Analysis of a case of Multiple pterygium syndrome due to a novel variant of CHRNG gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical characteristics and genetic etiology of a child with multiple pterygium syndrome (MPS).@*METHODS@#A child with MPS who was treated at the Orthopedics Department of Guangzhou Women and Children's Medical Center Affiliated to Guangzhou Medical University on August 19, 2020 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and her parents were also collected. Whole exome sequencing (WES) was carried out for the child. Candidate variant was validated by Sanger sequencing of her parents and bioinformatic analysis.@*RESULTS@#The child, an 11-year-old female, had a complain of "scoliosis found 8 years before and aggravated with unequal shoulder height for 1 year". WES results revealed that she has carried a homozygous c.55+1G>C splice variant of the CHRNG gene, for which both of her parents were heterozygous carriers. By bioinformatic analysis, the c.55+1G>C variant has not been recorded by the CNKI, Wanfang data knowledge service platform and HGMG databases. Analysis with Multain online software suggested that the amino acid encoded by this site is highly conserved among various species. As predicted with the CRYP-SKIP online software, the probability of activation and skipping of the potential splice site in exon 1 caused by this variant is 0.30 and 0.70, respectively. The child was diagnosed with MPS.@*CONCLUSION@#The CHRNG gene c.55+1G>C variant probably underlay the MPS in this patient.

Hipertermia maligna / Malignant huperthermia

Carriers of malignant hyperthermia (MH), a subclinical metabolic myopathy, respond differently to the general population in response to triggering agents, such as volatile anesthetics and succinylcholine. Its incidence ranges from 1:10,000 to 1:250,000 anesthesias. Using etiological treatment, the current mortality rate is around 5%. The biochemical, metabolic, and physiological deterioration generally associated with MH is a direct result of a sudden and progressive increase in intracellular calcium in striated muscle cells. This generates a hypermetabolic state, with a rapid increase in body temperature that can lead to a fatal outcome if not diagnosed and treated in time. The genetic factors that determine susceptibility to MH are complex, with the participation of more than one gene. Its clinical symptoms are highly variable, from mild or moderate to fulminant attacks with severe muscle hypermetabolism and rhabdomyolysis. Capnography and pulse oximetry have great clinical diagnostic value. Other early symptoms of an MH attack may include sinus tachycardia, supraventricular or ventricular arrhythmia, and isolated masterean spasm or generalized muscle stiffness. The rise in temperature is a late sign. After an attack, or in possibly susceptible patients, the laboratory diagnosis is made with the in vitro contracture test, in which the contraction of muscle fibers, obtained through a skeletal muscle biopsy, is studied in the presence of halothane or caffeine. In patients known to be susceptible to MH, neuraxial and regional techniques should be preferred if surgery allows it; otherwise, trigger-free anesthetic methods (TIVA) should be available. Management of the MH crisis is based on three main actions: 1) stopping the administration of halogenates; 2) hyperventilation with 100% oxygen, and 3) administration of intravenous dantrolene.

La hipertermia maligna (HM) es una miopatía metabólica subclínica, cuyos portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante: anestésicos volátiles y succinilcolina. Su incidencia tiene rangos entre 1:10.000 a 1:250.000 anestesias. Su mortalidad actual usando tratamiento etiológico es de 5%. El deterioro bioquímico, metabólico y fisiológico asociado clásicamente al cuadro de HM es el resultado directo de un aumento súbito y progresivo del calcio intracelular de las células musculares estriadas, que genera un estado hipermetabólico, calor y un rápido aumento de la temperatura corporal, que puede llevar a un desenlace fatal si no se diagnostica y se trata a tiempo. Su herencia es complicada: se trata de una transmisión multigénica, en que la susceptibilidad a la HM depende de más de un gen. Los síntomas clínicos son muy variables, desde leves o moderados hasta crisis fulminantes con hipermetabolismo muscular severo y rabdomiólisis. La capnografía y la oximetría tiene un gran valor diagnóstico clínico. Otros síntomas tempranos de una crisis de HM pueden incluir taquicardia sinusal, arritmia supraventricular o ventricular y espasmo de maséteros aislado o rigidez muscular generalizada; el aumento de la temperatura es un signo tardío. Después de la crisis o en los pacientes posiblemente susceptibles, el diagnóstico de laboratorio se hace con el test de contractura , basado en la contracción de fibras musculares tomadas a partir de una biopsia de músculo estriado en presencia de halotano o cafeína. En los pacientes conocidamente susceptibles a HM se debe preferir las técnicas neuroaxiales y regionales si la cirugía lo permite; en caso contrario, debe disponerse de métodos anestésicos libres de agentes desencadenantes (TIVA). El manejo de la crisis de HM está basado en tres medidas principales: 1) la detención de la administración de halogenados; 2) la hiperventilación con oxígeno al 100% y 3) la administración de dantrolene endovenoso.

