Keywords
malignant hyperthermia - STAC3 - Native American myopathy - cleft palate
Introduction
Congenital myopathy type 13 (CMYO13) (OMIM 255995), also known as Bailey–Bloch myopathy, is a rare autosomal recessive disorder primarily affecting muscle function. CMYO13 was first described by Bailey and Bloch in a child of Native Indian descent in North Carolina who presented with cleft palate (CP), arthrogryposis, and malignant hyperthermia (MH).[1] A year later, Stewart et al 1988 described six children of Native American descent with similar clinical manifestations.[2]
Since its first description in North Carolina, multiple CMYO13 patients have been reported in a variety of non-Native American populations that include Qatar, Turkey, Puerto Rico, Russia, and Cameron Island (see [Fig. 1] for the global distribution of STAC3 Native American myopathy [NAM] variant).[3]
[4]
[5] The prevalence of CMYO13 patients is approximately 1 in every 100,000 to 200,000 individuals of Native American descent. Within the native Lumbee population in North Carolina, where the disease was first described, the prevalence is estimated to be 1 in every 5,000.[6]
Fig. 1 Global distribution of reported STAC3 (p.W284S) variants. The number within each of the markers represents the number of patients reported, see [Table 1]. Created with BioRender.com.
In this review, we will provide an overview of the current understanding of the etiology, clinical phenotype, and genetic basis of CMYO13, as well as the current state of research in this area. We will also discuss the challenges and future directions for the study of CMYO13 to improve our understanding of this condition and improve the lives of those affected.
Clinical Phenotype
CMYO13 patients typically present during infancy with hypotonia, muscle weakness, and delayed gross motor milestones. However, a milder form of the disease has recently been described in non-Native American patients.[3]
[4]
[7]
[8] Patients' serum creatine kinase is typically in the normal range, and electromyography shows myopathic changes. A unique feature of this disease, as first described by Bailey and Bloch and shared only with two other muscle diseases, is patients' susceptibility to MH (5, 6).
CMYO13 is characterized by early-onset infantile onset hypotonia, myopathic facies, short stature, and delayed gross motor milestones early in life. In a study done by Zaharieva et al[5] on 18 patients from 12 multiethnic families, five patients were found to be weak in uteromanifested either by decreased fetal movements and/or polyhydramnios. Thirteen patients (72%) could walk at the last follow-up. With more cases reported worldwide, the phenotypic spectrum CMYO13 is expanding to include milder, less affected cases with minimal muscle weakness.[3]
Similar to congenital myopathies, CMYO13 patients typically present with proximal arm/leg and axial weakness. The progression of weakness is variable in the literature, as some patients' weaknesses are observed to be static while others are progressive.[3]
[5]
[7]
[8] Such rapid progression of muscle weakness in some CMYO13 cases is rarely observed in congenital myopathies. The degree of weakness in CMYO13 can lead to difficulty with activities of daily living, such as walking, standing, and climbing stairs. In addition to proximal muscular involvement, distal muscle weakness, in the form of foot drop, has been reported in one adult patient.[6]
Musculoskeletal contractures are a prominent feature of the disease found mainly in knees, ankles, neck, and elbows, adversely affecting patients' ambulation ability. Furthermore, spinal deformities in the form of scoliosis and/or kyphosis have also been reported in 11 out of 18 patients in one series.[5] These deformities might require surgical correction, where precautions must be taken to avoid MH intraoperatively.
Due to respiratory muscle weakness, patients typically require noninvasive respiratory support. In a study by Zaharieva et al, 8 out of 18 patients had respiratory impairment, in which 4 required continuous positive airway pressure.[5] Such a high percentage indicates the propensity to respiratory muscle weakness in CMYO13 and the severity of diaphragmatic involvement. Furthermore, neonatal respiratory failure requiring tracheostomy tube placement has been described in a few cases.[4]
[9] In line with the literature, 75% (3 out of 4) of the adult patients in our Saudi cohort required noninvasive respiratory support. In addition to muscle weakness, progressive scoliosis contributes to respiratory muscle weakness, leading to restrictive lung disease.
Conductive hearing loss is another feature reported in 33% (6 out of 18) patients in one CMYO13 series.[4] Typically, hearing loss is mild to moderate, with some patients requiring hearing aids. Hearing loss, if untreated, tends to affect children's language development in a disease where cognitive ability is typically intact.
