Muscle Ultrasound Abnormalities in Individuals with RYR1-Related Malignant Hyperthermia Susceptibility.

BACKGROUND: Variants in RYR1, the gene encoding the ryanodine receptor-1, can give rise to a wide spectrum of neuromuscular conditions. Muscle imaging abnormalities have been demonstrated in isolated cases of patients with a history of RYR1-related malignant hyperthermia (MH) susceptibility. OBJECTIVE: To provide insights into the type and prevalence of muscle ultrasound abnormalities and muscle hypertrophy in patients carrying gain-of-function RYR1 variants associated with MH susceptibility and to contribute to delineating the wider phenotype, optimizing the diagnostic work-up and care for MH susceptible patients. METHODS: We performed a prospective cross-sectional observational muscle ultrasound study in patients with a history of RYR1-related MH susceptibility (n = 40). Study procedures included a standardized history of neuromuscular symptoms and a muscle ultrasound assessment. Muscle ultrasound images were analyzed using a quantitative and qualitative approach and compared to reference values and subsequently subjected to a screening protocol for neuromuscular disorders. RESULTS: A total of 15 (38%) patients had an abnormal muscle ultrasound result, 4 (10%) had a borderline muscle ultrasound screening result, and 21 (53%) had a normal muscle ultrasound screening result. The proportion of symptomatic patients with an abnormal result (11 of 24; 46%) was not significantly higher compared to the proportion of asymptomatic patients with an abnormal ultrasound result (4 of 16; 25%) (P = 0.182). The mean z-scores of the biceps brachii (z = 1.45; P < 0.001), biceps femoris (z = 0.43; P = 0.002), deltoid (z = 0.31; P = 0.009), trapezius (z = 0.38; P = 0.010) and the sum of all muscles (z = 0.40; P < 0.001) were significantly higher compared to 0, indicating hypertrophy. CONCLUSIONS: Patients with RYR1 variants resulting in MH susceptibility often have muscle ultrasound abnormalities. Frequently observed muscle ultrasound abnormalities include muscle hypertrophy and increased echogenicity.

Continuous fetal head flexion as a marker for prenatal diagnosis of lethal multiple pterygium syndrome: a case report.

Lethal multiple pterygium syndrome (LMPS) is a fatal hereditary disease associated with abnormalities such as pterygium-induced congenital contractures. Fetal hydrops is present in more than half of all patients with LMPS, and all patients with LMPS are either stillborn or die in the early neonatal period. Ultrasonography findings for the prenatal diagnosis of LMPS include the detection of cutaneous webbing at multiple joints, multiple joint contractures, absent limb movement, and increased nuchal translucency. Here, we describe a patient who was diagnosed as having LMPS due to continuous fetal head flexion, despite the absence of the usual characteristics of the condition, including pterygium at the joints. Thus, continuous fetal head flexion can be a useful marker for prenatally diagnosing LMPS.

[Fetal Escobar syndrome--a case report]. / Zespól Escobara u plodu--opis przypadku.

The Escobar variant of multiple pterygium syndrome (MPS) is a rare, autosomal recessive disorder which may lead to many serious or even lethal fetal abnormalities. MPS is characterized by pterygia, arthrogryposis (joint contractures), and intrauterine growth restriction (IUGR). In the case described below, increased fetal nuchal translucency was the first abnormality diagnosed already in the first trimester of pregnancy. Other symptoms of the disease were found during the second trimester of pregnancy using ultrasonography examination. Also, genetic amniocentesis revealed no genetic disorders and the Escobar syndrome was diagnosed post mortem. Parental and maternal genetic examinations were performed and allowed for early prenatal diagnostics in the next pregnancy resulting in the birth of a healthy newborn.

Prenatal diagnosis and genetic analysis of fetal akinesia deformation sequence and multiple pterygium syndrome associated with neuromuscular junction disorders: a review.

Fetal akinesia deformation sequence is a clinically and genetically heterogeneous disorder characterized by a variable combination of arthrogryposis, fetal akinesia, intrauterine growth restriction, developmental abnormalities such as cystic hygroma, pulmonary hypoplasia, cleft palate, cryptorchidism, cardiac defects and intestinal malrotation, and occasional pterygia of the limbs. Multiple pterygium syndrome is a clinically and genetically heterogeneous disorder characterized by pterygia of the neck, elbows and/or knees, arthrogryposis, and other phenotypic features such as short stature, genital abnormalities, craniofacial abnormalities, clubfoot, kyphoscoliosis, and cardiac abnormalities. Fetal akinesia deformation sequence may phenotypically overlap with the lethal type of multiple pterygium syndrome. This article provides a comprehensive review of prenatal diagnosis and genetic analysis of fetal akinesia deformation sequence and multiple pterygium syndrome associated with neuromuscular junction disorders. Prenatal diagnosis of fetal akinesia along with cystic hygroma, increased nuchal translucency, nuchal edema, hydrops fetalis, arthrogryposis, pterygia, and other structural abnormalities should include a differential diagnosis of neuromuscular junction disorders. Genetic analysis of mutations in the neuromuscular junction genes such as CHRNA1, CHRND, CHRNG, CNTN1, DOK7, RAPSN, and SYNE1 may unveil the pathogenetic cause of fetal akinesia deformation sequence and multiple pterygium syndrome, and the information acquired is helpful for genetic counseling and clinical management.

Prevalence and patterns of scoliosis in children with multiple pterygium syndrome.