Hipertermia maligna: aspectos moleculares e clínicos / Malignant hyperthermia: clinical and molecular aspects / Hipertermia maligna: aspectos moleculares y clínicos

CONTEÚDO: A hipertermia maligna (HM) é uma doença farmacogenética potencialmente letal que acomete indivíduos geneticamente predispostos. Manifesta-se em indivíduos susceptíveis em resposta à exposição a anestésicos inalatórios, relaxantes musculares despolarizantes ou atividade física extrema em ambientes quentes. Durante a exposição a esses agentes desencadeadores, há um aumento rápido e sustentado da concentração de cálcio mioplasmático (Ca2+) induzido pela hiperativação dos receptores de rianodina (RYR1) do músculo esquelético, causando uma alteração profunda na homeostase de Ca2+, caracterizando um estado hipermetabólico. RYR1, canais de libertação de Ca2+ do retículo sarcoplasmático, é o principal local de susceptibilidade à HM. Várias mutações no gene que codifica a proteína RYR1 foram identificadas, mas outros genes podem estar envolvidos. Atualmente, o método padrão para o diagnóstico de sensibilidade à HM é o teste de contratura muscular para exposição ao halotano-cafeína (CHCT) e o único tratamento é o uso de dantroleno. No entanto, com os avanços no campo da genética molecular, um pleno entendimento da etiologia da doença pode ser fornecido, favorecendo o desenvolvimento de um diagnóstico preciso, menos invasivo, com o teste de ADN, e também proporcionar o desenvolvimento de novas estratégias terapêuticas para o tratamento da HM. Logo, esta breve revisão tem como objetivo integrar os aspectos clínicos e moleculares da HM, reunindo informações para uma melhor compreensão desta canalopatia.

CONTENT: Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic disorder that affects genetically predisposed individuals. It manifests in susceptible individuals in response to exposure to Inhalant anesthetics, depolarizing muscle relaxants or extreme physical activity in hot environments. During exposure to these triggering agents, there is a rapid and sustained increase of myoplasmic calcium (Ca2+) concentration induced by hyperactivation of ryanodine receptor of skeletal muscle (RyR1), causing a profound change in Ca2+ homeostasis, featuring a hypermetabolic state. RyR1, Ca2+ release channels of sarcoplasmic reticulum, is the primary locus for MH susceptibility. Several mutations in the gene encoding the protein RyR1 have been identified; however, other genes may be involved. Actually, the standard method for diagnosing MH susceptibility is the muscle contracture test for exposure to halothane-caffeine (CHCT) and the only treatment is the use of dantrolene. However, with advances in molecular genetics, a full understanding of the disease etiology may be provided, favoring the development of an accurate diagnosis, less invasive, with DNA test, and also will provide the development of new therapeutic strategies for treatment of MH. Thus, this brief review aims to integrate molecular and clinical aspects of MH, gathering input for a better understanding of this channelopathy.

CONTENIDO: La hipertermia maligna (HM) es una enfermedad farmacogenética potencialmente letal que afecta a individuos genéticamente predispuestos. Se manifiesta en los individuos susceptibles en respuesta a la exposición a los anestésicos inhalatorios, relajantes musculares despolarizantes o actividad física extrema en ambientes calientes. Durante la exposición a esos agentes desencadenantes, existe un aumento rápido y constante de la concentración de calcio mioplasmático (Ca2+) inducido por la hiperactivación de los receptores de rianodina (RYR1) del músculo esquelético, causando una alteración profunda en la homeostasa de Ca2+, y caracterizando un estado hipermetabólico. RYR1, canales de liberación de Ca2+ del retículo sarcoplasmático, es la principal región de susceptibilidad a la HM. Varias mutaciones en el gen que codifica la proteína RYR1 han sido identificadas, pero otros genes pueden estar involucrados también. Actualmente, el método estándar para el diagnóstico de la sensibilidad a la HM es el test de contractura muscular para la exposición al halotano-cafeína (CHCT) y el único tratamiento es el uso de dantroleno. Sin embargo, con los avances en el campo de la genética molecular, un pleno entendimiento de la etiología de la enfermedad puede ser suministrado, favoreciendo así el desarrollo de un diagnóstico preciso, menos invasivo, con el test de ADN, y también proporcionar el desarrollo de nuevas estrategias terapéuticas para el tratamiento de la HM. Por eso, esta breve revisión intenta integrar los aspectos clínicos y moleculares de la HM, reuniendo informaciones para lograr una mejor comprensión de esa canalopatía.

Escobar syndrome in three male patients of same family.