MH is a genetic condition that affects how the body regulates muscle tone and can lead to elevated muscle tone and high body temperature during anesthesia. MH is a severe life-threatening pharmacogenetic reaction to anesthetic agents that is characterized by severe muscle rigidity, tachycardia, increased oxygen consumption, rise in end-tidal Carbon Dioxide, and rhabdomyolysis following exposure to an inhaled anesthetic or a depolarizing neuromuscular blocking agent. MH, among other features, is considered to be a hallmark of CMYO13 disease, first reported by Bailey and Bloch in 1987.[1]
[10]
MH is hypothesized to be caused by excessive calcium release from the sarcoplasmic reticulum (SR), causing severe muscular contraction. The exact reason why the specific anesthetic agents cause such a reaction is not apparent.[11] MH was first described in ryanodine receptor 1 (RYR1) mutation carriers, an essential receptor in the excitation–contraction coupling (ECC), defined as the process by which nerve-conducted electrical signals are converted to mechanical muscle contraction.[12]
[13] MH, if left untreated, can lead to severe consequences for patients, including death. Supportive management with intravenous fluids, temperature control, and dantrolene—a dihydropiridine (DHPR) receptor blocker—is the mainstay of treatment for MH reaction.[11]
MH has also been described in another calcium-channel-encoding gene called CACNA1s, which encodes the α1s subunit of DHPR[14]. Patients' phenotypes are variable and includes severe hypokalemic periodic paralysis, typically triggered by exercise and a carbohydrate-rich diet. This disease, however, accounts for a minority of MH cases (around 1% of all MH cases).[15]
[16] All three MH-predisposing genes, RYR1, STAC3 (Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 3), and CACNA1S, are functionally related and collectively contribute to the maintenance of skeletal muscle calcium homeostasis.[17]
Histopathological findings of this disease are nonspecific. Abnormalities in fiber size, the predominance of type 1 fiber/ slow myosin fibers, small type 1 fibers, and focal areas of myofibrillar disruption resembling mini cores have all been reported in biopsies of patients with CMYO13. No inflammatory infiltrates, as seen in limb-girdle muscular dystrophy, have been observed.[18] The histopathological examination of muscle biopsies of patients conducted by Stewart et al in 1988 has demonstrated the presence of degenerating atrophic fibers with hypertrophy in other fibers. Adenosine triphosphate and nicotinamide adenine dinucleotide staining shows type 2 fiber predominance.[2]
Genetics and Etiology of CMYO13 Gene
Genetics and Etiology of CMYO13 Gene
Located in chromosome 12q13–14, STAC3 encodes a protein with two Src homology three (SH3) domains and a cysteine-rich (C1) domain. Unlike the nervous-system-expressed STAC1 and STAC2, this gene, STAC3, is exclusively expressed in the skeletal muscles with no presence in smooth or cardiac muscles. The absence of its expression in the latter two supports its significance in ECC, as cardiac and smooth muscles are unaffected by STAC3 variants. A homozygous missense mutation in exon 10 of STAC3 (c.851 G > C; p.Trp284Ser)—hereafter described as the Native American variant—was first described in all patients of Native American descent in 2008[6] but has also been reported in other ethnicities—including our local cohort. Other mutations in STAC3 have since been reported globally in non-Native Americans.
ECC takes place in sarcolemma invaginations, also called T-tubules, where the L-type voltage-gated calcium channels—DHPR—are located. The activation of DHPR leads to the opening of RYR1 located on the SR, a calcium-containing compartment within the muscle fibers.[19] The depolarization of the muscle cell membrane, known as the sarcolemma, also activates the DHPRs, releasing the calcium cation from SR to the cytosol. The release of calcium, in turn, leads to the displacement of tropomyosin and, therefore, the activation of actin–myosin machinery, leading to muscle contraction. The linkage between the voltage-gated calcium channel (Cav1.1) and RYR1 receptors has been enigmatic. However, the discovery of STAC3 as a connector protein, likely through the tandem SH3 domains, between the two receptors has provided a better understanding of the mechanics of ECC ([Fig. 2]). Specifically, Rufenach and Van Petegam demonstrated that the STAC3 p.Trp284Ser variant, which lies withing the first SH3 domain of the tandem SH3 domain, is sufficient to disrupt the voltage-gated calcium channel (Cav1.1 also known as DHPR) activity[20]
[21] The STAC3 SH3 domain is thought to link the DHPR α 1s subunit in the sarcolemma invaginations, the T-tubules, and the Ryanodine receptor type 1 receptors in the SR. This linkage is likely to be essential in ECC and the disruption of normal ECC might interfere with muscle contractility and loss of muscle tone.
