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BJA Education Mar 2024
Review
PubMed: 38375493
DOI: 10.1016/j.bjae.2023.12.003 -
European Journal of Paediatric... Jul 2022CLN3 disease (MIM# 204200), the most prevalent of the neuronal ceroid lipofuscinoses (NCL), is an autosomal recessive disorder with juvenile onset characterized by...
CLN3 disease (MIM# 204200), the most prevalent of the neuronal ceroid lipofuscinoses (NCL), is an autosomal recessive disorder with juvenile onset characterized by blindness, epilepsy, dementia, psychiatric manifestations, and motor deterioration. Problems related to behavior, emotions and thought are among the main features. Antidepressant and antipsychotic drugs have been employed with variable results. Neuroleptic malignant syndrome (NMS) has previously been described in two patients with NCL, one with CLN3 disease and one with adult onset NCL of unclear genetic origin. Our aims were to describe the occurrence of drug-induced hyperthermia in pediatric patients with CLN3 disease from West and South Sweden and to delineate the range of associated clinical features. Our study identified four patients presenting with seven episodes of severe drug-induced hyperthermia and either NMS-like or Serotonin syndrome (SS)-like features. Possibly provoking drugs were risperidone, clozapine, olanzapine, haloperidol, quetiapine, and sertraline. The course was atypical, frequently prolonged, associated with rhabdomyolysis and status dystonicus, and resulted in the death of three of the patients. Our study points to a vulnerability to drug-induced hyperthermia in patients with CLN3 disease which we believe could be underreported. Interestingly the proposed pathophysiological mechanisms behind NMS and SS on one hand and CLN3 on the other hand seem to converge in a common mechanism involving dysregulation of the sympathetic nervous system.
Topics: Adult; Child; Humans; Hyperthermia, Induced; Membrane Glycoproteins; Molecular Chaperones; Neuronal Ceroid-Lipofuscinoses; Rhabdomyolysis
PubMed: 35716526
DOI: 10.1016/j.ejpn.2022.06.007 -
Journal of the Formosan Medical... Feb 2021Malignant hyperthermia (MH) is a life-threatening pharmacogenetic disease with only two known causative genes, RYR1 and CACNA1S. Both are huge genes containing numerous...
BACKGROUND/PURPOSE
Malignant hyperthermia (MH) is a life-threatening pharmacogenetic disease with only two known causative genes, RYR1 and CACNA1S. Both are huge genes containing numerous exons, and they reportedly only account for 50-70% of known MH patients. Next-generation sequencing (NGS) technology and bioinformatics could help delineate the genetic diagnosis of MH and several MH-like clinical presentations.
METHODS
We established a capture-based targeted NGS sequencing framework to examine the whole genomic regions of RYR1, CACNA1S and the 16.6 Kb mitochondrial genome, as well as 12 other genes related to excitation-contraction coupling and/or skeletal muscle calcium homeostasis. We applied bioinformatics analyses to the variants identified in this study and also to the 48 documented RYR1 pathogenic variants.
RESULTS
The causative variants were identified in seven of the eight (87.5%) MH families, but in none of the 10 individuals classified as either normal controls (N = 2) or patients displaying MH-like clinical features later found to be caused by other etiologies (N = 8). We showed that RYR1 c.1565A>G (p.Tyr522Cys)(rs118192162) could be a genetic hot spot in the Taiwanese population. Bioinformatics analyses demonstrated low population frequencies and predicted damaging effects from all known pathogenic RYR1 variants. We estimated that more than one in 1149 individuals worldwide carry MH pathogenic variants at RYR1.
CONCLUSION
NGS and bioinformatics are sensitive and specific tools to examine RYR1 and CACNA1S for the genetic diagnosis of MH. Pathogenic variants in RYR1 can be found in the majority of MH patients in Taiwan.