BACKGROUND: Although scoliosis is a predominant feature of multiple pterygium syndrome (MPS), the pattern of deformity and the progression of the curvature have not been well described. The purpose of this study was to assess the prevalence of scoliosis among patients with MPS, and to characterize the abnormalities of the vertebrae and to assess the progression of the scoliosis. METHODS: From 1969 to 2008, we identified 19 patients with MPS but only 16 patients (8 boys and 8 girls) had complete data. Medical records and radiographs of these 16 patients were reviewed. Magnetic resonance imaging was performed in 8 patients to evaluate intraspinal anomalies. Functional mobility score was used to assess the ambulatory ability. RESULTS: Of 16 patients, 13 patients (81.3%) had scoliosis. The mean age when the scoliosis was first noticed was 3.3±2.6 years (range, 1 mo to 8.2 y). The mean Cobb angle at first visit was 37.4±18.1 degrees (range, 14.0 to 75.0 degrees). With a mean follow-up of 4.0±4.9 years, the Cobb angle at the last visit was 43.3±19.1 degrees (range, 20.0 to 72.0 degrees). Congenital scoliosis was observed in 7 patients (3 unilateral unsegmented bar, 3 fusion of the cervical spine, 1 block vertebrae), whereas neuromuscular scoliosis was observed in 1 patient. A common radiographic finding was narrowing of the intervertebral disc space with decreased height of vertebrae in the thoracic area. Intraspinal anomalies were seen in 4 patients (3 tethered spinal cords, 1 syrinx). At the last follow-up, 5 of 13 patients who had scoliosis were able to walk at school without assistance (Functional mobility scale-500 ≥5). CONCLUSIONS: Scoliosis is common among children with MPS. It is frequently accompanied by fusion of the cervical area. Intraspinal anomalies such as tethered cord syndrome and syringomyelia are common associated anomalies. Therefore, it is important to look for intraspinal anomalies. Closed monitoring of the patient's ambulatory ability and bowel and bladder continence is also needed. LEVEL OF EVIDENCE: Level IV, Diagnostic Study.

CHRNG genotype-phenotype correlations in the multiple pterygium syndromes.

BACKGROUND: Germline mutations in the CHRNG gene that encodes the γ subunit of the embryonal acetylcholine receptor may cause the non-lethal Escobar variant (EVMPS) or the lethal form (LMPS) of multiple pterygium syndrome (MPS). In addition CHRNG mutations and mutations in other components of the embryonal acetylcholine receptor may present with fetal akinesia deformation sequence (FADS) without pterygia. METHODS: In order to elucidate further the role of CHRNG mutations in MPS/FADS, this study evaluated the results of CHRNG mutation analysis in 100 families with a clinical diagnosis of MPS/FADS. RESULTS: CHRNG mutations were identified in 11/41 (27%) of families with EVMPS and 5/59 (8%) with LMPS/FADS. Most patients with a detectable CHRNG mutation (21 of 24 (87.5%)) had pterygia but no CHRNG mutations were detected in the presence of central nervous system anomalies. DISCUSSION: The mutation spectrum was similar in EVMPS and LMPS/FADS kindreds and EVMPS and LMPS phenotypes were observed in different families with the same CHRNG mutation. Despite this intrafamilial variability, it is estimated that there is a 95% chance that a subsequent sibling will have the same MPS phenotype (EVMPS or LMPS) as the proband (though concordance is less for more distant relatives). Based on these findings, a molecular genetic diagnostic pathway for the investigation of MPS/FADS is proposed.

Caffeine impairs intramuscular energy balance in patients susceptible to malignant hyperthermia.

Malignant hyperthermia (MH) is a metabolic myopathy with an abnormal release of calcium by the sarcoplasmic reticulum (SR), triggered by volatile anesthetics and succinylcholine. Similarly, caffeine enhances Ca(2+)release by the SR in vitro. In a prospective, randomized study, high-energy phosphates were studied by intramuscular 31-phosphorus magnetic resonance spectroscopy ((31)P-MRS) in 10 MH-susceptible (MHS) and 7 MH-nonsusceptible (MHN) subjects before and after injection of 0.5 ml caffeine (20 mM). Intramuscular energy balance, measured by the ratios of P(i)/PCr and P(i)/gamma-ATP, did not differ between MHS and MHN patients before and after intramuscular caffeine injection. However, within each group, P(i)/PCr and P(i)/gamma-ATP increased significantly only in the MHS group. Intramuscular caffeine injection seemed to impair the metabolic balance in MHS individuals. This may reflect a local calcium overload leading to consumption of high-energy phosphates and increase of inorganic phosphate. Intramuscular stimulation by caffeine and (31)P-MRS may provide a valuable tool to investigate MH-related metabolic disturbances.

Ultrasonography: not useful in detecting susceptibility to malignant hyperthermia.

MH is a rare, potentially fatal complication of general anesthesia. Halothane-caffeine contracture testing of a muscle biopsy is the only accepted diagnostic test for MH. A previous report indicated that ultrasonography may aid in diagnosis of MH. Using sonographic examination of the thigh and calf, we evaluated eight patients with proved susceptibility to MH and eight control patients. Two radiologists independently evaluated the sonograms for echogenicity and definition of fascial planes. We detected no consistent and reliable differences between control and MH patients. We conclude that, in our hands, ultrasonography is not useful in differentiating patients with MH from normal persons.