Fig. 2 The role of STAC3 in regulating RYR1 and DHPR function in skeletal muscle. STAC3 protein is functionally associated with DHPR and RYR1 at the T-tubules, as is evident by the inability of STAC3-knockout muscle fibers to produce calcium transients. DHPR, dihydropyridine receptor; RYR1, ryanodine receptor; SERCA, sarcoplasmic endoplasmic reticulum calcium ATPase; STAC3, SH3 and cysteine-rich domain-containing protein 3. Created with BioRender.com.
RYR1 encodes a protein critical in regulating calcium release from the SR, a network of membranes in muscle cells that store calcium ions. Specific mutations in the RYR1 gene, mainly gain-of-function, autosomal dominantly inherited variants, can disrupt the normal functioning of this protein and lead to an abnormal release of calcium from the SR, resulting in muscle weakness and wasting.[22]
Animal studies have shown that the STAC3 protein is functionally associated with DHPR and RYR1 at the T-tubules, as is evident by the inability of Stac3-knockout muscle fibers to produce calcium transients, an essential catalyst of muscle contraction. Furthermore, experimental animal models have shown defective locomotion and muscle contractility. Analysis of zebrafish models revealed a defect in ECC.[23]
[24] In addition, experimental DHPR-and-STAC3-expressing cells have good calcium current, which can be reversed with STAC3 elimination.[25]
Studies are conflicting on the role of STAC3 developmentally. On the one hand, Bower et al[26] have shown that knocking out STAC3 gene prevented myofiber fusion in C2C12 myoblasts, concluding STAC3′s role in muscle fiber fusion. On the other hand, knockdown of STAC3 in C2C12 myoblasts, done by a subsequent study, revealed multinucleated myofibers' presence. The same study has also shown the inhibitory effect of STAC3 knockout on the myofibers' differentiation abilities. The authors of the study took a step further by overexpressing STAC3 gene, which showed the inhibition of the terminal differentiation of myotubes.[27]
Cleft Palate in STAC3-Related Myopathy
Cleft Palate in STAC3-Related Myopathy
CP represents humans' third most common congenital deformity, only surpassed by clubfoot and cleft lip. CP affects around 1 in 1,700 live births,[28] with more females predilection (57%) than males. Thirty percent of patients occur in the context of Mendelian syndrome, while 70% happen in isolation.[29]
CP is a common yet overlooked clinical feature of CMYO13, found in almost 89%; all of whom harbored the Native American variant, all harboring the Native American variant [Table 1]). Such a high incidence of CP in CMYO13 surpasses most other muscle-disease-causing genetic defects ([Table 2]). The remaining three patients may have had an occult CP, also called submucous CP, which is commonly missed in clinical practice.
Table 1
List of all Native American myopathy patients published in the English literature and the rate CP
|
Studies
|
Total number
|
Number of CP patients
|
%[a]
|
Ethnicity
|
|
Zaharieva et al 2018[5]
|
18
|
6
|
33
|
Pan-ethnic
|
|
Gromand et al 2022[43]
|
7
|
7
|
100
|
Comoran Islands
|
|
Waldrop et al 2017[44]
|
1
|
1
|
100
|
Caucasian
|
|
Murtazina et al 2022[45]
|
1
|
0
|
0
|
Russian
|
|
Telegrafi A et al 2017[46]
|
5
|
5
|
100
|
Qatar and Puerto Rico
|
|
Sean Mock et al 2021[47]
|
5
|
5
|
100
|
Native American
|
|
Grzybowski et al 2017[7]
|
1
|
1
|
100
|
Turkish
|
|
Urtizberea 2019
|
1
|
1
|
100
|
Kuwait
|
|
Bailey and Bloch 1987[1]
|
1
|
1
|
100
|
Native American
|
|
Stamm et al 2008[6]
|
14
|
11
|
78
|
Native American
|
|
Habib et al 2003[9]
|
1
|
1
|
100
|
Native American
|
|
Stewart et al 1989[2]
|
6
|
6
|
100
|
Native American
|
|
Meluch et al 1989[10]
|
1
|
1
|
100
|
Native American
|
|
Abel et al 2003[48]
|
1
|
1
|
100
|
Native American
|
|
Almomen et al 2024[8]
|
7
|
6
|
83%[b]
|
Saudi Arabian
|
Abbreviation: CP, cleft palate.
a Percentage of CP.
b One neonate, who died at the age of 20 days, was not included as no information about CP was found.
