakness, cleft palate and multiple skeletal anomalies, all with ptosis and kyphosis or scoliosis, and hypothesised that this was King syndrome [16, 28].

The Stamm series, with 14 Lumbee individuals from five families, established the natural history: myopathic facies in all; ptosis, down-turned corners of the mouth and high-arched or cleft palate in most; short or down-slanting palpebral fissures, telecanthus and micrognathia as additional features; generalised weakness and atrophy, congenital joint contractures, reduced reflexes and a high frequency of foot deformities; oral hypotonia with poor feeding, progressive scoliosis and variable restrictive respiratory insufficiency; normal cognition despite marked motor delay; and 36% mortality by 18 years of age, with three deaths in the first year, one from severe pulmonary hypoplasia and another from apnoea secondary to enterococcal pneumonia [17, 29]. Malignant hyperthermia occurred in 4 of the 14 patients (29%) [29].

GeneReviews compiled the 21 clinically described Lumbee patients and the 23 non-Lumbee patients with molecular confirmation. Of the 44 combined, myopathic facies was present in 44 of 44, hypotonia in 41 of 41, palatal anomalies in 36 of 44 (cleft palate in 25), congenital contractures in 35 of 43, ptosis in 33 of 39, scoliosis, kyphosis or kyphoscoliosis in 31 of 39, poor feeding in 29 of 40, short stature in 19 of 29, malignant hyperthermia in 19 of 44, respiratory compromise in 16 of 29 and cryptorchidism in 13 of 21 boys [17]. The true frequency of malignant hyperthermia susceptibility is probably higher than observed, because some patients were never operated on or exposed to a trigger [17].

The Zaharieva series, with 18 patients from 12 families and the largest molecular cohort published up to 2018, was the one that established that the disease is not restricted to Native Americans and defined the range of severity. The cohort comprised 17 patients homozygous for the founder variant and one compound heterozygote for this variant and c.997-1G>T; the families, apparently unrelated, were of African, Afro-Caribbean, Comorian, Middle Eastern or South American ancestry [52]. Onset was at birth in all cases. There was polyhydramnios in three pregnancies and reduced fetal movements in another three; four newborns had low birth weight; most presented with hypotonia at birth and unilateral or bilateral talipes; ten had cleft palate or high palate and one had a bifid uvula with elevation of the right hemidiaphragm; six infants had contractures of the neck, elbows, wrists, fingers or toes; fifteen had feeding difficulties at birth or in infancy and eight had respiratory distress of varying degree in the first days of life, one of them with severe perinatal asphyxia and cardiac arrest [52]. At last assessment, all 18 patients remained ambulant, at least over short distances, with mild to moderate limb weakness, predominantly proximal, axial weakness in 11, leg muscle atrophy in 11, ptosis and facial weakness in all and no case of ophthalmoplegia; there were contractures, mainly of the fingers and ankles, in 14, joint laxity in 7 (three without associated contractures, all from the same family) and scoliosis, kyphosis or spinal rigidity in 11 [52]. Respiratory compromise was reported in 8 patients, four of whom were on non-invasive ventilation at last assessment; 13 children had faltering growth in infancy and six required a nasogastric tube or gastrostomy; six had speech delay or dysarthria, seven had documented hearing loss and five of the eleven boys had cryptorchidism [52]. A sister and two maternal cousins in one of the families had a similar but more rapidly progressive condition, with early death of two of them; as they were not available for assessment, they were not included in the count, which makes the series a sample that underestimates the severe end of the spectrum [52].

The largest series with a uniform genotype is the South African one, with 31 patients homozygous for the founder variant, from various ethnolinguistic groups of southern Africa and with a median age of 40 months at data collection. In it, hypotonia was present in 31 of 31, myopathic facies in 27 of 28 (96%), reduced muscle bulk in 25 of 29 (86%), global weakness in 22 of 27 (81%), developmental delay in 27 of 27, palatal anomalies in 26 of 28 (93%, with cleft in 11 and high palate in 16), swallowing difficulties in 13 of 24 (54%), speech impairment in 13 of 17 (76%), talipes equinovarus in 17 of 29 (59%), camptodactyly in 12 of 30 (40%), arthrogryposis in 11 of 29 (38%), spinal anomalies in 14 of 27 (52%, scoliosis in 8), pectus carinatum in 7 of 28 (25%) and cryptorchidism in 7 of 16 boys (44%) [20]. A weak cry at birth (16 of 17) and neonatal hypotonia (27 of 28) were almost universal, and 18 of 26 (69%) had respiratory distress at birth [20].

Two findings in this series alter diagnostic reasoning. The first is global areflexia in 21% and global hyporeflexia in 62% of patients, which may lead to confusion with spinal muscular atrophy [20]. The second is joint laxity in 14%, coexisting with contractures in two patients, a pattern also described in the Zaharieva series, where it is considerably more frequent. The primary text of that series documents joint laxity in 7 of the 18 patients (39%), in four of them coexisting with contractures and in the other three without associated contractures, all siblings from the same family; the 47% attributed to that series in derived tabulations results from a smaller denominator of 15 patients, so the correct frequency for the full cohort is 7 of 18 [17, 20, 52]. The documented course was heterogeneous: static in 6 of 27, with progressive worsening in 6 of 27 (three slowly, three rapidly) and with improvement in 15 of 27 (56%), consistent with the observation that infants who survive the initial respiratory and feeding difficulties tend to improve slowly [20].

Growth is a persistent problem. Almost half of the South African patients were born small for gestational age, but birth length was normal in 13 of 18; at the last visit, 16 of 23 (70%) had weight below −2 standard deviations for age and 10 of 23 (43%) below −3, with faltering growth in 17 of 26 (65%) and short stature in 10 of 22 (45%), a frequency similar to the 8 of 18 (44%) in the Zaharieva series [20]. Adult height usually falls below the 3rd centile [17]. The cause is multifactorial: hypotonia, weakness, palatal anomalies and respiratory insufficiency reduce caloric intake [20].

Maximum motor ability in the 15 patients old enough for assessment in the table compiled by GeneReviews was walking in 11, walking over short distances in 2, running in 1 and independent sitting in 1, and some patients become wheelchair users in adolescence [17]. The primary data of the Zaharieva series are less pessimistic and refer to a different cohort: at last assessment, all 18 patients remained ambulant, at least over short distances [52]. The North American orthopaedic cohort of 26 patients followed between 2014 and 2025, with a median age of 22 days at diagnosis and 4 years at data collection (25 days to 55 years), quantified the musculoskeletal burden: scoliosis in 19 of 23 (83%), hyperkyphosis in 11 of 23 (48%), joint contractures in 14 of 23 (61%) and congenital foot deformity in 14 of 23 (61%, with 13 clubfeet and one bilateral vertical talus), with median weight and height at the 1st centile [69].

Respiratory compromise may arise at any age. The pulmonary series of five homozygous patients illustrates the spectrum: one without identified respiratory complications; one with normal spirometry until 14 years and a fall in forced vital capacity to a moderate restrictive pattern at that age; a girl with progressive decline in forced vital capacity, forced expiratory volume in one second and peak cough flow between 11 and 15 years, who started bilevel non-invasive ventilation at 15 years because of rising end-tidal CO2 and began using assisted cough; a boy with respiratory distress at birth, four months of neonatal intensive care and a malignant hyperthermia crisis at 7 months during neurosurgery; and a girl with tracheostomy and continuous ventilation at 6 months for restrictive chest wall disease [57]. Computed tomography showed, in two of these patients, dependent lower-lobe opacities attributed to aspiration and atelectasis, without interstitial disease [57].

Other organs are affected less frequently. Hearing loss, in most cases conductive, was documented in 7 of the 18 patients in the Zaharieva series and in 2 of 24 in the South African series, and in that same Zaharieva series six patients had speech delay or dysarthria; facial haemangiomas are a described finding; dental malocclusion, mandibular prominence and malar hypoplasia occurred in 8 of Zaharieva's 18 patients [17, 20, 52]. Structural cardiac anomalies are uncommon and probably coincidental: two of the 18 South African patients with data had patent ductus arteriosus or atrial septal defect, and one patient in the pulmonary series had mild aortic root dilatation with mitral and tricuspid regurgitation [20, 57]. Two patients in the Zaharieva series had recurrent bradycardia and ventricular hypertrophy, which resolved after the first year of life; the authors consider the finding probably unrelated to the disease, because STAC3 is not expressed in the heart, and leave the question open until there is prolonged follow-up of more patients [52]. Intelligence is typically normal and intellectual disability is rare, with two of six South African patients assessed after 6 years of age showing mild impairment [17, 20]. Brain imaging was normal in 8 of 10 South African patients studied [20].