Topics: Computational Biology; High-Throughput Nucleotide Sequencing; Humans; Malignant Hyperthermia; Mutation; Ryanodine Receptor Calcium Release Channel; Taiwan
PubMed: 32919876
DOI: 10.1016/j.jfma.2020.08.028 -
Contact in Context 2023Dantrolene sodium is a direct-acting skeletal muscle relaxant. Dantrolene sodium for injection is indicated, along with suitable supportive measures, for the management...
Dantrolene sodium is a direct-acting skeletal muscle relaxant. Dantrolene sodium for injection is indicated, along with suitable supportive measures, for the management of sudden, severe hypermetabolism of skeletal muscle typical of malignant hyperthermia crises in patients of any age. The formulation scanned in this work was designed to be injected intravenously. Intra-lot and inter-lot variability in the spectra of REVONTO (dantrolene sodium) was measured in the Drug Quality Study (DQS) using Fourier transform near-infrared spectrometry (FTNIR). Spectra of 69 vials from lot 20REV01A contained two groups (n=56 vials, n=13 vials) when scanned with an FTNIR. The two groups of spectra in lot 20REV01A were found to be 66.7 SDs apart using a subcluster detection test, suggesting that the two groups were manufactured differently. As a result, all available samples of dantrolene were examined. A library of spectra of 141 vials of dantrolene from 4 lots were found to contain 3 separate groups, also suggesting that different vials contain different materials.
PubMed: 37424832
DOI: 10.6084/m9.figshare.23317136 -
British Dental Journal Feb 2023
PubMed: 36765204
DOI: 10.1038/s41415-023-5564-8 -
European Journal of Anaesthesiology Jul 2021Ryanodine receptor type 1 (RYR1) sequence variants are pathogenic for malignant hyperthermia. Variant carriers have a subtle increase in resting myoplasmic calcium...
BACKGROUND
Ryanodine receptor type 1 (RYR1) sequence variants are pathogenic for malignant hyperthermia. Variant carriers have a subtle increase in resting myoplasmic calcium concentration compared with nonaffected individuals, but whether this has metabolic effects in daily life is unknown.
OBJECTIVES
We analysed the potential effect of malignant hyperthermia-pathogenic RYR1 sequence variants on BMI as a single factor. Due to the heterogeneity of genetic variants predisposing to malignant hyperthermia, and to incomplete information about their regional distribution, we describe the prevalence of RYR1 variants in our population.
DESIGN
A retrospective cohort study.
SETTING
A single University hospital.
PATIENTS
Patients from malignant hyperthermia families with pathogenic RYR1 sequence variants were selected if BMI was available.
OUTCOME MEASURES
BMI values were compared amongst malignant hyperthermia susceptible (MHS) and malignant hyperthermia-negative individuals using hierarchical multivariable analyses adjusted for age and sex and considering family clustering. Variant prevalence was calculated.
RESULTS
The study included 281 individuals from 42 unrelated malignant hyperthermia families, 109 of whom were MHS and carriers of the familial RYR1 sequence variants. Median [IQR] BMI in MHS individuals with pathogenic RYR1 variants was 22.5 kg m-2 [21.3 to 25.6 kg m-2]. In malignant hyperthermia-negative individuals without variants, median BMI was 23.4 kg m-2 [21.0 to 26.3 kg m-2]. Using multivariable regression adjusted for age and sex, the mean difference was -0.73 (95% CI -1.51 to 0.05). No carrier of a pathogenic RYR1 sequence variant was found to have BMI higher than 30 kg m-2. Only 10 RYR1 variants from the list of the European MH Group were found in our cohort, the most common being p.Val2168Met (39% of families), p.Arg2336His (24%) and p.Arg614Cys (12%).
CONCLUSION
The observed tendency towards lower BMI values in carriers of malignant hyperthermia-pathogenic RYR1 sequence variants points to a possible protective effect on obesity. This study confirms regional differences of the prevalence of malignant hyperthermia-pathogenic RYR1 sequence variants, with just three variants covering 75% of Swiss MHS families.
