The objective of this study was to evaluate the effect of natural bleachingproducts on the color, whiteness, and superficial properties of dental enamel.Seventy fragments of bovine teeth were obtained (6mm x 6mm x 2mm). Initialsurface roughness , microhardness , color , and surface gloss  readings were done. Samples were separated into five groups (n=14)according to the treatments used: CT-conventional toothpaste (negative control);CH-charcoal; TU-turmeric; BP-banana peel, and CP16%-16% carbamide peroxide gel, and then brushed for 560 cycles (T1)and 1200 cycles (T2), equivalent to 14 and 30 days of brushing. New measurementswere performed after T1 and T2. The whiteness index for dentistry change (∆WID)and Weight loss (Wl) were calculated. CP16% demonstrated the highest (p<.05)color change (ΔE00) and ∆WID . Surface glossalterations were lower for TU, CP16%, and BP. CT and CH increased surfaceroughness (p<.05). CP16% decreased enamel microhardness. CH presented mediumabrasiveness, and CT and TU, low abrasiveness. The popular bleaching productswere not efficient for tooth whitening. Furthermore, brushing with charcoalincreased the enamel surface roughness, and CP16% decreased enamel microhardnessover time Whitenedteeth give people more social acceptance and satisfy their appearance Tooth whitening products have a well-known action mechanism. Hydrogen peroxideoxidizes the chromogens’ double bonds, which become lighter colored. For thewhitening gels based on the carbamide peroxide agent, carbamide peroxide breaks downin the presence of water, releasing the hydrogen peroxide ,Because of the current unachievable beauty standards and social pressure that arebroadcasted through social media, every day, new videos and profiles emerge from theinternet recommending the use of homemade products, to obtain tooth whitening, withthe promise of fast and cheap dental bleaching, without any scientific evidenceabout their efficacy and safety to the oral health Currently, activated charcoal is one of the most popular and appealing products. Itis being commercialized as an oral hygiene product due to its adsorption capacityfor pigments responsible for tooth color change ,,Curcumin is the most bioactive component of turmeric, and it is known for itsantioxidant, antibacterial, and anti-inflammatory activities. Besides, curcuminpresents low water solubility, low chemical stability, and oral biodisponibility,Banana peels are commonly considered as residue. However, they present in theircomposition important compounds, such as flavonoids, alkaloids, tannins, quinones,and saponins, which have antioxidants and anti-inflammatory properties Therefore, the aim of the study was to analyze the effect of brushing with popularnatural agents, used by the population to obtain tooth whitening but not indicatedfor that purpose, on the color, whitening, and superficial properties of dentalenamel. The null hypothesis was that there would be no difference in the dentalenamel brushed with natural substances compared to the conventional toothpasteregarding the color change, surface gloss, surface roughness, and microhardness.The sample size (n=14) was based on data obtained from a pilot study anddetermined on www.openepi.com, with a confidence interval of 95% and power of80%. For this study, sound bovine teeth without cracks or fractures were used.After removing the roots, the crowns were cut using a low-speed diamond saw underwater cooling to obtain70 fragments (6 mm x 6 mm x 2 mm).The enamel surface was polished using abrasive papers under refrigeration  so that the surface roughness would not exceed 0,4 µm.Then, the samples were separated and stored in artificial saliva at 37 ºC.The surface roughness, microhardness, color, and surface gloss readings were doneat 3 different times: before the treatments (T0), after 560 brushing cycles(T1), and after 1200 brushing cycles (T2).The initial surface roughness readings  were done. Three readings were performed on the enamel surface of eachsample: in the middle, 1 mm to the right, and 1 mm to the left. The mean valueof the readings was used as the initial surface roughness value. To calculatethe surface roughness alteration, the following formula was employed:i is the initial surface roughness value and Rɑfthe final one. ΔRɑ was calculated after T1 and T2 (Rɑf).Where RɑFor the Knoop microhardness analysis , a statical vertical load of 25 g was applied for 5 seconds i is the initial microhardness value and KHNf thefinal one. ΔKHNr was calculated after T1 and T2 (KHNf) andpresented as percentages (%).Where KHNFor the color readings, a spectrophotometer was employed . The samples were placed over a whitebackground  in a standardized lightbox. The standard illuminant used wasD65, which simulates the daylight spectrum.Three color readings were performed for each sample using the CIE L* a* b*coordinates, and the mean of the three readings was considered the color valueon the L*, a*, and b* axis. For standardization purposes, samples with values ofL*, a*, and b* ranging over 0.5 in each coordinate were discarded.,,,The color stability was calculated using the L*, a*, and b* initial and finalvalues, with the CIEDE2000 formula L, SC, and SH are the weightingfunctions for the lightness, chroma, and hue components, respectively; andKL, KC and KH, the parametric factorsaccording to different viewing parameters set to 1 ,Where ΔL’, ΔC’, and ΔH’ are the differences in lightness, chroma, and hue,respectively, between two measures and RT (rotation function) is a function thataccounts for the interaction between chroma and hue differences in the blueregion. S,The color variation values were compared to the perceptibility  andacceptability D) analysis correlates thewhitening visual perception, avoiding bias from the subjective visual factor onthe dental color evaluation. It is calculated using the L* a* and b*coordinates, with the following formula:The whitening index for dentistry (WID was determined after each tested time. Whiteness differences(∆WID) were calculated after T1 and T2 in relation to baselinevalues. CIELAB values close to reference white indicate higher whiteness value. So, positive ∆WID values indicatehigher whitening perceptibility, and lower (or negative) ones indicate lowerwhitening perceptibility. The ∆WID values were compared to theperceptibility  and acceptability  thresholds The WIFor the surface gloss analysis, a glossmeter was used , with 45º geometry reading Three readings were performed for each sample, and the mean of the readings wasconsidered the gloss value. The gloss alteration was calculated by the final andinitial values difference for each time (T1 and T2), using the followingformula:0 is the initial gloss value and GUtx is the value afterT1 and T2.GUtThe samples were separated into five groups (n = 14) according to the treatmentused  was treated using the 16% carbamide peroxidegel  After treatments, the samples were rinsed with distilled water for 10 seconds,immersed in artificial saliva, and stored at 37 ºC.The weight loss test was performed to measure the abrasiveness of the productsused. For that 18 plexiglass samples  with 90 mm x 30 mm x 4 mm were used. The plexiglasssamples were immersed in distilled water and stored at 37 ºC. After one month,three weightings were performed for each sample, and the mean was used as theinitial mass value. Then, the samples were randomly separated into three groups(n = 6) according to the product used for the simulated brushing. The plexiglasssamples were brushed for 41 minutes  Where wI is the initial mass value