Quality of life was assessed in a study using the Pediatric Quality of Life Inventory and a dedicated questionnaire on genetic testing, counselling and caregiver burden: health-related quality of life was reduced, with marked worsening in the transition from adolescence to adulthood in the physical, social and emotional domains [70].

4. Clinical Recognition and Red Flags

4.1. The hypotonic infant

Central hypotonia is much more frequent than peripheral neuromuscular disease in hypotonic neonates, and the most frequent neonatal neuromuscular cause is congenital myotonic dystrophy, followed by neonatal myasthenia, congenital muscular dystrophies and nemaline and myotubular congenital myopathies [59]. The ENMC estimates that congenital myopathies account for less than 10% of all neonatal hypotonia [1]. The history should include a three-generation pedigree seeking consanguinity, muscle weakness and unexplained infant deaths in relatives' offspring (the X-linked pattern in myotubular myopathy), fetal movements, polyhydramnios, perinatal asphyxia, gestational age, when hypotonia was first noticed, progression and feeding ability [59]. An alert and responsive child with hypotonia that remains static over hours or days suggests a peripheral neuromuscular cause; a marked myopathic face is characteristic of myotonic dystrophy and myotubular myopathy; lethargy and progression over hours or days suggest a central or metabolic cause; tongue fasciculations, contractures and clubfoot, tendon reflexes and maternal signs of myotonic dystrophy or myasthenia should be assessed [59].

4.2. Clinical subtype clues

The tables in the 2014 diagnostic consensus remain the most useful tool for prioritising the diagnostic hypothesis and interpreting sequencing results [6]. The following table brings together clues in infants (younger than 2 years) and older children.

Adapted from tables 1, 2 and 5 of the 2014 consensus [6].

4.3. Signs suggesting another diagnosis

Some findings are poorly compatible with congenital myopathy and should direct attention to alternative diagnoses: increased reflexes or other central nervous system abnormalities (unless hypoxic encephalopathy coexists), tongue fasciculations (suggestive of spinal muscular atrophy), dysmorphism other than the “myopathic face”, elevated lactate or metabolic acidosis, rapid deterioration in the first year, extreme hyperlaxity (more suggestive of collagen VI disease, although it may occur with RYR1), muscle pseudohypertrophy (muscular dystrophy or Pompe disease), and creatine kinase above five times the upper limit, which should prompt consideration of dystrophy [6]. Creatine kinase is non-specifically elevated during the first week of life [6]. In an adult with subacute proximal or axial weakness beginning after 40 years, with dysphagia, weight loss or a monoclonal protein, sporadic late-onset nemaline myopathy should be considered; it is now classified among the paraproteinaemic myopathies and is treatable [5, 71].

4.4. Red flags altering urgency

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

The ENMC established that a diagnosis of congenital myopathy requires compatible symptoms and either a confirmed genetic diagnosis explaining the presentation or a compatible muscle biopsy; in the absence of both, the terms probable or possible congenital myopathy are used, and the patient should be placed within a broader category of congenital muscle disease that keeps alternative diagnoses open [1]. This formulation replaces the previous model in which biopsy preceded genetic testing and single-gene sequencing was guided by histology [1, 6].

5.2. Non-genetic investigations

Creatine kinase is normal or mildly elevated; values above five times normal suggest dystrophy, although they can occur in some subtypes (RYR1 forms with exertional myalgia or a congenital dystrophy presentation, TTN) [1, 6]. Electroneuromyography shows early, rich recruitment with low-amplitude motor unit potentials and excludes neurogenic involvement; repetitive stimulation at 3 Hz and single-fibre electromyography help exclude congenital myasthenic syndromes, although some congenital myopathies have neuromuscular junction abnormalities; the examination is less well tolerated and more difficult to interpret in neonates and infants [1]. In infants, the paediatric team's first-line tests include blood glucose, ammonia and blood gas analysis, and, when hypotonia is central, genomic microarray, organic acids and amino acids, SNRPN methylation and DMPK expansion testing [59].

5.3. Muscle imaging

Magnetic resonance imaging is the preferred technique and detects fibrofatty replacement on T1-weighted sequences or Dixon fat images; because congenital myopathies frequently involve muscles of the head (pterygoids, tongue), neck, arms and trunk, whole-body MRI is preferred [1]. Patterns are well characterised for SELENON, dominant RYR1, DNM2, MYH7 and ACTA1, and are more heterogeneous in other entities, such as the NEB-related nemaline form; yield is higher in patients with moderate weakness and lower in infants; ultrasound is an alternative when MRI would require sedation and helps select the biopsy site [1]. In preliminary unpublished results presented at the workshop, three experts who assessed, while blinded, 30 whole-body MRIs of children with variants in ten genes with well-defined patterns obtained complete concordance with the genetic result in more than 80% of cases, 100% for pathogenic variants and 75% and 80% for likely pathogenic variants and variants of uncertain significance, respectively [1].

Source: 2014 diagnostic consensus, table 5 and figure 3 [6].

In congenital myopathy 13, lower limb muscle MRI was described in four patients of the Zaharieva series, with conventional T1-weighted sequences: involvement was slightly asymmetric, more distal than proximal and more posterior than anterior, with semimembranosus the most affected muscle; asymmetry of biceps femoris and semitendinosus occurred in a single patient; in the legs, tibialis anterior and the posterior compartment muscles were relatively spared in one patient, whereas another had mild asymmetric involvement of tibialis anterior and another asymmetric involvement of soleus [52]. The number of patients examined is too small to constitute a discriminating pattern, and the usefulness of imaging in the disease is to support suspicion and guide the biopsy site, not to replace genetic testing.

5.4. Muscle biopsy

Biopsy is no longer required as the first examination when genetic testing has a short turnaround time and the result is unequivocal, but remains relevant for inconclusive genetic results, characterisation of new entities and as a source of material for immunohistochemistry, protein studies, transcriptomics, mitochondrial DNA and cellular models [1]. Age affects sensitivity: biopsies at different ages may show different findings, neonatal biopsies are difficult to interpret because of the small fibre size, and a repeat biopsy may be considered in inconclusive cases [1, 5]. In dominant C-terminal RYR1 variants, central cores often emerge later, so early biopsies may show only type 1 fibre uniformity [1]. Severe forms involving MTM1, DNM2, RYR1 and ACTA1 may show endomysial fibrosis and fatty infiltration mimicking a dystrophy, but necrosis is rare or absent [6].

Sources: 2014 diagnostic consensus and Brazilian textbook Table 15.3.6 [3, 4, 6].

5.5. Genetic strategy

The ENMC recommends a “genetics-first” approach whenever available: a massively parallel sequencing panel, exome or genome as the first-line test, selected according to local availability, age, clinical condition, age at onset and family history; exome or genome sequencing is the first option in some paediatric settings (neonatal hypotonia, unusual presentations with extramuscular involvement, critically ill infants), while neuromuscular panels may be more appropriate in older children and adults [1]. In neonatal intensive care units, rapid exome or genome sequencing has a yield of 20% to 60%, shortens time to diagnosis and influences management; it has been proposed as first-line testing for unexplained hypotonia, alongside rapid chromosomal microarray and targeted testing for Prader–Willi syndrome, DM1 and spinal muscular atrophy [1].

The 2014 consensus described situations in which targeted genetic testing should precede biopsy that remain valid: exclusion of spinal muscular atrophy or congenital DM1, investigation of characteristic phenotypes with poorly informative biopsy (SELENON, LMNA), and severely affected neonates in whom treatment limitation is being considered, testing MTM1, DMPK or severe nemaline forms (ACTA1, KLHL40); in these cases it recommends obtaining biopsies from more than one muscle, blood for DNA and a fibroblast line immediately after death [6]. In the same document, subtype priorities were: MTM1 first in severely affected boys, with muscle complementary DNA analysis if genomic sequencing is negative; DNM2 first if there is a dominant family history; SELENON first if the phenotype is typical; and TPM3 when rods are restricted to type 1 fibres [6].