Table 2
List of cleft palate (CP) incidence among myopathy-causing genes found in our MeSH MEDLINE database review (see text for more information)
|
Myopathy-causing gene/disease
|
Mode of inheritance
|
Number of CP cases, (%)
|
|
PGM1-CDG
|
AR
|
28/58 (49)[30]
|
|
SLC22A5
|
AR
|
2/757 (0.2)[31]
|
|
POMT1
|
AR
|
4 /21 (19)[32]
[33]
[34]
|
|
Phosphofructokinase deficiency
|
AR
|
One case[35]
|
|
Fetal akinesia deformation sequences
|
AR
|
One case[36]
|
|
PIEZO2
[a] (c.8057G > Ap.Arg2686His)
|
AD
|
Twelve cases[37]
|
|
RYR1
|
AR
|
One case[38]
|
|
ZC4H2
|
XLR/XLD
|
One case[39]
|
|
Mitochondrial myopathy
|
N/A[b]
|
One case[40]
|
|
Alpha sarcoglycanopathy
|
AR
|
One case[41]
|
|
MYMK
|
AR
|
Two cases[42]
|
a PIEZO2 is not a cause of muscle disease but was found in our search.
b No confirmed genetic diagnosis.
A review of the MeSH MEDLINE database looking for “cleft palate” AND “Myopathy” on October 10th, 2022, has revealed 154 results. Another search was followed by using “cleft palate” AND “Myopathy” in the Medline search. After merging the two search results, 256 results were found. All titles and abstracts—when available—were reviewed, looking for human muscle diseases. STAC3-related myopathy, PGM1, POMT2-related myopathy, and SLC22A5 were all associated with CP, with STAC3 being the highest, with an incidence of around 83% among all cases reported ([Table 1]).
An online search using the FaceBase database, an NIH-based database for craniofacial researchers (https://www.facebase.org/, using the term “Cleft palate” under the “Homo sapiens” yielded 26 results and showed no muscle-disease-causing genes, thereby indicating the rarity of such entity in muscle disease. The high incidence of CP in CMYO13 presents a unique opportunity to study this poorly understood phenomenon.
We have reviewed all the scientific literature for cases of STAC3-related myopathy and found 58 cases of different ethnicities, including 29 patients of Native American descent. Among all CMYO13 of all ethnicities, 75% (52 out of 69) had CP. The figure was as high as 89% among the Native Americans (26 out of 29 patients) ([Table 2]).
A review of models for CP in the literature has revealed six popular animal models; none is based on a gene with exclusive muscle expression. For example, Fgfr1 and Fgfr2 affect the hard, bony palate. The mutations of Ffgr1/2 cause craniofacial bony abnormalities such as craniosynostosis with skeletal bone dysplasia and no muscle involvement. The absence of the latter precludes its use in understanding soft palate development.
According to our literature search, none of the models can be reliably used to study muscular soft palate development. Hence, we propose that the STAC3-based animal model harboring the Native American variant may be suitable for studying muscle embryological development in the soft palate due to its exclusive muscle expression and high CP incidence. We propose that calcium regulation within the palate muscles might contribute to soft palate development.
Conclusion
To summarize, CMYO13 is a rare and complex muscle disease characterized by early-onset hypotonia, muscle weakness, delayed gross motor milestones, and a propensity for MH. The phenotypic spectrum of CMYO13 is broadening as more cases are reported globally, with some patients exhibiting milder forms of the disease. Awareness of this disease by pediatricians and surgeons—particularly its susceptibility to MH–is crucial to avoid serious consequences.
Future research should focus on expanding our understanding of NAM's underlying pathophysiology and potential therapeutic interventions as our understanding of the disease evolves. Developing a non-invasive diagnostic protocol, such as magnetic resonance imaging (MRI), would be greatly beneficial to CMYO13 patients. Not only will this be useful for CMYO13 patients, but it will also be informative for understanding MH. Developing animal models—including CP animal models—and in vitro systems will be critical for studying disease mechanisms and testing potential treatment strategies. Collaboration between researchers, clinicians, and patient advocacy organizations is essential to facilitating data sharing, improving diagnostic tools, and improving patient care.