and wF the final one. Weight loss values under21 mg indicate low abrasiveness; between 21 and 40 mg, medium abrasiveness andover 41 mg, high abrasiveness Initially, two bovine teeth samples were obtained and polished as a control, andtwo of each group were randomly selected after treatments. The surfacemorphology of the enamel was analyzed through scanning electron microscopy . For that, the samples were desiccated for 12 hours using adesiccator with silica gel. Then, the samples were placed in aluminum stubs, sputter-coated withgold-palladium alloy , and observed at 200x and 1000x magnifications  The data were submitted to the Shapiro-Wilk (p < .05) normality test andanalyzed by 2-way ANOVA (variation factors: treatments and time), with repeatedmeasures, and by Bonferroni’s test (p < .05), with the exception of theweight loss (Wl), which was analyzed through one-way ANOVA and Tukey’s test (p< .05).00  throughout 30 days of treatment . The turThe results obtained after the abrasiveness test  showed tSEM images were obtained from the samples treated and not treated (used as control),allowing the comparison between them . In the The enamel surface treated with CP16% showed at the 200x magnification interprismaticamong prismatic enamel, all over the surface with a uniform distribution . SEM imaThe aim of this study was to evaluate the effect of brushing with popular naturalagents, used by the population to obtain tooth whitening but not indicated for thatpurpose, such as turmeric, charcoal, and banana peel, widely spread on the internetwithout any scientific evidence. The null hypothesis was that there would be nodifference in the color, whitening and superficial properties of the dental enamelbrushed with those products, in comparison to a conventional toothpaste, as anegative control. A positive control group was also included in this study, with 16%carbamide peroxide gel, since its efficacy is already known in the literature, tocompare the potential bleaching effect of these natural products with awell-established whitening agent. The null hypothesis was rejected because thebleaching agents altered all the properties tested, except for the color.00 of the samples treated with the natural products compared toconventional toothpaste, regardless of the brushing time. The CP16% presented highercolor change, different (p < .05) from all the other groups, as demonstrated inother studies ,,Regarding color variation, there was no significant difference (p > .05) in, regardless of the time of use, results similar to the ones found by Franco etal. (2020) 00 > 1,8) irrespective of thebrushing time.Despite the lack of significant differences among the natural agents, all treatmentsresulted in color change above the perceptibility threshold  study The activated charcoal is highly porous, and the whitening effect of the product isbased on its capacity to adsorb and retain chromophores of the diet in the oralcavity. Despite this, there was a slight positive change for the charcoal group forthe WIThe tooth surface morphology affects the quantity and type of light reflected. Arougher surface allows higher diffuse reflection, while a flat surface results inspecular reflection. The amount of light reflected over the enamel surface afterbrushing increased. Thereby, surface gloss can alter color perception Changes in the enamel surface roughness interfere with the perception of color andsurface gloss because those alterations can lead to scattering and diffuse lightreflection The samples brushed with the conventional toothpaste and charcoal revealed highersurface roughness values. They increased the surface gloss, probably theabrasiveness of the products may have caused alterations on the enamel surface thatchanged the reflection of the light The relative microhardness expresses the increase or decrease of the enamelmicrohardness after treatments, related to the initial values. Negative relativemicrohardness values demonstrate a decrease in the final microhardness, and positivevalues indicate an increase in the microhardness. So, analyzing the results foundthere was no significant difference (p > .05) between T1 and T2 for all thetreatments. Only CP16% decreased the microhardness of the enamel, similar (p >.05) to the turmeric and banana peel groups but different (p<.05) from theconventional toothpaste and charcoal groups.Harrington et al. (1982) When associating the weight loss and surface roughness results, rougher enamelsurfaces for charcoal were found, followed by conventional toothpaste, corroboratingthe results found by Palandi et al. (2020) The SEM analysis corroborates the surface roughness, microhardness, and weight lossresults. The images obtained as control showed a smooth enamel surface with somescratches. These irregularities may have resulted from the polishing process,necessary for the standardization of the enamel surface. Considering that a roughsurface contributes to enamel staining According to Silva et al. (2018) Based on the results found, it was concluded that the popular natural agents used toobtain tooth bleaching but not indicated with that purpose did not present whiteningefficacy, regardless of the time of use. Changes in the surface gloss of the enamelare related to alterations in the surface roughness of this substrate. The proposedbleaching agents can alter the enamel surface roughness. The conventionaltoothpaste, charcoal, and carbamide peroxide gel caused alteration in the enamelsurface, different from turmeric and banana peel.


To date, only twenty-one cases diagnosed postnatally with mosaic trisomy 12 have been reported. The most frequent phenotypic manifestations are developmental delay, dysmorphic facial features, congenital heart defects, digital alterations, and pigmentary disorders. In the present report, detailed clinical and genetic profiles of three unrelated new patients with mosaic trisomy 12 are described and compared with previously reported cases.In the present report, we include the clinical, cytogenetic, and molecular description of three Mexican patients diagnosed postnatally with mosaic trisomy 12. At phenotypic level, the three patients present with developmental delay, dysmorphic facial features, congenital heart defects and skin pigmentary anomalies. Particularly, patient 1 showed unique eye alterations as bilateral distichiasis, triple rows of upper lashes, and digital abnormalities. In patient 2 redundant skin, severe hearing loss, and hypotonia were observed, and patient 3 presented with hypertelorism and telecanthus. Hyperpigmentation with disseminated pigmentary anomalies is a common trait in all of them. The cytogenetic study was carried out under the strict criteria of analysis, screening 50–100 metaphases from three different tissues, showing trisomy 12 mosaicism in at least one of the three different tissues analyzed. With SNParray, the presence of low-level mosaic copy number variants not previously detected by cytogenetics, and uniparental disomy of chromosome 12, was excluded. STR markers allowed to confirm the absence of uniparental disomy as well as to know the parental origin of supernumerary chromosome 12.The detailed clinical, cytogenetic, and molecular description of these three new patients, contributes with relevant information to delineate more accurately a group of patients that show a heterogeneous phenotype, although sharing the same chromosomal alteration. The possibility of detecting mosaic trisomy 12 is directly associated with the sensitivity of the methodology applied to reveal the low-level chromosomal