Congenital myopathy 13 adds a situation in which testing for a single variant is the rational first line. Testing for NM_145064.3:c.851G>C can be performed on its own when ancestry is Lumbee, and the authors of the South African series recommend the same in patients of African ancestry who combine a congenital myopathy phenotype, palatal anomaly (cleft or high palate) and joint contractures, including talipes equinovarus and arthrogryposis, as it is also the most efficient route in resource-limited settings [17, 20]. In that series, 30 of the 31 patients had undergone at least one genetic test before diagnosis, 21 had been tested for SMN1 exon 7 deletion, 6 for recurrent RYR1 variants, 4 for 15q11-q13 methylation and 4 for DMPK expansion, and 21 had had at least one cytogenetic study, a sequence of investigations that targeted testing avoids [20]. Outside these settings, STAC3 should be included in the congenital myopathy panel; because of the rarity of the disease, some panels do not include it, and a neuromuscular panel without STAC3 was one of the documented causes of diagnostic delay [17, 20]. Muscle biopsy is not confirmatory, shows only non-specific myopathic changes, with small type I and type II fibres, fibre type disproportion, increased central nuclei and, on electron microscopy, lipid droplets and subsarcolemmal mitochondrial aggregates, and requires anaesthesia in a patient at risk of malignant hyperthermia, so genetic testing should precede it [17, 20]. The six quadriceps biopsies of the Zaharieva series, obtained between the first month and 9 years of age, confirm this non-specificity and refine the picture: variation in fibre size in all, without excess adipose or connective tissue, and predominance of type I or slow myosin fibres in most, the small fibres being mainly of this type; some biopsies showed occasional fibres with internal nuclei and whorled or split fibres; some very small fibres expressed fetal myosin but not developmental myosin, indicating that they were not regenerating fibres and constituting a finding of unknown origin, common to several myopathies [52]. Electron microscopy in three patients showed myofibrillar loss, irregular and interrupted Z lines with minicore areas and disorganised sarcomeres, mitochondria of variable size, shape and distribution, dilated sarcoplasmic reticulum in some samples and preserved triad structure, with the transverse tubular component often prominent and slightly dilated [52]. Because minicore-type areas may suggest a RYR1- or SELENON-related myopathy, this pattern does not distinguish STAC3 disorder and reinforces that the diagnosis is molecular. Creatine kinase is normal in most: 16 of 21 South African patients with an available value had normal creatine kinase, and the four elevated values (two to five times the upper limit) were obtained mainly in the neonatal period [20].

5.6. Test limitations and reporting

The proportion of variants detected by a method (for example, 90% of MTM1 variants by sequencing) is not equivalent to the clinical sensitivity of the test. In the Beggs cohort, 30% of patients with clinicopathological evidence of congenital myopathy remained without a genetic diagnosis; in the Swedish study, one in five patients remained undiagnosed despite next-generation sequencing; and the ENMC reports up to 40% of cases without a genetic diagnosis [1, 7]. In a prospective Taiwanese study in which exome sequencing was the first examination, without prior biopsy, the yield was 69.6% (16 of 23) in suspected congenital myopathy, and 58.8% of patients diagnosed with neuromuscular disorders received a diagnosis different from the initial clinical impression [72]. Panels should be updated regularly; in 2026 the French FILNEMUS network published the 2025 update of its gene lists, organised into 13 phenotype panels and a core muscle gene panel [73].

The report should state the gene, transcript with version (for example NM_000252.3 for MTM1, NM_000540.3 for RYR1), HGVS nomenclature, zygosity, phase when relevant, the five-class ACMG/AMP classification and technical limitations (coverage, CNV, regions not analysed). Exome and genome analyses carry a risk of secondary findings, requiring counselling before and after testing [1]. For RYR1, the criteria of the ClinGen expert panel and the European malignant hyperthermia group's matrix apply to malignant hyperthermia susceptibility rather than pathogenicity for myopathy.

5.7. Integrated algorithm

6. Differential Diagnosis

The differential diagnosis includes other causes of infantile hypotonia, late-onset neuromuscular diseases with proximal weakness and acquired mimics. Overlap is particularly marked with congenital myotonic dystrophy, congenital myasthenic syndromes, congenital muscular dystrophies, metabolic myopathies, spinal muscular atrophy and Prader–Willi syndrome [3, 6].

Congenital myopathy 13 requires differential reasoning in two directions. In the downward direction, the phenotype was attributed, before molecular diagnosis, to Carey-Fineman-Ziter syndrome in the Qatari sibship and to Moebius syndrome in Telegrafi's Puerto Rican sibship, and in the second Brazilian patient of the Gomes series, in whom apparent involvement of the sixth cranial nerve suggested Moebius syndrome until the variant was identified [51, 55]. In the upward direction, the most frequent confusion is with spinal muscular atrophy, because of hypotonia with areflexia, and with recessive RYR1-related centronuclear myopathy and Prader-Willi syndrome, diagnoses for which tests were available earlier in southern African health systems [20]. Reverse screening is equally informative: neither the 12 patients with a clinical diagnosis of Carey-Fineman-Ziter syndrome nor the 50 with Moebius syndrome or other congenital facial weakness screened by Telegrafi had rare coding STAC3 variants, so phenotypic overlap does not mean that the gene explains a relevant proportion of these syndromes [55].

The 2014 consensus excluded from the group three entities historically grouped with congenital myopathies: sporadic adult-onset nemaline myopathy, spheroid body myopathy and sarcotubular myopathy (reclassified with limb-girdle dystrophies and myofibrillar myopathies), and rapidly progressive FHL1-related reducing body myopathy [6]. The distinction between central and internal nuclear abnormalities also matters: central nuclei, located at the centre of the fibre, are typical of myotubular myopathy, whereas eccentric internal nuclei occur in other centronuclear forms and in chronic regeneration [4].

7. Treatment and Risk Management Strategies

7.1. Principles and reference documents

No disease-modifying therapy is approved for any congenital myopathy, and care relies on a multidisciplinary team comprising neurology, genetics, respiratory medicine, orthopaedics, rehabilitation, gastroenterology and nutrition, oral health, and occupational, physical and speech therapies [5]. The reference document remains the consensus statement of the International Standard of Care Committee for Congenital Myopathies, published in 2012: 59 experts from 10 disciplines, organised into five working groups, reached consensus through two rounds of online surveys (48 and 52 respondents to 66 questions) and a three-day workshop in Stanford in May 2010, with 35 members from 8 countries [5]. The recommendations are based on expert consensus, without formal evidence grading, because no prospective clinical trial had been conducted in this group of diseases [5]. The 277th ENMC workshop announced revision of this standard of care by a dedicated working group; at the time of this article, the revision had not been identified as published [1]. No subsequent specific North American or European guideline was identified; the 2012 consensus is international and includes experts from the United States, Europe, Australia and Brazil [5].

7.2. Neurological care and follow-up

The consultation to communicate the diagnosis should take place as soon as a clinical diagnosis is established, even without a genetic diagnosis, allowing time for questions and, if the family wishes, involving other relatives; it should address the diagnosis, prognosis by organ system, recurrence risk, treatment plan and support resources, emphasise associated risks such as malignant hyperthermia with RYR1 and respiratory involvement with SELENON, and recommend an alert card or bracelet [5]. Follow-up is every 3 or 4 months before 12 months and every 6 to 12 months thereafter, adjusted to severity; each visit monitors breathing, speech and swallowing, the heart, orthopaedics and growth, and reassesses the diagnosis in patients without a specific diagnosis, considering repeat biopsy [5]. Anticipatory guidance includes a healthy weight, exercise, nutrition with vitamin D supplementation, vaccination and reminders about malignant hyperthermia risk [5].

Myalgia is frequent, particularly with RYR1, and may be treated with non-steroidal anti-inflammatory drugs, gabapentin and massage; activity modification and mobility aids address fatigue and exercise intolerance [5]. Patients rarely perceive ophthalmoparesis or ptosis; ptosis surgery has uncertain benefit and is considered only with impaired vision, while incomplete closure requires lubrication against corneal abrasion [5].

7.3. Respiratory care

All patients should be considered at risk of potentially silent respiratory failure. Assessment should be early and regular, comparing each patient with themselves because height does not reflect lung growth with scoliosis or contractures [5].

Table 2 of the 2012 consensus [5]. Low-risk patients undergo these tests at least annually and high-risk patients more frequently, for example every 6 months.