We describe three male individuals from a consanguineous south Indian family affected with the multiple pterygium syndrome (Escobar syndrome). Common clinical features included short stature, multiple pterygium, skeletal anomalies, and normal intelligence. The first report of this condition was made in 1902 from this same place (Pondicherry) and the disease received its present popular name Escobar syndrome in 1982. The genetic defect for this condition was identified in 2006 as mutation in the fetal acetylcholine receptor.

Molecular Genetic Analysis of the Ryanodine Receptor Gene (RYR1) in Korean Malignant Hyperthermia Families / 대한진단검사의학회지

BACKGROUND: Malignant hyperthermia (MH) is genetically heterogeneous, with mutations in the gene encoding the skeletal muscle ryanodine receptor (RYR1) at 19q13.1 accounting for up to 80% of the cases. However, the search for known and novel mutations in the RYR1 gene is hampered by the fact that the gene contains 106 exons. We aimed to analyze mutations from the entire RYR1 coding region in Korean MH families. METHODS: We investigated seven affected MH individuals and their family members. The entire RYR1 coding region from the genomic DNA was sequenced, and RYR1 haplotyping and mutational analysis were carried out. RESULTS: We identified nine different RYR1 mutations or variations from seven Korean MH families. Among these, five previously reported mutations (p.Gly248Arg, p.Arg2435His, p.Arg2458His, p.Arg2676Trp, and p.Leu4838Val) and four novel variations of unknown significance (p.Arg2508Cys, p.Met4022Val, p.Glu2669Lys, and p.Ala4295Val) were identified. In two families, two variations (R2676W & M4022V, R2435H & A4295V, respectively) were identified simultaneously. Four of the observed nine mutations or variations were located outside the hotspot region of RYR1 mutations. CONCLUSIONS: These data indicate that RYR1 is a main candidate gene in Korean MH families, and that comprehensive screening of the entire coding sequence of the RYR1 gene is necessary for molecular genetic investigations in MH-susceptible individuals, owing to the presence of RYR1 mutations or variations outside of the hotspot region.

Multigenerational Brazilian family with malignant hyperthermia and a novel mutation in the RYR1 gene

Malignant hyperthermia (MH) is a pharmacogenetic disease triggered in susceptible individuals by the administration of volatile halogenated anesthetics and/or succinylcholine, leading to the development of a hypermetabolic crisis, which is caused by abnormal release of Ca2+ from the sarcoplasmic reticulum, through the Ca2+ release channel ryanodine receptor 1 (RyR1). Mutations in the RYR1 gene are associated with MH in the majority of susceptible families. Genetic screening of a 5-generation Brazilian family with a history of MH-related deaths and a previous MH diagnosis by the caffeine halothane contracture test (CHCT) in some individuals was performed using restriction and sequencing analysis. A novel missense mutation, Gly4935Ser, was found in an important functional and conserved locus of this gene, the transmembrane region of RyR1. In this family, 2 MH-susceptible individuals previously diagnosed with CHCT carry this novel mutation and another 24 not previously diagnosed members also carry it. However, this same mutation was not found in another MH-susceptible individual whose CHCT was positive to the test with caffeine but not to the test with halothane. None of the 5 MH normal individuals of the family, previously diagnosed by CHCT, carry this mutation, nor do 100 controls from control Brazilian and USA populations. The Gly4932Ser variant is a candidate mutation for MH, based on its co-segregation with disease phenotype, absence among controls and its location within the protein.

Hipertermia maligna: adelantándose a las complicaciones / Malignant hyperthermia: moving forward before the complications

La hipertermia maligna (HTM) es una enfermedad fármaco-genética de carácter autosómico dominante de baja incidencia pero potencialmente mortal, caracterizada por un síndrome hipermetabólico del músculo estriado esquelético, que puede desencadenar la destrucción completa de éste, resultando en aumento de la temperatura corporal, alto consumo de oxígeno, hiperpotasemia, falla renal y arritmias. A continuación se da a conocer el caso de un paciente de 6 años portador de una distrofia muscular de Duchenne con antecedentes familiares de hipertermia maligna y que se sometió a cirugía adenoamigdaliana en la cual se tomaron las medidas anestésicas para prevenir la aparición de una crisis.

Actualizaciones en hipertermia maligna / Malignant hyperthermia: update

La hipertermia maligna es una miopía metabólica donde todos los anestésicos inhalatorios (excepto el N2O) y la succinilcolina son agentes gatillantes.La herencia en humanos es autosómica dominante. Se presenta en todas las edades y razas siendo más frecuente en niños y adultos jóvenes. La alteración fisiológica básica es un aumento desmedido del calcio intracelular muscular. La HM se puede desencadenar durante la anestesia o en el período de recuperación, siendo el aumento del CO2 el signo clínico más sensitivo y específico. El tratamiento precoz con drantoleno es efectivo.E l único test diagnóstico aceptado en la actualidad es el de contractura con halotanocafeína.