TRIAL REGISTRATION
This manuscript is based on a retrospective analysis.
Topics: Body Mass Index; Cohort Studies; Humans; Hyperthermia; Malignant Hyperthermia; Mutation; Retrospective Studies; Ryanodine Receptor Calcium Release Channel; Switzerland
PubMed: 33259453
DOI: 10.1097/EJA.0000000000001399 -
Anasthesiologie, Intensivmedizin,... May 2021Malignant hyperthermia is a rare, subclinical pharmacogenetic syndrome leading to potentially life-threatening skeletal muscle hypermetabolism. Providing a safe and...
Malignant hyperthermia is a rare, subclinical pharmacogenetic syndrome leading to potentially life-threatening skeletal muscle hypermetabolism. Providing a safe and trigger-free anesthesia in predisposed individuals is essential to avoid serious harm to the patient. Especially the management of malignant hyperthermia predisposition in the context of pregnancy poses a huge challenge to the attending anesthesiologist. In May 2019 the European Malignant Hyperthermia Group published a guideline on malignant hyperthermia during pregnancy. The article summarizes and discusses the recommendations and provides practical advice for treatment of pregnant women or their fetus with known or suspected susceptibility to malignant hyperthermia.
Topics: Anesthesia; Anesthesiology; Female; Humans; Hyperthermia; Malignant Hyperthermia; Pregnancy; Syndrome
PubMed: 34038975
DOI: 10.1055/a-1260-8975 -
Medicine Mar 2023Malignant hyperthermia (MH) is a life-threatening syndrome caused by sudden, uncontrolled skeletal muscle hypermetabolism in response to inhalation anesthetics and...
Malignant hyperthermia (MH) is a life-threatening syndrome caused by sudden, uncontrolled skeletal muscle hypermetabolism in response to inhalation anesthetics and depolarizing relaxants. The estimated incidence of MH is between 1:10,000 and 1:250,000 anesthetic procedures. In Poland, due to lack of reporting, the incidence of MH is unknown. Dantrolene is imported as a life-saving drug (target import) and temporally authorized for sale. The aim of the study was to evaluate the prevalence of malignant hyperthermia in Poland and to assess the accessibility to dantrolene in Poland. A questionnaire was conducted among the chiefs of anesthesia and intensive care units in Poland. During the years 2014 to 2019, 10 episodes of MH have been reported in 238 surveyed polish anesthesia departments. The estimated prevalence is 1:350,000. Eight patients survived the MH crisis. Dantrolene is stocked in 48 (20%) anesthesiology departments. Among the surveyed hospitals, only in 38 (16%) it is possible to administer dantrolene within 5 minutes of suspecting a MH reaction. Less than half units (44%) have an algorithm for the management of MH episode in the operating theaters. The results of the study revealed, that the prevalence of MH in Poland is lower than the prevalence reported in other countries. Access to dantrolene in Poland is limited.
Topics: Humans; Malignant Hyperthermia; Dantrolene; Poland; Surveys and Questionnaires; Anesthetics, Inhalation
PubMed: 36897682
DOI: 10.1097/MD.0000000000033238 -
International Orthopaedics Aug 2021This paper describes the life and work of Louis Ombrédanne, one of the founding fathers of the SICOT, a notorious French orthopaedic and paediatric surgeon with a... (Review)
Review
This paper describes the life and work of Louis Ombrédanne, one of the founding fathers of the SICOT, a notorious French orthopaedic and paediatric surgeon with a strong interest in plastic surgery and reconstruction of post-traumatic defects and also with limb lengthening and treatment of sequalae. Born in Paris in 1871 as a son of a general practitioner doctor, Ombrédanne was a brilliant student enjoying anatomy and surgery since the early years. He was appointed as a Surgeon in 1902 in Paris and became Professor of Surgery in 1907. During the First World War, he worked in Verdun, one of the most exposed hospitals near the battlefield where over 700.000 people died and many cases were affected by head and neck burns and destructions, requiring surgical reconstruction. After the war, Ombrédanne developed Pediatric Surgery and it seems that his powerful drive and charisma explain why these specialties are studied together with orthopaedics in Europe and later in the World. Many innovations like the anaesthetic inhaler with face mask were authored by Ombrédanne and also techniques of limb lengthening, thoracic plasty. He described malignant hyperthermia in children and worked in the Sick Children Hospital in Paris, today Hôpital Necker. In 1929, Ombrédanne participated with a group of enthusiastic surgeons and teachers from many countries to the creation of SICOT during a historical meeting held in Hotel Crillon in Paris. This paper introduces Ombrédanne's work to the current readers and is a tribute to the work of our ancestors who made possible the development of our specialty.