A supine vital capacity more than 20% below the sitting value indicates diaphragmatic weakness and risk of nocturnal hypoventilation, regardless of symptoms [5]. All patients should receive pneumococcal and influenza vaccines in addition to the routine schedule and learn assisted cough techniques (mechanical insufflation–exsufflation, air-stacking, manually assisted cough) and secretion mobilisation during stable periods; bronchodilators and mucolytics are not routinely recommended [5]. Non-invasive bilevel ventilation with a backup rate is the recommended modality for hypoventilation; continuous positive airway pressure does not treat hypoventilation and is not recommended for the usual complications [5]. Tracheostomy is considered when non-invasive ventilation is required 24 hours a day or after repeated extubation failures, with family involvement, and is not an emergency [5]. In acute respiratory infections, chest radiography, oximetry and blood gas analysis, intensified cough assistance and ventilation are recommended, and antibiotics are frequently used given the potential severity of bacterial pneumonia [5]. Anaesthesia, even for minor procedures, may cause prolonged respiratory depression; before spinal fusion, initiation of preoperative non-invasive ventilation or extubation to non-invasive ventilation should be considered [5].

In SELENON-related myopathy, respiratory surveillance should follow its own schedule, independently of motor function: sitting and supine spirometry, respiratory muscle strength and assessment for nocturnal hypoventilation. In Scoto's series of 41 patients, the mean age at initiation of nocturnal non-invasive ventilation was 13.9 years (from 1 to 33 years), and two patients died of respiratory failure at 10 and 22 years [65]. Nocturnal non-invasive ventilation appears to stabilise the decline in forced vital capacity and respiratory strength, according to a respiratory physiology study [78]. Inspiratory muscle training was evaluated in nemaline myopathy in a trial registered as completed (NCT03728803) [79].

7.4. Cardiac surveillance

The 2012 consensus recommends assessment by a cardiologist approximately every 2 years in asymptomatic patients, particularly when the genetic diagnosis is uncertain, and more frequently if symptoms or abnormalities on electrocardiography or echocardiography are present; with MTM1 and RYR1, in the absence of signs, routine surveillance is probably unnecessary, while acknowledging the theoretical risk of cor pulmonale in severe respiratory disease [5]. In congenital titinopathies, cardiac assessment at diagnosis and annually thereafter is recommended, with electrocardiography and echocardiography [36]. A genetic diagnosis enables targeted cardiomyopathy screening, for example with TTN [1].

7.5. Rehabilitation, orthopaedics and bone health

The consensus found no evidence that exercise is harmful in congenital myopathies and recommends regular, symmetrical endurance exercise, preferably concentric, at least 2 to 3 times per week, adjusted to fatigue and post-exertional pain, avoiding high-impact sports [5]. Standing is recommended even in very weak children, with care when tightening standing-frame straps because of the risk of metaphyseal fractures; powered wheelchairs can be provided from 2 years; botulinum toxin is contraindicated in the skeletal muscle of children with primary muscle disease, for any indication, because disuse atrophy may render the patient non-ambulant [5].

Source: 2012 consensus [5].

7.6. Feeding, digestive motility, speech and oral health

Growth should be measured at each visit, at least every 3 months in infants, using arm span or ulna length when the child cannot stand, with dietary assessment and annual calcium and vitamin D measurement [5]. Feeding assessment by a specialist therapist includes an oromotor examination and trials with liquids and food; videofluoroscopy is indicated when the examination suggests dysfunction, even without coughing, because of the possibility of silent aspiration [5]. Nasogastric tubes are not intended for prolonged use; gastrostomy should be strongly considered in neonates with very severe myopathy and when a child cannot meet caloric requirements orally, while maintaining oral stimulation to avoid aversion; excessive weight gain also compromises walking and transfers [5]. In nemaline myopathy, feeding difficulties are frequent in the first year (17 of 19 children assessed in one series) and tend to improve; gastrostomy was associated with better growth and fewer respiratory problems [5].

Gastro-oesophageal reflux is treated with proton pump inhibitors, H2 antagonists and antacids, thickening, upright positioning and head-of-bed elevation, with antireflux surgery in selected cases; dysmotility and constipation are treated with hydration, mobilisation, stool softeners and laxatives, and some physicians use erythromycin as a prokinetic [5]. There is no consensus treatment for sialorrhoea: botulinum toxin and salivary gland ligation are not recommended; systemic anticholinergics may be effective but thicken secretions; a small study suggested a benefit of L-tyrosine for sialorrhoea in nemaline myopathy [5]. Speech therapy addresses articulation, respiratory control and hypernasality, with augmentative communication when necessary, a speech prosthesis or pharyngoplasty in selected cases [5]. Paediatric dental care is recommended by the first year, with twice-daily brushing, visits every 6 months and orthodontics at 6 to 8 years; extensive orthodontic treatment in children with marked facial weakness is not recommended because of recurrence, and surgery for severe malocclusion should not be considered because of the anaesthetic risk [5].

7.7. Anaesthesia and malignant hyperthermia

Malignant hyperthermia is the central anaesthetic concern, although the risk varies with genotype. The risk is highest in RYR1-related myopathies, particularly with dominant or de novo variants and in King-Denborough syndrome, is less well defined with recessive variants, and also exists in STAC3-related myopathy (Native American myopathy); there is little evidence of susceptibility in other genetically defined congenital myopathies [5, 33]. Patients with X-linked myotubular myopathy are not susceptible to malignant hyperthermia, but suxamethonium should be avoided [4, 80]. Because many patients undergo surgery without a genetic diagnosis or with non-specific histology, the consensus recommends avoiding volatile agents (except nitrous oxide) and suxamethonium whenever possible, using a “clean” technique with a prepared machine, cardiorespiratory and end-tidal CO2 monitoring, available dantrolene and intensive care support; prophylactic dantrolene is not recommended even with established susceptibility [5]. The recommended dose in a crisis is that of the current European Malignant Hyperthermia Group guideline: dantrolene 2.5 mg/kg intravenously as early as possible, repeated until stabilisation [21, 33]. The 2012 consensus specified dantrolene from 1 mg/kg to 10 mg/kg [5]. By comparison, the European SmPC of Agilus® (120 mg) indicates the same dose of 2.5 mg/kg by rapid intravenous injection in adults and children, repeated every 10 minutes while tachycardia, hypoventilation, acidosis and hyperthermia persist, not exceeding 300 mg per dose and re-examining the diagnosis if a cumulative dose of 10 mg/kg or more is being considered [81]; in the United States, the labels of Dantrium® Intravenous and Ryanodex® indicate a minimum of 1 mg/kg, repeated up to a cumulative maximum of 10 mg/kg, with the same dose per kilogram in paediatrics, so the guideline's initial dose is higher than the minimum dose in these labels [82, 83]. The GeneGuidance database also notes the contraindication to calcium channel antagonists with dantrolene and a fatal outcome after ondansetron in a child with RYR1-related multiminicore disease [33]. The 2022 ENMC consensus on anaesthesia in neuromuscular disorders is the most recent European reference in this domain [84].

In congenital myopathy 13, trigger avoidance is part of routine management rather than an ancillary precaution. The agents to avoid are potent volatile anaesthetics (halothane, isoflurane, sevoflurane and, by the same class, desflurane and enflurane) and depolarising muscle relaxants (suxamethonium and decamethonium), and GeneReviews considers it imperative that the patient informs the anaesthetist and treating physicians of the diagnosis before any procedure, so that safe agents are chosen [17]. The practical implication is considerable because these patients undergo surgery frequently: in the North American orthopaedic cohort, 13 of 23 patients (57%) had at least one orthopaedic intervention, 18 of 23 (78%) at least one non-orthopaedic surgery and 20 of 23 (87%) at least one general anaesthetic, mainly for gastrostomy, cleft palate repair, ptosis correction, kyphoscoliosis surgery and clubfoot correction [22, 69].

The Brazilian series of three malignant hyperthermia crises in patients homozygous for the founder variant describes the presentation and treatment in detail. The crises occurred in a 2-year-old boy during clubfoot correction, in a 12-year-old boy during distraction of a spinal growing system and in a 15-year-old girl during spinal fusion; all were triggered by sevoflurane, with associated suxamethonium in one case, and all began 10 to 15 minutes after the start of the halogenated agent, with hypercapnia or muscle rigidity as the first sign [22]. Two patients reached severe hypercapnia (end-tidal CO2 of 120 and 133 mmHg, for a normal range of 35 to 45 mmHg); there was hyperthermia up to 39.9 ºC, tachycardia up to 179 per minute, acidosis with a pH of 6.92 in the most severe case, hypotension and, in one patient, rhabdomyolysis with creatine kinase of 1,152 U/L (upper limit 140) [22]. The clinical grading scale score for malignant hyperthermia ranged from 33 to 63 points, corresponding to probabilities from “greater than likely” to “almost certain” [22]. The first patient improved with discontinuation of sevoflurane alone; the second received hyperventilation with 100% oxygen, intravenous dantrolene in two administrations of 2.5 and 2 mg/kg and adrenaline; the third received a dantrolene bolus of 2.5 mg/kg followed by a maintenance infusion of 0.25 mg/kg per hour [22]. All three patients survived, as did all patients with a crisis described in the literature compiled by GeneReviews [17, 22]. The bolus dose used matches that of the European Malignant Hyperthermia Group guideline, and the maintenance infusion of 0.25 mg/kg per hour corresponds to the practice described in the report rather than to a guideline or label dosage [21, 22].