mosaicism, as well as with the possibility to perform the analysis in a suitable tissue. The incidence of chromosome aneuploidy in newborns is approximately 0.3%, being trisomy 13, 18, and 21 the most common abnormalities –19.It is known that the clinical manifestations associated with chromosomal mosaic alterations depend on the timing of the mosaicism-inducing event, the specific type of affected cells, the level of mosaicism, the chromosome involved, the distribution of abnormal cells in different tissues and the presence of UPD , 20, 21.In the present report, we include the clinical, cytogenetic, and molecular description of three unrelated Mexican patients diagnosed postnatally with mosaic trisomy 12, with a brief description of the phenotype, and discussion of the common clinical features previously reported for this group of patients.Patients were diagnosed by the Genetics and Dermatology Departments of three different hospitals. This study was approved by the Research Ethics committee with National Commission of Bioethics registration number “CONBIOETICA-09-CEI-025-20,161,215”. Signed informed consent was obtained according to the recommendations of the Helsinki Declaration.th finger and hallux valgus in both feet were also observed. In addition, pigmentary mosaicism with disseminated hypo and hyperpigmentation following fine Blaschko lines was observed  and length 50 cm z −0.10 SD) , OFC was not available. She presented with congenital heart defects reverted by surgery at 2 years old. Physical examination showed sparse eyebrows, bilateral distichiasis and triple rows of upper lashes, eyelid ptosis and narrow eyelid fissure. Depressed and broad nasal bridge, midface hypoplasia, high-arched palate, and posteriorly rotated ears were also observed , length 51 cm (z 1.14 SD), OFC was not available. Apgar score was 5/8. Physical examination revealed mild dolichocephaly with a prominent forehead, anterior hairline slightly resembles widow’s peak, with frontal upsweep. He showed sparse eyebrows, straight palpebral fissures, epicanthus, nystagmus, and other abnormal ocular movements. Depressed and broad nasal bridge, anteverted nares, midface hypoplasia and long philtrum were detected , length was 51 cm (z 0.33 SD) and OFC was 36 cm (z 1.03 SD). Apgar score was 6/8. Physical examination showed arched eyebrows, hypertelorism, telecanthus, depressed nasal bridge and anteverted nares. He presented with cardiac alterations reverted by surgery at 4 months. Pigmentary mosaicism with disseminated hyperpigmentation, following broad and fine Blaschko lines in the trunk and limbs respectively, was observed  lymphocytes following conventional techniques and interpreted according to the International System for Human Cytogenetic Nomenclature 2020 . Fresh bIn order to rule out the presence of trisomy 12 as low-level mosaic in PB of the 3 patients, CytoScan™ 750 K array  (NCBI GRCh37/hg19 UCSC) was performed and both, CNVs and at the same time, UPD12 were excluded in PB lymphocytes of all patients , cardiac alterations 15/24), developmental delay (10/24) and skin pigmentation alterations (10/24), are common features present in most previously reported cases and in the patients described herein . These cardiac alterations are also present in patients with mosaic tetrasomy 12p or Pallister-Killian syndrome  , 29; sugAt pigmentation level, all three patients reported here showed fine Blaschko lines, been hyperpigmentation with disseminated dermatosis the most frequently observed pigmentation pattern. In previous studies of patients with pigmentary mosaicism, the hypopigmentation was the most frequent type of pigmentation ranging 50–100%) –34. The 0–100% –3KRT2A, ADAMTS20, WNT1, SILV, VPS33A and KITLG. Copy number gains could modify the expression of any of these genes and probably generate skin pigmentary alterations [KITLG gene located in 12q21.32, implicated in hematopoiesis, gametogenesis, and importantly in melanogenesis, has been directly associated with pigmentary alterations. Mosaic activating KITLG pathogenic variants have been detected, thus extra copies of this gene produced by trisomy 12 could be associated with the pigmentary findings [KRAS gene, has also been associated with the presence of pigmentation abnormalities, such as cafe-au-lait spots. The increased gene dosage could deregulate the RAS/MAPK pathway, which is crucial for controlling pigmentation [Cutaneous manifestations are commonly caused by somatic mosaicism, and it is known that the presence of differential skin pigmentation is related with the presence of two distinct genotypes in each type of skin , 35–37. erations . It is ifindings –40. Duplentation .In our Institution, we have studied a very large and heterogeneous group of patients with pigmentary mosaicism. As part of the approach to study, in these patients with such diverse phenotypic manifestations, a very strict cytogenetic and molecular analysis is performed to find the genetic origin. As a result of this strategy of analysis, we were able to identify and diagnose the three patients reported here.The cytogenetic study was carried out under strict criteria for screening to discard the presence of mosaicism in the three different tissues analyzed. It is important to note that the cytogenetic analysis in PB was normal in all three patients. Until now, only 4/13 patients previously reported with cytogenetic analysis in PB, showed trisomy 12 mosaicism in this tissue , 13, andImportantly, 11/24 reported patients  presented six or more clinical manifestations involving at least four different systems. In general, neurological, and pigmentary alterations are the ones that occurred less frequently in the above-mentioned patients; however, all three patients in the present study had neurological and pigmentary manifestations. Musculoskeletal deformities, principally hand/feet digital alterations, and cardiac alterations such as patent ductus arteriosus and atrial/ventricular septal defects are frequently observed in patients with mosaic trisomy 12, as well as in our patients (Table Molecular analysis with SNP array ruled out the low-level mosaic of copy number variations in PB of three patients. Same analysis detected mosaic trisomy 12 in PB of three previously reported patients , 18. STRThe coexistence of disomic and trisomic cells in the same individual could be explained as follows: A non-disjunctional meiotic event generating a trisomic zygote, followed by mitotic trisomy rescue, generating an individual with a diploid biparental cell line and trisomic cell line . By chanIn summary, trisomy 12 mosaicism is a phenotypically heterogeneous entity that occurs with very low frequency, thus, detailed clinical and cytogenomic description of these new three patients contributes relevant information to delineate more accurately a group of patients that share genetic characteristics. Our analysis strategy, looking for chromosomal abnormalities in a large number of metaphases on three different tissues, allowed us to rule out whether the alteration is confined only to a single tissue, and to accurately detect the proportion of abnormal cells. The molecular analysis discards the presence of trisomic cells in other tissues, and the presence of UPD12 originated by a non-disjunctional event. Finally, the modifications in gene expression associated with pigmentary alterations could be originated by the triple dose associated with mosaic trisomy 12. The search for biological evidence to establish these associations constitute a research challenge in patients with this entity.