Topics: Child; Europe; History, 20th Century; Humans; Orthopedic Procedures; Orthopedics; Surgeons; World War I
PubMed: 33559691
DOI: 10.1007/s00264-021-04963-0 -
BMC Anesthesiology Apr 2021Malignant hyperthermia is a rare but life-threatening pharmacogenetic muscle disorder characterized by abnormal hypermetabolic reactions and commonly triggered in...
BACKGROUND
Malignant hyperthermia is a rare but life-threatening pharmacogenetic muscle disorder characterized by abnormal hypermetabolic reactions and commonly triggered in susceptible individuals by volatile anesthetics or succinylcholine, or both. Unfortunately, the specific medicine dantrolene is not readily available in many countries including China. The aim of this study was to find the characteristics of malignant hyperthermia under the situation that dantrolene is not readily available.
METHODS
The cases of malignant hyperthermia reported on the most commonly used databases in China from 1985 to 2020 were analyzed. The inclusion criteria were the MH episodes only related to anesthesia. The exclusion criteria were dubious MH episodes only caused by Ketamine administration or MH episodes irrelevant to anesthesia. Independent samples t-test and Pearson's chi-squared test were applied to assess the difference between the survived and death cases.
RESULTS
Ninety-two cases of malignant hyperthermia reported on the most commonly used databases in China from 1985 to 2020 were analyzed. Median (IQR [range]) age was 18.5 (11.8-37.0 [0-70.0]) years. Compared with the survived cases, the death cases had higher maximum end-tidal partial pressure of CO (P = 0.033), the maximum arterial partial pressure of CO2 (P = 0.006), temperature first measured when the patient was first discovered abnormal (P = 0.012), and maximum temperature (P < 0.001). Besides, the death cases had less minimum pH (P < 0.001) and higher potassium (P < 0.001) and were more likely to have coagulation disorders (p = 0.018). Concerning treatment, cases used furosemide (P = 0.024), mannitol (P = 0.029), blood purification treatment (P = 0.017) had the advantage on the outcome. Creatine phosphokinase, myoglobin, and MB isoenzyme of creatine phosphokinase differed greatly among cases during the first week. 43 (46.7%) cases had congenital diseases. 12 (13.0%) cases were reported with abnormal laboratory test results or abnormal signs that are possibly relevant before anesthesia.
CONCLUSIONS
In countries that dantrolene is not readily available, early warning, diagnosis, and prompt effective therapies are crucial for MH patients to survive.
Topics: Adolescent; Adult; Aged; Arterial Pressure; Blood Coagulation Disorders; Carbon Dioxide; Child; Child, Preschool; China; Creatine Kinase; Creatine Kinase, MB Form; Dantrolene; Databases, Factual; Female; Humans; Hydrogen-Ion Concentration; Infant; Infant, Newborn; Male; Malignant Hyperthermia; Middle Aged; Muscle Relaxants, Central; Myoglobin; Potassium; Tidal Volume; Young Adult
PubMed: 33863282
DOI: 10.1186/s12871-021-01328-3