The Zaharieva series is the source with the largest number of anaesthetic episodes and documents an adverse reaction to general anaesthetics in 10 of the 18 patients (56%), the highest frequency described in any cohort of the disease [52]. A full description of the course is available for one of them, an infant who, at 6 months, after five uneventful general anaesthetics, underwent inhalational induction with 8% sevoflurane, 50% nitrous oxide and 50% oxygen for approximately 45 minutes, because of difficult venous access: upper limb tone increased, end-tidal CO2 rose, heart rate fell from 164 to 139 per minute at induction but reached 208 per minute 50 minutes later, with a mean arterial pressure of 53 mmHg, and one hour after induction core temperature was 39.6 ºC with a marked increase in upper and lower limb tone; administration of dantrolene was followed by immediate improvement, with a progressive fall in heart rate and temperature and reduced tone [52]. The laboratory point is the one that most alters practice: in this patient there was no myoglobinuria nor any rise in creatine kinase or potassium, and the peak creatine kinase was 69 U/L fourteen hours after the event; in another patient post-event creatine kinase was around 600 U/L with normal myoglobin, and in two additional patients post-event creatine kinase and myoglobin were normal [52]. “Classical” malignant hyperthermia usually sets in rapidly, with subsequent cardiovascular collapse, and almost always leaves laboratory markers of muscle injury (elevated creatine kinase, myoglobinuria and hyperkalaemia); in patients with STAC3 variants onset was more gradual and these markers were absent, so the authors classify the picture as a “malignant hyperthermia-like” reaction, consistent with the absence of a shift in agonist sensitivity and of raised resting calcium observed in myotubes (section 2.6) [52]. The operational consequence is twofold: the response to intravenous dantrolene is maintained and justifies having it available, but a normal postoperative creatine kinase does not exclude an episode triggered by a halogenated agent in a patient with STAC3, and waiting for rhabdomyolysis before acting is an error.

Two aspects of this case series have a direct consequence for planning. The first is that previous uneventful anaesthesia does not protect: two of the three Brazilian patients had had two and four uneventful inhalational anaesthetics, and the same was true of the patient in the original description and of the patient in the Zaharieva series with five previous uneventful anaesthetics [17, 22, 52]. The second is the variable expressivity of crises: in two of the five previously published cases muscle rigidity was the only sign, and three of the five did not develop rhabdomyolysis, which means that an abortive or attenuated crisis may go undiagnosed [22]. Conversely, 10 of the 30 patients in the STAC3 group of the African cohort underwent surgery with precautionary measures for malignant hyperthermia susceptibility and had an uneventful intraoperative course, documenting the effectiveness of trigger-free anaesthesia [56]. Penetrance is incomplete: the frequency of crises was 29% in Stamm's 14 patients, 56% in the 18 patients of the Zaharieva series, 22% in 18 South African patients with a known anaesthetic history and 18% in the 44 patients of the African cohort, and neither of the two Brazilian patients of Gomes had a crisis, despite having undergone clubfoot correction [20, 29, 51, 52, 56]. A normal contracture test does not cancel the anaesthetic risk conferred by a molecular diagnosis of STAC3, because discordance between genetic testing and contracture testing and inter-laboratory variability of results are documented [33].

For myopathy-associated RYR1 variants, the 277th workshop emphasised that dominant C-terminal variants associated with typical central cores do not, in most cases, confer malignant hyperthermia susceptibility, except for certain specific variants, whereas dominant variants in other regions are associated with atypical cores and susceptibility [1]. This heterogeneity does not change the practical recommendation to avoid triggers until specialist assessment has taken place.

7.8. Genotype-specific management

In X-linked myotubular myopathy, GeneReviews recommends, after diagnosis, assessment of pulmonary function to plan long-term ventilation, feeding and swallowing, ophthalmological function and, in older children, the spine; investigation for spherocytosis (osmotic fragility testing) if haemolysis or unexplained anaemia is present and for pyloric stenosis if an infant has vomiting; and referral to genetics [4]. Given the risk of aspiration pneumonia and respiratory failure in moderate and severe forms, tracheostomy and gastrostomy should be seriously considered; communication in ventilated patients is supported by a tracheostomy speaking valve, sign language and communication devices; neuropsychological assessment guides schooling [4]. Surveillance includes annual pulmonary assessment, polysomnography every 1 to 3 years (unless symptoms occur), spinal examination particularly in late childhood and adolescence, annual ophthalmological examination (ophthalmoplegia, ptosis, myopia, eyelid closure) and assessment of dental occlusion; annual blood count, liver tests and abdominal ultrasound are options, without evidence that they detect peliosis before haemorrhage [4]. The 2026 review of liver disease proposes that episodic cholestasis and subclinical structural changes of the bile canaliculus are present in most patients, warranting clinical attention to liver function, particularly in the context of gene therapy [10]. Families should be informed that acute abdominal pain or unexplained anaemia are emergencies [4].

Unexplained motor decline in myotubular myopathy should prompt assessment of neuromuscular transmission: a patient with a mild form, decrement on repetitive stimulation and single-fibre jitter regained walking with pyridostigmine [4]. Pyridostigmine is used off-label by many patients, with anecdotal reports of improvement, but has not been studied systematically and there is no validated dose for this indication [4]. In the absence of a guideline dose for congenital myopathies, dosage is extrapolated from the myasthenia gravis label, with individual titration and use outside the label conditions: the Portuguese SmPC of Mestinon® 60 mg indicates 1 to 3 tablets (60 to 180 mg) 2 to 4 times a day, or higher doses if necessary, and, in paediatrics, a dose determined by titration [85]; the US label indicates an average dose of 600 mg/day (ten tablets or ten 5 mL teaspoonfuls of 60 mg/5 mL oral solution), from 60 to 360 mg/day in mild cases up to 1,500 mg/day in severe cases, or 1 to 3 extended-release 180 mg tablets once or twice a day, with a minimum interval of 6 hours [86]. In KLHL40-related nemaline myopathy, a single patient had a sustained response to high-dose acetylcholinesterase inhibitors, constituting a case report rather than evidence of efficacy [87].

In SELENON-related myopathy, management focuses on respiratory surveillance (section 7.3), scoliosis (surgery at a mean age of 13.9 years in Scoto's series) and low weight (21 of 41 patients were underweight without evident feeding difficulties) [65]. In SPEG-related centronuclear myopathy and titinopathies, cardiac surveillance is a priority [36]. In congenital myopathy 13 there is no treatment that halts or reverses the disease, and care is organised by a multidisciplinary neuromuscular team, with occupational therapy and physiotherapy for range of motion and mobility, adaptive devices, feeding support, speech therapy, scoliosis management and respiratory support [17]. The type and timing of cleft palate surgery should be decided by a craniofacial team, given the associated comorbidities, and ptosis intervention is coordinated with ophthalmology, because of amblyopia, visual field loss and the compensatory head-extended posture caused by uncorrected ptosis [17]. The recommended initial evaluation after diagnosis includes growth measurement, neurology and neuromuscular clinic consultation with physical medicine and rehabilitation, orthopaedic assessment of kyphoscoliosis, foot deformities and contractures, ophthalmological examination with extraocular movements, acuity and visual field, feeding assessment with a clinical trial of different teats and, when indicated, videofluoroscopic swallowing study, chest radiograph and upper gastrointestinal contrast study, referral to a craniofacial team, respiratory medicine assessment with polysomnography, spirometry, maximal inspiratory and expiratory pressures and peak cough flow, and genetics clinic consultation to review the natural history, inheritance, recurrence risk and prognosis; the surgical history should be specifically reviewed for episodes compatible with malignant hyperthermia [17].