Hereditary spherocytosis (HS) has a defect in the vertically connected proteins on the cell membrane of red blood cells (RBC). Hereditary elliptocytosis (HE) has a defect in proteins that connect the cell membrane horizontally. We reported two families of RBC membrane disorders in Taiwanese, one was HS and the other was HE.Case 1. A 19-year-old male student with chronic jaundice and splenomegaly. His mother, maternal uncle, grandmother, and many members of older generations also had splenomegaly and underwent splenectomy. Case 2. A 40-year-old man has experienced pallor and jaundice since the age of 20 and was found to have splenomegaly, and gall bladder stones in the older age. His younger sister also had pallor and jaundice for a long time.In case 1, a peripheral blood smear showed 20% spherocytes. Eosin-5-maleimide labeled RBC by flow cytometry showed a result of 30.6 MCF . He was diagnosed with HS. The gene analysis identified a heterozygous mutation with c.166A > G (p.Lys56Glu) in the SLC4A1 gene in this proband, his mother, and maternal uncle. In case 2, more than 40% of ellipsoid RBC present in the peripheral blood smear. He was diagnosed with HE. Genetic analysis of the SPTA1 gene identified a novel heterozygous exon2, c.86A > C, p.Gln29Prol mutation.The two patients had compensated anemia, clinical follow-up instead of splenectomy was done.The two patients had normal daily activities and lives.We reported two Taiwanese families, one was hereditary spherocytosis affected by a heterozygous mutation with c.166A > G (p.Lys56Glu) in SLC4A1, and the other was hereditary elliptocytosis caused by a novel heterozygous SPTA1 gene mutation, c. 86A > C, p.Gln29Prol. These 2 seemingly common hereditary red blood cell membrane protein defects induced by hemolysis are usually underdiagnosed or misdiagnosed. Red blood cell membrane disorders are a heterogeneous group of inherited disorders caused by certain mutations in genes that encode proteins that link the membrane cytoskeleton to the lipid bilayer. Deficiency or dysfunction of these proteins leads to reduced deformability of red blood cell (RBC) in the splenic trapping and narrow capillary beds, which causes hemolysis. In addition, defects in some membrane proteins have abnormal ionic permeability, with an increasing influx of sodium into the intracellular space. RBC membrane disorders can be categorized as altered membrane structural organization (hereditary spherocytosis and hereditary elliptocytosis) and altered membrane transport function (hereditary stomatocytosis and hereditary xerocytosis).,3 Among these diseases, hereditary spherocytosis (HS) and hereditary elliptocytosis (HE) are the most common types in the world.–8Normal erythrocytes have a lipid bilayer membrane with proteins that adhere to the cytoskeleton and confer a normal biconcave shape, providing optimal surface/volume ratio, maintaining structural integrity, and adequate ion permeability.–5 HS is widely distributed around the world, especially in the Caucasian ethnic group.–10 HE, is a defect in proteins that connect the cell membrane horizontally.–5 A distribution of HE has obvious regional characteristics. The prevalence of HE, especially the Southeast Asian ovalocytosis (SAO) subtype, is higher in malaria-endemic areas.HS is a defect in the vertically connected proteins on the cell membrane of red blood cells. while in the case of HE, a novel mutation was newly discovered. We provided detailed personal and family history, physical examinations, and laboratory findings for these 2 underdiagnosed disorders to raise awareness among physicians and reviewed related literature.In the study, we reported 2 families of RBC membrane disorders in Taiwanese, 1 was HS and the other was HE. In the case of HS, the genetic mutation  was previously published,In this investigation, 1 patient was diagnosed with HS and the other with HE at Changhua Christian Hospital. Hemolytic anemia, elevated bilirubin, splenomegaly, spherocytes or elliptocytes in the peripheral blood smear, and family history were used to diagnose HS and HE. Both patients were tested for osmotic fragility, flow cytometry of eosin-5-maleimide labeled red blood cell (EMA-labeled RBC), and genetic analysis using next generation sequencing (NGS) and polymerase chain reaction. Following the manufacturer’s instructions, NGS sequencing libraries were created using the Agilent SureSelect Human All Exon V6 kit . The libraries were sequenced on an Illumina NovaSeq 6000 platform, and Genomics BioSci& Tech Co. generated 150 bp paired-end reads. The variations of RBC membrane diseases candidate genes were chosen for Sanger sequencing, and the amplified product was sequenced according to the manufacturer’s instructions using an automated DNA sequencing analyzer, ABI3130xl . All patients gave their informed consent to participate in this study, which was carried out in accordance with the Declaration of Helsinki and approved by our institution’s Ethics Committee.The proband was a 19-year-old male student with chronic jaundice and mild splenomegaly. He had a history of neonatal hyperbilirubinemia , which was relieved by phototherapy. He has had no notable symptoms or signs except that hyperbilirubinemia and mild splenomegaly were persistently detected on several occasions during the health examination at high school. His mother also had splenomegaly and suffered from abdominal pain and pallor at the age of 10. She received a splenectomy 1 year later. The patient’s maternal uncle, grandmother, and many members of older generations also had splenomegaly and underwent splenectomy. His parents did not pay attention to his symptoms until January 2018, when he was brought to our clinic to seek a possible cause.On physical examination, he was well developed and without a pale face. But he was found to have icteric sclera and mild splenomegaly. Laboratory tests revealed that WBC was 11,000/uL, platelet was 3,11,000/uL, Hb was 14.9 gm/dL, MCV was 88.2 fl, MCHC was 37%, white blood cell classification was normal, total bilirubin was 5.26 mg/dL, direct bilirubin was 0.33 mg/dL, GOT was 17 IU/L, GPT was 7 IU/L, LDH was 164 U/L, haptoglobin was < 8.0 mg/dL, and Coombs’ test was negative. A peripheral blood smear showed 20% anisocytosis and 20% spherocytes , and SAO according to its phenotype. Most cases are a common type of hereditary elliptocytosis, and more than 90% of inherited genes are heterozygous. These people have no clinical symptoms or only mild hemolytic anemia, while HPP, occurring in homozygous or compound heterozygous patients, accounts for < 10% of HE, will suffer from moderate to severe hemolytic anemia and need regular blood transfusions. Most of the inherited forms are AD, and only the most serious HPP types are inherited by autosomal recessive. In addition, SAO is prevalent in Southeast Asia. The main causes are band 3 defects, and its related mutant gene comes from SLC4A1 deletion of 27 base pairs that lead to the loss of 9 amino acids, which is also AD inherited  have ANK1 mutations are most commonly present, followed by SPTB mutations (about 30%).–21 But some investigations reported that Chinese HS patients are affected by band 3 deficiency. Because of the small number of reported cases, it is necessary to collect more data to determine the actual rates of erythrocyte membrane protein deficiency in Chinese HS patients. The latest report by Keiko Shimojima Yamamoto et al from NGS analysis of 13 Japanese with hereditary spherocytosis demonstrated that ANK1 variants were found to be the most common, being found in 46% (6/13) of the patients and followed by SPTB variants identified in 31% (4/13) of the patients. This distribution of the variants was similar to those observed in other Asian countries but was different from those observed in non-Asian countries. The distribution of HS-related variants was also different from that identified in a previous study on Japanese patients with HS. No epidemiological data for HS in Taiwan has been reported.HS is widely distributed around the world, especially in the Caucasian ethnic group. The prevalence rate can reach 1/2000 in North America and Northern Europe.The true prevalence of HE is unknown because many mildly affected individuals are likely to remain undiagnosed. The global prevalence has been estimated to be 1 in every 2000 to 4000 people (0.05%–0.025%).