King-Denborough Syndrome (KDS) is a congenital myopathy (CM) characterised by myopathy, dysmorphic features and susceptibility to malignant hyperthermia. The objective of this study was to investigate the genotype-phenotype correlation in Black African patients presenting with CM, specifically those with KDS-like phenotypes, who remained undiagnosed for over 25 years. A cohort of 67 Black African patients with CM was studied, of whom 44 were clinically evaluated and diagnosed with KDS. Whole-exome sequencing (WES) was performed as part of an international genomics study (ICGNMD) to identify potential pathogenic mutations. Genomic assessments focused on identifying relevant genes, including RYR1 and STAC3, and establishing genotype-phenotype correlations. The study identified RYR1 and STAC3 mutations as the predominant genetic causes of KDS in this cohort, with mutations in both genes exhibiting autosomal recessive inheritance. While RYR1 has previously been linked to autosomal dominant mutations, STAC3, which was formerly associated exclusively with Native American Myopathy/Bailey-Bloch Myopathy, congenital hypotonia, and susceptibility to malignant hyperthermia, is now newly associated with CM-KDS in this study. This establishes the first genotype-phenotype correlation for 44 Black African individuals with KDS. This study marks a significant milestone in research on understudied African populations with CM, emphasising the lengthy diagnostic journey these patients endured. The findings highlight the pressing need for improved access to genomic medicine in underserved regions and underscore the importance of expanding research and diagnostic capabilities in Africa. This work contributes to the advancement of genetic medicine in underrepresented populations, facilitating better diagnostic and therapeutic outcomes.

STAC3 disorder, or Native American myopathy, is characterised by congenital myopathy, hypotonia, musculoskeletal and palatal anomalies, and susceptibility to malignant hyperthermia. A STAC3 c.851 G > C (p.Trp284Ser) pathogenic variant, common in the Lumbee Native American tribe, has been identified in other populations worldwide, including patients of African ancestry. We report on the frequency of STAC3 c.851 G > C in a cohort of 127 patients presenting with congenital hypotonia that tested negative for spinal muscular atrophy and/or Prader-Willi syndrome. We present a clinical retrospective, descriptive review on 31 Southern African patients homozygous for STAC3 c.851 G > C. The frequencies of various phenotypic characteristics were calculated. In total, 25/127 (20%) laboratory-based samples were homozygous for STAC3 c.851 G > C. A carrier rate of 1/56 and a predicted birth rate of 1/12 500 was estimated from a healthy cohort. A common haplotype spanning STAC3 was identified in four patients. Of the clinical group, 93% had a palatal abnormality, 52% a spinal anomaly, 59% had talipes equinovarus deformity/deformities, 38% had arthrogryposis multiplex congenita, and 22% had a history suggestive of malignant hyperthermia. The novel finding that STAC3 disorder is a common African myopathy has important clinical implications for the diagnosis, treatment and genetic counselling of individuals, with neonatal and/or childhood hypotonia with or without arthrogryposis multiplex congenita, and their families. The spread of this variant worldwide and the allele frequency higher in the African/African-American ancestry than the Admixed Americans, strongly indicates that the STAC3 c.851 G > C variant has an African origin which may be due to an ancient mutation with migration and population bottlenecks.

STAC3 gene congenital myopathy and malignant hyperthermia (MH) represent an important crossroads between neurology and anesthesia, where the prompt recognition of the clinical characteristics, and the collaboration between neurologists and anesthesiologists, are essential to early diagnosis and prevention of adverse critical events. This gene is associated with a congenital myopathy first reported as Native American myopathy (NAM), a rare condition characterized by dysmorphisms, contractures, muscular complaints, and scoliosis. As a rare pharmacogenetic hypermetabolic disease, MH is triggered by halogenated agents and/or succinylcholine, linked to variants in the RYR1, CACNA1S, or STAC3 genes. Our objective was to analyze the characteristics of a Brazilian case series of STAC3 gene myopathy associated with MH and to review previous reports. We report three MH crises, in two boys and one girl, 2 to 15 years old. All of them received halogenated agents and one additionally received succinylcholine. Two patients presented two to four previous uneventful general anesthesia. The MH crises in this series of patients with STAC3 gene mutations demonstrated variable clinical characteristics (expressivity) and occurrence (penetrance). Neuromuscular patients with findings suggestive of STAC3 myopathy should increase diagnostic suspicion regarding the risk of MH. Conversely, the careful evaluation of the anesthetic antecedents of neuromuscular patients can help to restrict the candidate genes. Additionally, Brazilian neurologists can notify neurological patients with antecedents of adverse events during anesthesia to the Brazilian Registry of Neurological Diseases (Registro Brasileiro de Doenças Neurológicas, REDONE, in Portuguese).

Understanding the early stages of human congenital myopathies is critical for proposing strategies for improving musculoskeletal muscle performance, such as restoring the functional integrity of the cytoskeleton. SH3 and cysteine-rich domain 3 (STAC3) are proteins involved in nutrient regulation and are an essential component of the excitation-contraction (EC) coupling machinery for Ca2+ releasing. A mutation in STAC3 causes debilitating Native American Myopathy (NAM) in humans, while loss of this gene in mice and zebrafish (ZF) results in premature death. Clinically, NAM patients demonstrated increased lipids in skeletal muscle, but it is unclear if neutral lipids are associated with altered muscle function in NAM. Using a CRISPR/Cas9 induced stac3-/- knockout (KO) zebrafish model, we determined that loss of stac3 leads to delayed larval hatching which corresponds with muscle weakness and decreased whole-body Ca2+ level during early skeletal development. Specifically, we observed defects in the cytoskeleton in F-actin and slow muscle fibers at 5 and 7 days post-fertilizations (dpf). Myogenesis regulators such as myoD and myf5, mstnb were significantly altered in stac3-/- larvae. These muscle alterations were associated with elevated neutral lipid levels starting at 5 dpf and persisting beyond 7 dpf. Larva lacking stac3 had reduced viability with no larva knockouts surviving past 11 dpf. This data suggests that our stac3-/- zebrafish serve as an alternative model to study the diminished muscle function seen in NAM patients. The data gathered from this new model over time supports a mechanistic view of lipotoxicity as a critical part of the pathology of NAM and the associated loss of function in muscle.

Congenital myopathy type 13 (CMYO13), also known as Native American myopathy, is a rare muscle disease characterized by early-onset hypotonia, muscle weakness, delayed motor milestones, and susceptibility to malignant hyperthermia. The phenotypic spectrum of congenital myopathy type 13 is expanding, with milder forms reported in non-native American patients. The first description of the disease dates to 1987 when Bailey and Bloch described an infant belonging to a Native American tribe with cleft palate, micrognathia, arthrogryposis, and general-anesthesia-induced malignant hyperthermia reaction; the cause of the latter remains poorly defined in this rare disease. The pan-ethnic distribution, as well as its predisposition to malignant hyperthermia, makes the identification of CMYO13 essential to avoid life-threatening, anesthesia-related complications. In this article, we are going to review the clinical phenotype of this disease and the pathophysiology of this rare disease with a focus on two unique features of the disease, namely cleft palate and malignant hyperthermia. We also highlight the importance of recognizing this disease's expanding phenotypic spectrum-including its susceptibility to malignant hyperthermia-and providing appropriate care to affected individuals and families.