Contractures are treated with physiotherapy, stretching, night splints or serial casting, avoiding prolonged periods of immobilisation, particularly after surgery; talipes equinovarus may require serial casting, splints and surgery; and scoliosis is initially treated with bracing, with frequent progression to surgery [17]. For feeding difficulties, specific cleft palate bottles, feeding therapy and, when intake is insufficient or there is a risk of aspiration, nasogastric tube or enteral feeding are used, sometimes with gastrostomy and airway protection procedures [17]. Respiratory support includes non-invasive or invasive ventilation and mechanical assisted cough, with aggressive treatment and prevention of lower respiratory tract infections, including influenza vaccination and the pneumococcal polysaccharide vaccine, and assessment for ascending or descending microaspiration [17]. Because of the progressive nature of respiratory compromise, the authors of the pulmonary series recommend pulmonary function tests every 6 months even when the first ones are normal, and individualised plans, as no correlation between variant and respiratory course has been identified [57]. Rehabilitation care, respiratory surveillance and nutrition otherwise follow the 2012 international consensus, which GeneReviews cites as the basis of the surveillance plan [5, 17]. The sources consulted describe no therapeutic trials or targeted therapies in development for STAC3 disorder; GeneReviews refers the reader to trial registries and notes that there may be no trials for this condition [17].

7.9. Investigational therapies and developments in the past 12 months

No targeted therapy is authorised. Clinical programmes have focused on X-linked myotubular, dominant centronuclear and RYR1-related myopathies.

Developments in the past 12 months have changed the landscape of myotubular myopathy. The AT132 programme was stopped for strategic reasons (the company's April 2026 announcement, rather than a regulatory decision), and the first ASP2957 trial began recruitment in December 2025 [12, 13]. The 2026 review by Pannia and colleagues summarises the problem affecting these programmes: all four patients who died in ASPIRO had liver dysfunction before administration, although they met the protocol criteria (transaminases up to five times the upper limit and no peliosis on imaging); the observed injury was severe intrahepatic cholestasis, probably distinct from hepatotoxicity in other adeno-associated vector programmes; in mice with myotubular myopathy fed purified diets, AT132 increased the incidence and severity of cholestasis, with early mortality; and ASP2957, like AT132, does not express MTM1 in the liver because it uses a muscle promoter [10]. Astellas has initiated an observational study of cholestasis in boys with myotubular myopathy, with liver assessment approximately every 6 weeks (NCT06581146) [97]. For RYR1-related myopathies, the new development is the start, in September 2026, of the first placebo-controlled phase 2 trial of Surlorian [14]. Also published in 2026 were the protocol for the READYCOM natural history study, which prepares trial readiness in congenital myopathies in the Netherlands, and the international survey of patients with RYR1-related disorders concerning trial participation [98, 99]. A Cochrane review of treatments for RYR1-related disorders has been registered but is published only as a protocol [100].

These data require cautious interpretation. ASPIRO was open-label, its design changed during implementation, and its analyses were considered exploratory; the control group combined patients from a previous observational study and patients with deferred treatment; the percentage reduction in ventilation hours does not in itself reflect survival or safety, and deaths from cholestasis at the high dose weigh more heavily in the assessment than the average functional gain [11]. The phase 1 ARM210 trial included seven patients, without a control group, and improvements in fatigue and strength were exploratory endpoints; they cannot be compared with other treatments [93]. The absence of published results for the trials of N-acetylcysteine in SELENON and salbutamol in the sources consulted does not mean that those results do not exist.

7.10. Regulatory status

7.11. Special populations and transition

Pregnancy in women with congenital myopathy has not been studied systematically; motor and respiratory deterioration may occur, particularly in forms with diaphragmatic weakness, and the risk of malignant hyperthermia with RYR1 affects the choice of anaesthesia for operative delivery; the consensus recommends considering all pregnancies high risk, with follow-up in high-risk obstetric care and possible involvement of respiratory medicine and cardiology [5]. Transition to adult care should be planned through an integrated plan involving paediatric and adult providers, future needs and the adolescent's progressive assumption of responsibility [5]. Adult patients may need to be invited back to neuromuscular clinics because many have never received guidance about their disease [1]. In severe chronic respiratory failure where prolonged ventilation is not desired, care options should be discussed with the family and team, including palliative care [5].

8. Reproductive Options and Family Counselling

Counselling depends on the gene and mode of transmission, and the pedigree remains the starting point: it can establish inheritance and help estimate recurrence risk, while identifying the variant in families without an informative pedigree determines the type of myopathy and inheritance [3]. In the nemaline myopathy series cited by the archived GeneReviews, approximately 20% of cases were autosomal recessive, approximately 30% autosomal dominant and approximately 50% simplex, explained by a de novo dominant variant or recessive inheritance [35].

Detection of MTM1 carriers ideally requires knowledge of the proband's variant; if the proband is unavailable, sequencing is performed, followed, if negative, by deletion and duplication analysis [4]. Prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible when the familial variant is known; given the possibility of germline mosaicism, prenatal diagnosis in a male fetus should be discussed even when the mother does not carry the variant in leucocytes [4, 58]. The best time to establish risk and discuss options is before pregnancy, and storing DNA from probands without a molecular diagnosis is recommended for future reanalysis [4, 59]. When a severely affected neonate dies without a diagnosis, muscle biopsies from more than one muscle, blood for DNA and fibroblasts collected immediately after death, and a complete autopsy with neuropathology, muscle histology and electron microscopy are essential for counselling [6, 58].

The ENMC notes that some recessive and X-linked congenital myopathies are included in reproductive carrier screening programmes [1]. In congenital myopathy 13, carrier testing of at-risk relatives requires prior identification of both variants in the family, and prenatal diagnosis and preimplantation genetic testing become possible after this identification [17]. Carrier frequency of the founder variant in southern Africa has two estimates that do not coincide and should be presented with their denominators: 5 heterozygotes among 278 healthy adults with exome data from the Deciphering Developmental Disorders in Africa study, that is 1.8% carriers (95% confidence interval 0.77% to 4.14%) and an allele frequency of 0.899%, corresponding to approximately 1 carrier in 56 and a predicted birth prevalence of approximately 1 in 12,500, with a range of 1 in 2,300 to 1 in 65,000; and a carrier rate of 0.13% in 750 dried blood spot samples from healthy newborns in the northern provinces of South Africa [20, 56]. The first estimate would imply at least 60 affected newborns per year in South Africa [20]. Both series are compatible with a founder effect and justify informing families that the risk for siblings is the usual recessive risk, but that the probability of an unrelated partner being a carrier is not negligible in these populations [20, 56]. Consanguinity is not a necessary condition: it was not reported in 25 of the South African families with available data, nor in the three Brazilian families with a malignant hyperthermia crisis, nor in the two Brazilian families described by Gomes [20, 22, 51]. Counselling should also include anaesthetic information: heterozygous parents and siblings are not considered susceptible to malignant hyperthermia on the basis of the Lumbee series, in which crises and disease occurred only in homozygotes, but an individual with a history of a crisis, an abnormal contracture test and a heterozygous STAC3 variant of uncertain significance has been described, so the family anaesthetic history should be taken and documented [22]. The allelic heterogeneity of RYR1 has specific implications: relatives of patients with RYR1-related myopathy should be informed of the anaesthetic risk, and counselling about malignant hyperthermia susceptibility includes cascade testing and in vitro contracture testing [58, 101]. In all cases, a variant of uncertain significance should not be used for prenatal or preimplantation diagnosis, and family segregation is described as an investigation [6].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Global frequency

Frequency estimates depend on the method: point prevalence counts only patients alive on a given date, whereas birth incidence includes those who have died, which is relevant in a group with early mortality [7].

Differences between studies reflect their methods and populations. In the Swedish study, birth incidence was almost four times point prevalence, and 25% of patients died during the study period [7]. In the meta-analysis, high heterogeneity and the lack of high-quality studies limit generalisation [9]. Hospital series and referral cohorts do not measure population prevalence: the Beggs cohort (1,110 patients) and the French adult cohort (142 patients) describe the genetic distribution among referred patients, rather than frequency in the population [1, 68].

9.2. Relative gene distribution and founder effects

In North American and European cohorts, RYR1 is the most frequent genetic cause: it was the most frequent in the Michigan paediatric population, accounted for 45% of a French adult cohort and is the most common cause in adults according to the ENMC, followed by recessive titinopathies [1, 8, 68]. In a Dutch national cohort of 48 patients with genetically characterised centronuclear myopathy, 18 had DNM2 variants, 14 MTM1, 9 RYR1 and 7 BIN1 [37]. In Sweden, the frequency of MYH2 was attributable to two large families, illustrating the effect of family clusters in small populations [7].