–26 SAO also confers resistance against Plasmodium falciparum infection, likely because of alterations in band 3, which is one of the malaria receptors. Generally, SAO individuals are asymptomatic. Due to its high prevalence in Southeast Asia, SAO is not a disease, but rather an erythrocyte polymorphism. In vitro, Plasmodium falciparum infection in elliptocytes carrying such spectrin alleles revealed that these alleles are genetic causes of malaria resistance. However, several spectrin mutations or polymorphisms have yet to be demonstrated in vivo as new drivers of innate resistance to malaria (11).HE is most common in individuals of African, Mediterranean, or Southeast Asian descent. It has been reported that in areas such as West Africa, the prevalence of HE is as high as 1% to 2%. In particular, SAO is a very common condition in the aboriginal peoples of Papua New Guinea, Indonesia, Malaysia, the Philippines, and southern Thailand, with a prevalence varying between 5% and 25%. In Japan, HE accounts for 13.5% of hereditary red cell membrane disorders. No epidemiological data on HE has been published in China. There are only a few cases and a few series of reports concerning Chinese hereditary elliptocytosis.–31 No cases have been reported from Taiwan.In Korea, HE is the cause of 1.4% of cases of hereditary hemolytic anemia.–34 Megaloblastic crises are caused by folate deficiency and can be corrected by adequate folate supplementation. Extramedullary hemopoietic tumors attributed to the ineffective hematopoiesis of hereditary spherocytosis have been described in many case reports. Other complications, such as growth failure and leg ulcers, are also reported.,36Typical manifestations of HS or HE include hemolysis with anemia, jaundice, reticulocytosis, gallstones, splenomegaly, spherocytes, or elliptocytes on the peripheral blood smear, and a positive family history of the disease. Some patients with HS may present with hematologic crises, which may be hemolytic, aplastic, or megaloblastic. The aplastic crisis is associated with parvovirus B19 infection. Hemoglobin and reticulocytes will decrease first, and then the erythroblasts in the bone marrow will also decrease.,9,37Several tests are available to confirm the diagnosis of HS and HE. But these tests can be omitted if classic findings  and positive family history have been identified. The mean fluorescence of EMA-labeled RBCs from individuals with HS is lower than controls, and this reduction in fluorescence can be detected in a flow cytometry-based assay. EMA is now a standard test for HS screening but has less efficacy in the case of HE. The osmotic fragility test (OFT) was conducted according to the fraction of hemoglobin released in hypotonic salt solutions of various osmolarities. OFT is an old method for detecting RBC membrane disorders, and it has a certain value in the diagnosis of HS, although the sensitivity is only 60% to 70%. As for HE, there will be no abnormalities of OFT in common HE and SAO except HPP and more severe HE in the OFT. In our 2 cases, case 1 carried HS, presented a low EMA level, and a positive finding of OFT, but case 2 carried HE in the normal range of these tests.EMA  is an eosin-based fluorescent dye that binds to RBC membrane proteins, especially band 3 and Rh-related proteins.,41 The sensitivities of these tests were evaluated in a 2012 study that tested samples from 150 individuals known to have HS. The results of sensitivity were as follows: 93% of EMA bindings, 68% of fresh osmotic fragility, 81% of incubated osmotic fragility, 95% of AGLT, and 61% of GLT.The glycerol lysis test (GLT) and the acidified GLT (AGLT) are modifications of the OFT that add glycerol (in the GLT) or glycerol plus sodium phosphate  to the hypotonic buffered salt solutions.,39 However, the technique of osmotic gradient ektacytometry has not been evaluated in formulating the guidelines because of a lack of its general availability.Osmotic gradient ektacytometry measures RBC deformability under defined shear stress as a function of suspended medium osmolality. The test is used to screen for inherited RBC membrane disorders such as HS, HPP, SAO, and hereditary stomatocytosis.Quantification of the amount of spectrin, ankyrin-1, band-3 protein, or protein 4.2 in the erythrocyte membrane can support the diagnosis of these diseases. However, some patients might have only a 10% to 15% reduction in the affected protein. The simplest method is SDS-PAGE of red blood cell membranes, but this technique reveals abnormalities in only 70% to 80% of patients.Polymerase chain reaction-based mutation screening techniques have been applied to the detection of HS and HE-associated mutations. Next-generation gene sequencing can also be used in transfusion-dependent cases in which the RBC phenotype cannot be evaluated.In Taiwan, cases of HS are occasionally encountered in clinical practice, but few associated studies have been published. The actual prevalence of HS in Taiwan is unknown.The family of Case 1 is a typical presentation of HS inheritance. Nine members of the family had splenomegaly, and 6 of them had undergone splenectomy. In a sense, we can mitigate HS by splenectomy. However, splenectomy is reserved for HS patients who have suffered moderate to severe hemolysis. Spleen size is not an absolute indication of splenectomy. Many people in this family have been overtreated, and the exact etiology of splenomegaly in these people has not been determined yet.In Case 1, obvious jaundice was found when he was born. We should take inherited hemolytic disease into consideration, especially unconjugated jaundice, which is predominant in the period of infancy. Although most cases of mild HS do not have major complications, it is a fact that the phenomenon of case 1 has been selectively neglected by physicians over the years. Notably, we found a heterozygous mutation with c.166A > G (p.Lys56Glu) in the SLC4A1 gene in case 1. We herein highlight that congenital hemolysis must be taken into diagnosis in the case of anemia, jaundice, splenomegaly, and family history. Physicians should be aware of inherited hemolytic diseases, especially HS, which is an AD inheritance prevalent.Cases of HE are rarely reported by Taiwanese, and no 1 has investigated the epidemiology of HE in Taiwan. As mentioned above, the endemic areas of HE are parallel to malaria-endemic areas. HE is prevalent in the prevalence of malaria. Southeast Asia is an area where malaria is endemic, so the prevalence rate is high, but northeast Asia, such as South Korea and Japan, has a low rate of prevalence. Taiwan is located at the junction of Northeast Asia and Southeast Asia, and its climate and environment are also in between. More than 90% of the Taiwanese ethnic group are Han people from mainland China, and only a few are aboriginal people. As a result of the intermarriage of the Han and the aboriginal people over the past 3 to 4 hundred years, Han and the aboriginal peoples may both carry each other’s genes. Therefore, needs more study to determine the origin of this variant gene carried by case 2. By the way, there was a study that investigated the evolutionary origins of Southeast Asian ovalocytosis, and the aborigines of Taiwan were also included in the Austronesian language group. However, the results of this report indicated that no causal mutation in the SLC4A1 gene has been found in the aborigines of Taiwan.The development of Case 2 was not affected by congenital hemolytic diseases. But in adulthood, he suffered from recurrent cholecystitis and cholangitis due to gallstones caused by hemolysis. Because of this, HE was discovered to have a novel mutation with heterozygous exon2, c.A86C, p.Gln29Prol mutation of the SPTA1 gene was found in case 2 of our study.We reported 2 Taiwanese families, 1 was hereditary spherocytosis affected by a heterozygous mutation with c.166A > G (p.Lys56Glu) in SLC4A1 (Band 3 protein), and the other was hereditary elliptocytosis caused by a novel heterozygous SPTA1 gene mutation, c. 86A > C, p.Gln29Prol. There were no similar case series reports in Taiwan. These 2 seemingly common hereditary red blood cell membrane protein defects induced by hemolysis are usually underdiagnosed or misdiagnosed. We highlighted these inherited hemolytic diseases herein to enhance the awareness of physicians and provide a literature review. We also had an interesting finding that Taiwan aborigines do not carry the SLC4A1 deletion, which exists in SAO and is popular in Southeast Asian people, although Taiwan aborigines belong to the Austronesian language family.Conceptualization: Ming-Ching Shen.Formal analysis: Ying-Chih Huang.Investigation: Yu-Hung Shih, Ying-Chih Huang.Methodology: Ying-Chih Huang.Resources: Ching-Yeh Lin, Hsuan-Yu Lin, Su-Feng Kuo, Jen-Shiou Lin.Software: Ying-Chih Huang.Supervision: Ming-Ching Shen.Writing – original draft: Yu-Hung Shih.Writing – review & editing: Ming-Ching Shen.