Known founder effects include the NEB exon 55 deletion in Ashkenazi Jews (carriers 1 in 108), the TNNT1 c.538G>T variant in Old Order Amish communities (carriers 6.5%), the KBTBD13 p.(Arg408Cys) variant in the Netherlands, the LMOD3 NM_198271.5:c.1648C>T p.(Leu550Phe) variant in Germany and Austria, the KLHL40 c.1516A>C variant in southern China and the STAC3 c.851G>C variant in the Lumbee of North Carolina, with approximately 1 affected individual in 5,000 in a population of approximately 60,000 enrolled members [17, 41, 45, 47, 49, 50].

The case of STAC3 illustrates how a variant initially considered private to an isolated population turned out to be widely distributed. The c.851G>C variant was later described in families from Qatar, Puerto Rico, Turkey, Russia, South America and the Middle East, in Afro-Caribbean and Comorian families, and in patients of African ancestry [17, 20]. The Zaharieva series was the work that made this distribution indisputable: none of the 18 patients had Native American ancestry, 17 were homozygous for the founder variant and the 12 families, apparently unrelated, were of African, Afro-Caribbean, Comorian, Middle Eastern or South American ancestry; on the basis of this clinical homogeneity across ethnicities, the authors proposed replacing the name “Native American myopathy” with “STAC3-related congenital myopathy” and recommended including the gene in the diagnostic work-up of any patient with congenital myopathy, regardless of ancestry, particularly with a history of episodes compatible with malignant hyperthermia [52]. In southern Africa it has become a frequent cause of congenital hypotonia: 25 of 127 patients (20%) with infantile or childhood hypotonia and negative testing for spinal muscular atrophy or Prader-Willi syndrome were homozygous for the variant, and the corresponding clinical series comprised 31 patients from the Sepedi, Sotho, Tswana, Tsonga, Xhosa, Zulu, Chichewa and Shona ethnolinguistic groups, with two additional cases from Mozambique and Malawi [20]. Gromand and colleagues described seven patients from the Comoros Islands, in the Mozambique Channel, all homozygous for the same variant, the second largest series with shared ancestry after the Lumbee [103]. The African cohort of congenital myopathy with a King-Denborough syndrome phenotype added 30 patients with the variant, 27 homozygous and 3 compound heterozygous with the c.834_836del deletion [56].

Haplotype analysis points to a common ancestral origin. In the five South African patients studied by single nucleotide polymorphism microarray, all homozygous, there were overlapping regions of homozygosity spanning STAC3, with four sharing a 1.8 Mb region and the fifth 442 kb, and the four polymorphisms amplified in the exon 10 region were homozygous with the same alleles in all 25 patients of the laboratory group [20]. In the northern South African cohort, the shared haplotype extended over approximately 1.4 Mb on both alleles [56]. In gnomAD version 4.0.0, the highest allele frequency is that of African and African American populations, 0.001 (75 of 75,066), followed by Latino and admixed American populations, 0.0001333, and Europeans, 0.000008; the frequency observed in the southern African sample was significantly higher than the African or African American gnomAD frequency (Fisher's exact test, p = 3 × 10⁻⁴) [20]. These data led the authors to propose an African origin of the variant, with an ancient mutation and migration and population bottleneck effects, and its presence in African Americans to reflect the African genetic contribution introduced by the slave trade in the sixteenth and seventeenth centuries; all African countries with described patients have predominantly Bantu-speaking populations, and southern Africa corresponds to the southern end of the Bantu expansion, with increasing genetic homogeneity towards the south [20]. The alternative hypothesis of heterozygote advantage, suggested by the physiological function of the protein, was considered less likely owing to lack of evidence [20]. Zaharieva and colleagues had earlier formulated the same hypothesis of African origin, noting that the ancestry of the Lumbee tribe is controversial and that admixture of Native Americans, European settlers and African Americans has been postulated, so the presence of the variant in populations of mainly African ancestry points to a possible common ancestor of African origin; they noted, however, the counter-argument of Telegrafi, in whose two families the variant was not on the same haplotype, implying independent mutational events and leaving open whether there is a single ancestor or recurrence of the mutation [52, 55]. KLHL40 was the most frequent cause of severe nemaline myopathy in the Japanese population, accounting for up to 28% of tested individuals [40]. In the Western Cape region of South Africa, congenital myopathies with central nuclei are the predominant subtype, and probable founder RYR1 variants have been identified, enabling targeted local testing [1]. The Ashkenazi NEB deletion has also been found in families without known Ashkenazi ancestry, so ancestry should not be used to exclude testing [46].

9.3. Portugal, Brazil and inequality of access

In Brazil there are specific data for congenital myopathy 13. The first two Brazilian patients with molecular confirmation, both homozygous for c.851G>C and without known Lumbee ancestry, were described at a neurogenetics centre in Ceará; the parents of one of them came from a locality in the Ceará backlands (sertão) where consanguinity is relatively frequent, although not documented in the families, and both families had lived in Ceará for at least three generations [51]. In a Brazilian series of individuals with a history of malignant hyperthermia, with exome data available in 61 patients (29 crisis survivors and 32 relatives), RYR1 variants were found in 38 (62.3%) and STAC3 variants in 3 (4.9%), a frequency higher than in international series, in which STAC3 accounts for less than 1% of cases; the variant was the same in the three non-consanguineous, unrelated Afro-Brazilian families, homozygous in the probands, and the authors attribute the excess to the higher proportion of people of African descent in the population studied [104]. In a North American malignant hyperthermia series, STAC3 variants were found in 1 of 57 patients [22]. Brazil has a reference centre and a permanent telephone hotline for malignant hyperthermia, and neurologists can report neurological patients with a history of adverse events during anaesthesia to the Brazilian Registry of Neurological Diseases [22].

No epidemiological data from Portugal were identified in the sources consulted. The Brazilian textbook Síndromes Genéticas: Reconhecer para Tratar presents European incidence and prevalence estimates and recommends starting investigations with a myopathy panel, followed by exome sequencing if the panel is negative, but provides no Brazilian population data [3]. The 2012 consensus and the 2014 diagnostic consensus included Brazilian experts [5, 6]. The absence of data in these sources does not demonstrate the absence of published studies. The ENMC emphasises that 86% of published genetic data derive from people of European ancestry, that many low- or middle-income countries have access only to tests for spinal muscular atrophy and Duchenne muscular dystrophy, and that variant interpretation in other populations is less reliable [1].

9.4. Referral networks and patient organisations

In the European Union, patients should be referred to centres within the European Reference Network for rare Neuromuscular Diseases (ERN EURO-NMD), which covers muscle diseases [15]. Relevant organisations and registries include the Myotubular Trust (United Kingdom), the Joshua Frase Foundation and MTM-CNM Family Connection (United States), the registry for patients with myotubular and centronuclear myopathies, the Congenital Muscle Disease International Registry, A Foundation Building Strength (nemaline myopathy), the RYR-1 Foundation and Team Titin [1, 4]. For congenital myopathy 13, GeneReviews lists the Malignant Hyperthermia Association of the United States, which maintains a permanent emergency hotline, the Muscular Dystrophy Association in the United States and Muscular Dystrophy UK [17]. The nemaline myopathy clinical research network and national natural history studies (United Kingdom, Belgium, Spain) are preparing trial readiness [105].

10. Illustrative Clinical Case

10.1. X-linked myotubular myopathy in a late-preterm neonate with severe asphyxia

Liao and colleagues reported in 2026 the case of a boy born at 36 weeks and 3 days, weighing 2.1 kg, to a 36-year-old mother with diet-controlled gestational diabetes and with a healthy 7-year-old sister [106]. At 36 weeks, ultrasound showed an amniotic fluid index of 447 (polyhydramnios); half an hour before delivery, approximately 2,000 mL of fluid was lost, and frequent fetal heart rate decelerations prompted emergency caesarean delivery. At birth, the neonate had no cry or effective spontaneous breathing, was cyanosed, had no limb tone and had a heart rate of approximately 40 per minute; he was intubated and ventilated, underwent chest compressions and received adrenaline and volume expansion, with Apgar scores of 2 at one minute and 6 at five minutes, while muscle tone remained 0 [106].

In the neonatal intensive care unit, blood gas analysis showed respiratory acidosis (pH 7.074 and pCO2 96.2 mmHg) with lactate of 1.22 mmol/L; creatine kinase was 112 U/L, the karyotype was 46,XY, chest radiography and transfontanelle ultrasound showed no significant abnormalities, and amplitude-integrated electroencephalography showed no relevant abnormalities [106]. Echocardiography showed dilated right-sided chambers with a left-to-right shunt and a patent ductus arteriosus, and testicular ultrasound suggested left cryptorchidism with a right hydrocele [106]. Despite invasive ventilation, antibiotics, caffeine citrate, mild hypothermia and nasogastric feeding, the child remained hypotonic, with abundant secretions and dependence on invasive ventilation, with failed extubation [106]. The authors considered congenital muscular dystrophy, congenital myasthenic syndromes and congenital myopathies in the differential diagnosis [106].

The parents initially declined genetic testing and accepted it on admission day 10; the exome result arrived on day 40 and identified the hemizygous variant NM_000252.3(MTM1):c.1260+2_1260+3del, at the canonical splice donor site of intron 11, classified by the authors as likely pathogenic under ACMG criteria (figure 4 of the article) [106]. VariantValidator confirmed the description on the MANE transcript and the genomic position NC_000023.11:g.150658029_150658030del; the coordinate given in the article (chrX:149826499) corresponds to another reference genome version [44]. Sanger sequencing showed that the mother and sister are heterozygous (figure 5 of the article) [106]. Following teleconsultation with a neurology centre, oral salbutamol, pyridostigmine and tamoxifen were administered for two weeks, without improvement; the family decided to withdraw treatment and the child died [106].

This case combines typical features of the severe form: polyhydramnios, prematurity, absent tone and effective breathing at birth, cryptorchidism, normal creatine kinase and ventilatory dependence [4]. It also illustrates two practical points. The first is the overlap between perinatal asphyxia and myopathy: severe hypotonia with respiratory failure attributed to asphyxia, without improvement and with abundant secretions, should prompt early genetic testing, and the diagnostic consensus recommends testing directed at MTM1, DMPK and severe nemaline forms in neonates in whom treatment limitation decisions are being considered [6]; the ENMC recommends rapid exome or genome sequencing in neonatal units when available [1]. The second is counselling: identifying the mother and sister as carriers establishes a 50% disease risk for each male child and enables prenatal or preimplantation diagnosis [4]. The pharmacological therapies used in the case are not part of the standard of care: pyridostigmine is used off-label without systematic studies, the tamoxifen trial in myotubular myopathy was terminated because of safety concerns, and salbutamol has no demonstrated efficacy in this disease [4, 91, 96].

10.2. Malignant hyperthermia crisis during spinal fusion in an adolescent with STAC3-related myopathy

Silva and colleagues described in 2025 a 15-year-old Afro-Brazilian girl, born to non-consanguineous parents, with congenital myopathy 13 confirmed by homozygosity for NM_145064.3:c.851G>C p.(Trp284Ser) [22]. The patient had delayed motor development, progressive scoliosis with a Cobb angle of 53º, joint hypermobility, finger and hand contractures, short stature, elongated facies, bilateral palpebral ptosis, facial diparesis, muscle hypotrophy, grade 4 limb paresis, hypotonia and global areflexia [22].

She underwent spinal fusion with an induction that included suxamethonium and sevoflurane. Fifteen minutes after the start of the halogenated agent, masseter rigidity appeared, followed by generalised muscle rigidity, hypercapnia with end-tidal CO2 of 61 mmHg, hyperthermia of 37.8 ºC, acidosis with a pH of 7.28, hypotension of 80/50 mmHg and rhabdomyolysis with creatine kinase of 1,152 U/L, for an upper limit of 140 U/L [22]. The condition improved with discontinuation of sevoflurane, hyperventilation and intravenous dantrolene, as a 2.5 mg/kg bolus followed by a maintenance infusion of 0.25 mg/kg per hour [22]. The clinical grading scale score for malignant hyperthermia was 50 points, corresponding to an almost certain probability of a crisis [22]. The patient survived without documented sequelae and did not undergo in vitro contracture testing, the diagnosis resting on the genetic result [22].

The case brings together the elements that define the entity: a syndromic phenotype with myopathic facies, ptosis, contractures, paradoxical hypermobility and progressive scoliosis; spinal surgery as a frequent indication for anaesthesia; and a crisis triggered by a halogenated agent with an associated depolarising relaxant [17, 69]. It also illustrates three practical points. The first is that masseter rigidity may be the opening sign, before hyperthermia, which makes continuous monitoring of end-tidal CO2 and core temperature indispensable [21, 22]. The second is that prior recognition of the diagnosis would have avoided the exposure: the recommended approach is trigger-free anaesthesia, with a prepared machine, available dantrolene and access to intensive care, and at-risk patients should carry a document or card stating this [5, 17]. The third is that the bolus dantrolene dose used corresponds to that of the current European guideline, whereas the maintenance infusion described in the report is not included in that guideline or in the labels cited in section 7.7, so it is described as the management of the case rather than as a reference dosage [21, 22]. The European Agilus® label provides, as an alternative, for repetition of the 2.5 mg/kg bolus every 10 minutes until stabilisation, not exceeding 300 mg per administration [81].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis by subtype

Survival into adulthood is likely in all congenital myopathies except when severe respiratory failure and profound weakness occur in the first year; the main exceptions are X-linked myotubular myopathy and severe neonatal ACTA1-related forms [5]. Limb weakness is generally non-progressive, and those who achieve walking rarely lose it in childhood, except in the late-onset DNM2 form; contractures, scoliosis, fractures and weight gain may compromise walking [5]. Severe respiratory failure after the first year is rare if it was absent in infancy, except with SELENON, TPM3, ACTA1, NEB and DNM2, where it may develop in adolescence or adulthood [5].

In myotubular myopathy, the 2017 natural history study found a more stable disease than expected, with few adverse events during the follow-up year and almost all deaths associated with respiratory failure, but a high burden on patients and caregivers; in the retrospective RECENSUS review, 90% required respiratory support at birth, and in the first year there were on average 3.7 operations and 35% of time was spent in hospital [61, 107]. These figures derive from patients who had not received gene therapy and from referral-centre cohorts, and should not be interpreted as individual risk.

11.2. Follow-up plan

12. Summary and Final Considerations

Congenital myopathies are a group of genetic muscle disorders with perinatal or childhood onset, generally non-progressive or slowly progressive, with non-dystrophic structural changes in muscle fibres. Classically divided into forms with rods, cores, central nuclei and fibre-type disproportion, they are now understood as a group involving more than 40 genes, nine of which explain most resolved cases, with genetic and allelic heterogeneity that has made histological classification insufficient [1, 6]. The 277th ENMC workshop adopted the acronym CMYO and a nomenclature combining inheritance, gene and histology, and recommended a genetics-first diagnostic strategy, excluding spinal muscular atrophy, myotonic dystrophy and copy-number variations, with biopsy reserved for unresolved cases [1]. Approximately 20% to 30% of patients remain without a molecular diagnosis, and large or poorly covered genes (TTN, NEB, exon 1 of SELENON) require complementary methods [1, 7].

Estimated frequency depends on the method: birth incidence of 14.9 per 100,000 live births and point prevalence of 3.9 per 100,000 in western Sweden, with substantial mortality explaining the difference [7]. Risks that alter management depend on the genotype: respiratory failure disproportionate to limb weakness with SELENON and in nemaline forms, malignant hyperthermia susceptibility with RYR1 and STAC3, cardiomyopathy with TTN, SPEG and MYH7, and cholestatic liver disease and peliosis in X-linked myotubular myopathy [1, 6, 10]. STAC3-related congenital myopathy 13, autosomal recessive and almost always due to the founder variant NM_145064.3:c.851G>C p.(Trp284Ser), combines myopathic facies, palatal anomaly, contractures, kyphoscoliosis, short stature and restrictive respiratory insufficiency with preserved intelligence; its defining targeted measure is lifelong avoidance of halogenated agents and suxamethonium, with dantrolene available, and its worldwide distribution and the estimated carrier frequency in southern Africa justify considering it in the hypotonic infant with palatal anomaly and contractures, before muscle biopsy [17, 20, 22]. Management continues to follow the 2012 international consensus, focusing on regular respiratory surveillance with bilevel non-invasive ventilation, prevention and treatment of scoliosis and contractures, regular exercise, nutrition, oral health and trigger-free anaesthesia; a revision of this standard of care has been announced [1, 5]. No disease-modifying treatment is authorised. Gene therapy for myotubular myopathy showed substantial functional gains in ASPIRO, but deaths from cholestasis led to the discontinuation of AT132 and transition to a new vector in phase 1/2; dynamin 2 reduction strategies were discontinued because of safety and tolerability, and the RyR1 stabiliser entered phase 2 in 2026 [10–14]. Genetic counselling depends on the gene, mode of transmission and possibility of parental mosaicism, and a precise molecular diagnosis is now a prerequisite for targeted comorbidity screening, reproductive planning and access to trials [1, 4].

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