Surgical masks (SMs) protect medical staff and reduce surgical site infections. Extended SM use may reduce oxygen concentrations in circulation, causing hypoxia, headache, and fatigue. However, no research has examined the effects of wearing SMs on oxygenation and physical discomfort of anesthesiologists.2), heart rate, and respiratory rate were determined at different times before and after SM use. Shortness of breath, dizziness, and headache were subjectively assessed based on the visual analog scale (VAS) scores.An electronic questionnaire was established and administered through WeChat, and a cross-sectional survey was conducted to determine SM use duration and related discomfort of operating room medical staff. Then, operating room anesthesiologists were enrolled in a single-arm study. Peripheral blood oxygen saturation , respiratory rate increased , and heart rate remained unchanged. As mask use duration increased, the VAS scores of shortness of breath, dizziness, and headache gradually increased.In total, 485 operating room medical staff completed the electronic questionnaire; 70.5% of them did not change SMs until after work, and 63.9% wore SMs continuously for more than 4 h. The proportion of anesthesiologists was the highest. After wearing masks for 4 h, the shortness of breath, fatigue, and dizziness/headache rates were 42.1, 34.6, and 30.9%, respectively. Compared with other medical staff, the proportion of subjective discomfort of anesthesiologists increased significantly with prolonged SM use from 1 to 4 h. Thirty-five anesthesiologists completed the study. There was no difference in anesthesiologist SpO2 and increase respiratory rates without affecting heart rates.In healthy anesthesiologists, wearing SMs for more than 2 h can significantly decrease SpO Since December 2019, coronavirus disease 2019 (COVID-19) has spread globally and attracted worldwide attention . HoweverIn daily work, anesthesiologists face long exposures to infected bodily fluids and blood, toxic surgical smoke, bacteria, and viruses in patients' respiratory tract and the possibility of needle stab injuries, resulting in anxiety and fear –8. As paAt present, there is a serious shortage of anesthesiologists in China. The number of sudden deaths of anesthesiologists in China has increased sharply in recent years, and most of them die due to heavy workloads . From 112), heart rate, respiratory rate, and subjective discomfort of anesthesiologists.It is unclear whether wearing SMs for a long time causes changes in anesthesiologists' oxygenation, heart rate, and respiratory rate and aggravates physical and mental fatigue and whether wearing SMs for a long time is related to the high rate of sudden death among Chinese anesthesiologists. The primary purpose of this study was to investigate the effects of wearing disposable lace-up SMs for long periods of time on peripheral blood oxygen saturation (SpOThis study was carried out in accordance with the Declaration of Helsinki (2013 Edition) and approved by Qilu Hospital of Shandong University Medical Ethics Committee (No. KYLL-202107-115). The requirement to obtain written informed consent was waived.https://www.wenjuan.com) and distributed via WeChat in 8 general hospitals in Shandong Province. The duration of mask use and the related discomfort of medical staff in the operating room were determined by a cross-sectional survey. The survey included demographic data , the reasons for wearing SMs in the operating room, the duration of continuous mask use, the number of mask changes per day, and personal discomfort related to continuous mask use for 1, 2, 3, and ≥4 h. After the questionnaire was released, participants were asked to familiarize themselves with the questions and reply to the questionnaire after 1 week of work. Only one submission per person was allowed to prevent duplication.First, an electronic questionnaire was designed on the Wenjuan platform  correctly and not remove them or expose their mouth and nose during the study. All subjects were informed that they could withdraw from the study at any time without any impact. The primary exclusion criteria were acute or chronic respiratory diseases or previous heart diseases, body mass index (BMI) ≥30 kg/m2 and pulse rate of the subject's right index finger were measured using a portable SpO2 patient monitoring system  in a sitting position. To eliminate the difference in oxygen content in the operating room, an oxygen detector  was used to detect the surrounding oxygen content. Another researcher also directly observed 30 s of chest movement and measured the respiratory rate. As a distraction strategy, the investigators pretended to measure the radial pulse so that participants did not realize that their respiratory rate was being measured.The enrolled anesthesiologists fully understood the study procedures, underwent testing in a familiar constant temperature operating room, and breathed indoor air. The subject ensured that the SM was correctly and continuously worn throughout the process. After resting for at least 10 min, the SpOParticipants underwent pulse oximetry evaluation. According to the questionnaire survey results, it was determined that data would be collected at 6 time points: 10 min before wearing an SM (T1), immediately after wearing a mask (T2), and after 1 h (T3), 2 h (T4), 3 h (T5), and 4 h (T6) of continuously wearing an SM. The visual analog scale (VAS) was used to record subjects' perception of the sensation of shortness of breath, dizziness, and headache at the same time points. All sensations were scored by means of a 10-point VAS from 0 (no discomfort) to 10 (worst discomfort imaginable). To minimize variability, data were collected twice at each point in time.2 decrease of 2% or more. For a 2% decrease in SpO2, a standard deviation of 3%, α of 5%, and power of 90%, a sample size of at least 24 participants was required. Considering the 10% shedding rate, at least 27 participants were required. According to the inclusion and exclusion criteria, we included 39 anesthesiologists. One participant whose resting oxygen saturation reading was lower than 96% and 3 participants who did not complete the test due to removing their masks were excluded, and a total of 35 subjects were included.The study sample size was calculated with PASS 11 . Before the release of the electronic questionnaire, we conducted a small-scale preliminary survey. The incidence of wearing SMs continuously for morethan 4 h was 55%. We assumed that the incidence was 50%, with α of 5%, absolute deviation of 5%, and the sample size of 402. Previous studies have shown that masks can reduce the blood oxygen saturation of medical staff by 1–3.5% , 21. We 2, heart rate, respiratory rate data, and subjective sensation scores of anesthesiologists wearing SMs at different durations were analyzed. SPSS 24.0  Graphpad prism 8.2.1  were used for the statistical evaluation and preparation of graphs.The result of electronic questionnaire was charted by Microsoft Excel software. The SpOp value of < 0.05 was considered statistically significant.The Shapiro–Wilk test was used to determine whether the measurement data conform to the normal distribution. The data with normal distribution were expressed as mean , and the non-normal distribution data were expressed as median . Univariate ANOVA was used for comparisons between groups. The non-normal distribution data were analyzed by the Kruskal–Wallis test. A n = 121/485) (n = 48/121)  . Due to  48/121) . As shown = 310/485) of the participants wore SMs continuously for more than 4 h (without removing the masks or exposing their mouths or noses) (n = 90/121) (n = 342/485) did not change their mask until after work (n = 109/121)  . Among t 90/121) . On a giter work . Among t109/121) .n = 377/485) wore SMs continuously for 1 h without any subjective discomfort. As the SM use time increased, this proportion decreased significantly (n = 148/485) had no discomfort (n = 204/485), 34.6% (n = 168/485), and 30.9% (n = 150/485), respectively  were enrolled . As show2 from T1 to T6 was 98.0, 98.0, 98.0, 98.0, 97.0, and 97.0%, respectively  and an increase in respiratory rate (p < 0.01).The mean SpOectively . As showp < 0.01)  .2 levels and significantly increased respiratory rates, but no change was observed in heart rates. Although the data showed statistically significant differences, these changes have clinical significance needs to be further studied. In addition, wearing SMs for more than 2 h caused mild shortness of breath, dizziness, and headaches.The results of the electronic questionnaire showed 70.5% of the respondents wore SMs from the beginning of a day's work to the end. Most staff (63.9%) continued to wear masks (without removing the mask or exposing their mouth or nose) for more than 4 h, with the highest proportion of anesthesiologists. Subjective discomfort, such as shortness of breath, dizziness and headache, inattention, lethargy, and fatigue, worsened with the prolonged use of SMs. Compared with operating room nurses, nurse anesthetists, and surgeons, with prolonged SM use, the proportion of subjective discomfort of anesthesiologists increased significantly, and was almost the highest in 1–4 h. Further research results showed that anesthesiologists wearing SMs for more than 2 h exhibited significantly reduced SpO2 of 53 surgeons before and after surgery. The results showed that the surgeon's pulse rate increased, and their blood oxygen saturation decreased by more than 1% after 1 h, which was related to SM or operational stress  The questionnaire was released in advance, and responses were required to be submitted 1 week after becoming familiar with the questions, which may introduce recall bias, and the subjects may have provided “ideal” answers. (2) The anesthesiologists involved in the study were younger and more tolerant of hypoxia caused by wearing SMs for a long time, so the time of oxygen saturation reduction and respiratory rate increase was longer. (3) There was no control group because the study was conducted in the emergency situation of the COVID-19 pandemic. According to the requirements of epidemic prevention and control and operating rooms, masks must be worn. (4) The sample size was too small to carry out age- and gender-controlled research.2 and increases in respiratory rates, without affecting heart rates, but may not be clinically significant. Shortness of breath, dizziness, and headache gradually worsen as the duration of SM use increases. Therefore, we recommend that anesthesiologists take off their masks and rest for a few minutes every 2 h or after each operation and replace the SM every 4 h according to the guidelines.In conclusion, our study demonstrates that in healthy anesthesiologists, wearing SMs for more than 2 h can lead to statistically significant decreases in SpOThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Qilu Hospital of Shandong University Medical Ethics Committee. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.XL, CF, SY, and RW contributed to data collection. CF, YL, SY, and SH contributed to statistical analysis. SY, FQ, and YL wrote the manuscript. SY, XL, FQ, and CF contributed to the inception of the study idea. SY, XL, FQ, and RW contributed to study design. SY, FQ, YL, and SH revised the manuscript. All authors approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: The health and developmental issues of people with Down syndrome (DS) are complex and are associated with many medical, psychological, and social problems from childhood through into adulthood. DS children have an increased risk of multiorgan comorbidities, including congenital heart disease. Atrioventricular septal defect (AVSD) is a congenital heart malformation that often occurs in DS people. Aim: Physical activity and exercise are recommended for patients with cardiovascular disease and are considered to be the gold standard of cardiac rehabilitation. Whole-body vibration exercise (WBVE) is considered a form of exercises. The aim of this case report is to show the effects of WBVE on sleep disturbances, body temperature, body composition, tone, and clinical parameters in a child with DS with corrected total AVSD. The subject is a 10-year-old girl, with free-type DS, who underwent surgery to correct a total AVSD at 6 months. She underwent periodic cardiological monitoring and was released to perform any type of physical exercise, including WBVE. WBVE improved sleep quality and body composition. Conclusion: WBVE leads to physiological effects that benefit the DS child. Down syndrome (DS) is a genetic condition caused by the tripling of chromosome 21 (T21) and is characterized by a wide range of physical and neurodevelopmental disabilities [DS children are more likely to develop multiorgan comorbidities . CongeniAll patients with cardiovascular diseases are recommended to engage in controlled physical activity and exercise, which are regarded as the gold standard of cardiac rehabilitation  and offeWBVE can be a helpful alternative for monotonous activities performed during cardiac rehabilitation . WBVE ocp < 0.05), suggesting that WBVE may be a useful intervention modality to improve balance and muscle strength in DS children.Eid et al.  investigConsidering an increased prevalence of obesity and muscle weakness in DS children, Emara et al.  examinedp < 0.05), with the study group experiencing significantly greater improvements than the control group (p < 0.05). These outcomes indicated that participation in the isokinetic training program induced greater improvements in muscle strength and postural balance in DS children. Therefore, the WBVE can be suggested for this population as an effective training modality. Finally, a study proposed by Eid et al.  investigPedro Ernesto University Hospital, registered under number 30649620.1.0000.5259. This study was approved by the Ethics Committee of the The legal guardian read and signed a Free and Informed Assent (FIA) before any procedure was performed. All procedures performed were considered non-invasive and demonstrated no obvious risk.The data collected, as well as the interventions, were carried out at the Laboratório de Vibrações Mecânicas e Práticas Integrativas (LAVIMPI), Policlínica Universitária Piquet Carneiro, Universidade do Estado do Rio de Janeiro, Brazil.Female patient, 10 years old, with free-type DS. The diagnosis of DS occurred in prenatal exams during pregnancy, which also identified total AVSD. At 6 months of age, she underwent surgery to correct the total AVSD and since then she has been undergoing periodic cardiological follow-up and is stable without medication. She was cleared by the cardiologist to perform any type of physical exercise, including WBVE.Before performing the first intervention, the legal guardian signed the FIA authorizing the participation, and then an anamnesis was carried out to collect data and information from pregnancy, birth, development, and physical condition until the moment of the initial assessment.Body temperature (BT) was measured by infrared thermography (IT) of the anterior region of the neck , before To evaluate the sleep disorder, the Reimão and Lefevre Children’s Sleep Questionnaire (QRL)  and the Body composition (BC) analysis was performed before the first intervention and after the second intervention, using the bioelectrical impedance In Body 370, Korea .The tonus was assessed before and after the first intervention and after the second intervention, through muscle palpation and passive joint movements ,35.2) was checked once before and once after the intervention. BP and HR were measured on the right arm  [2, the child remained seated and the finger oximeter  was placed on the index finger [Clinical parameters such as blood pressure (BP), heart rate (HR), and respiratory rate (RR) were evaluated 3 times before and 3 times after the interventions and the averages were recorded. Oxyhemoglobin saturation (SatO Brazil) . During  Brazil) . To measx finger . ®, DF Produtos Hospitalares Ltd.a, São Paulo, Brazil), with a frequency of 5 Hz, peak-to-peak displacement of 2.5 mm, five sets of 30 s with vibration, and 1 min of rest were performed. The first session (WBVE 1) in the sitting position on the ancillary chair with feet on the base of the vibrating platform and the second session (WBVE 2) sitting directly on the base of the platform. The interval between the WBVE 1 and WBVE 2 was 15 days. The child performed two interventions of WBVE on a side alternating vibrating platform , bilateral triceps brachii (TB), bilateral abdominals, bilateral hamstrings, and left triceps surae (TS); as well as normal tone of the bilateral pectorals, bilateral abdominal obliques (BO), bilateral quadriceps, and right TS. In passive joint movements, the girl presented hypotonia of bilateral shoulder flexors (SF) and shoulder extensors (SE), bilateral wrist extensors (WE), bilateral hip flexors (HF), bilateral hip adductors (HA), bilateral knee flexors (KF), bilateral ankle dorsiflexors (AD), and bilateral ankle plantar flexors (AP); as well as normal tone of bilateral elbow flexors (EF), bilateral elbow extensors (EE), and wrist flexors (WF).After WBVE 1, the palpation of the muscles showed hypotonia in the bilateral deltoid muscles, bilateral BB, bilateral TB, and left TS; as well as normal tone of the other groups. In the joints, he presented hypotonia in the bilateral SF, bilateral SE, bilateral WE, bilateral HA, bilateral KF, bilateral AD, and bilateral AP; as well as normal tone of bilateral EF, bilateral EE, bilateral WF, and bilateral HF.After WBVE 2, muscle tone was hypotonic in the bilateral deltoid, bilateral BB, bilateral TB, bilateral pectoral, bilateral TS, and bilateral hamstrings; as well as normal tone in the abdominals, bilateral obliques, and bilateral quadriceps. Joint tone was hypotonic in the bilateral SF, bilateral SE, bilateral EF, bilateral WE, bilateral HF, bilateral HA, bilateral KF, left AD, and left AP; as well as normal in the bilateral EE, bilateral WF, right AD, and right AP. After WBVE 1 and WBVE 2, it is possible to verify that there were slight alterations in the muscle tone. The changes in tone observed on the palpation of the muscle belly included: bilateral pectoral and abdominal from normal to hypotonic after the second intervention; bilateral hamstring from hypotonic to normal after WBVE 1; and right triceps surae from normal to hypotonic after WBVE 2. As for the tone verified through passive joint movement, it is possible to verify the changes: flexion of the left elbow from normal to hypotonic after WBVE 2; bilateral elbow extension from normal to hypotonic after WBVE 2; bilateral hip flexion from hypotonic to normal after the first intervention; and change in dorsiflexion and plantarflexion of the right ankle from hypotonic to normal after WBVE 2.Before WBVE 1, the body composition (BC) was 118.5 cm of height, 26 kg of body mass, 18.1 kg of lean mass, 19.1 kg of fat-free mass, 1.02 kg of bone mass, 14.2 kg of water total body, 3.7 kg of protein , 1.23 kg of minerals , 6.9 kg of body fat (excessive), 9.2 kg of muscle mass, body mass index of 18.5 kg/m2 , body fat percentage of 26.5% (much higher), and a waist-to-hip ratio 0.76 . After WBVE 2, the BC showed 119 cm of height, 25 kg of body mass, 18.4 kg of lean mass, 19.4 kg of fat-free mass, 1.03 kg of bone mass, 14.4 kg of body water total, 3.8 kg of protein , 1.23 kg of minerals , 5.6 kg of body fat , 9.4 kg of muscle mass, body mass index of 17.6 kg /m2 , body fat percentage of 22.2% (above), and a waist-to-hip ratio 0.76  .Height, lean mass, fat-free mass, bone mass, total body water, proteins, and muscle mass all increased after WBVE, according to data collected pre WBVE 1 and post WBVE 2. Post WBVE 2, body weight, body fat, body mass index, and fat percentage all decreased. Minerals and the waist-hip ratio remained stable.Post the WBVE 2 session, a new round of QRL responses was collected. Only five questions changed, suggesting that the sleep pattern had improved. After two sessions of WBVE, the child under investigation stopped urinating during naps, woke up in the morning in less than 15 min, did not arrive late to school from oversleeping despite family members waking up, did not have any trouble staying awake at school in the mornings, and had no need or desire to sleep longer.In the DSDC performed before WBVE 1, the total score (TS) was 45; sleep initiation and maintenance disorder (SIMD) 15; sleep breathing disorders (SBD) 5; arousal disorders (AD) 6; sleep-wake transition disorders (SWTD) 6; excessive daytime sleepiness (EDS) 11; sleep hyperhidrosis (SH) 2. In the DSDC performed after WBVE 2, the TS was 43; SIMD 14; SBD 5; AD 3; SWTD 10; EDS 9; SH 2. These findings are also in Comparing the results before WBVE 1 and after WBVE 2, it is possible to verify that, qualitatively, there was a decrease in TS, SIMD, AD, and EDS as well as an increase in SWTD after WBVE 2. The SBD and SH did not change.The current case report shows that the WBVE can be used in DS children who have undergone surgery to correct a total AVSD. In the current case report, even for the child performing only two interventions, the WBVE provided benefits and positive outcomes of quick and easy execution.WBVE is a potential intervention for improving motor function and bone growth in children with disabilities, although most of the evidence comes from adult trials. It is crucial to understand the mechanisms of both disabled and non-disabled children. WBVE appears to be a safe intervention and the protocol should be appropriate for both disabled and non-disabled children, considering the biomechanical parameters of each patient . The outPartial AVSD is more common in non-chromosomal cases, while total AVSD is more common in DS people . The AVSThermoregulatory mechanisms are responsible for maintaining the optimal temperature of the body. Exercise speeds up oxygen transport and blood circulation, which raises metabolism and, ultimately, body temperature . Dębiec-Hypotonia is the primary cause of balance and postural control disorders in DS children and adolescents . SkeletaWeight gain and growth are measures of overall health in DS people. Obesity affects 25% of DS children and 50% of DS adults, exacerbating a range of issues such as obstructive sleep apnea, diabetes, and cardiopulmonary conditions. Obesity diagnosis and early intervention to encourage healthy diet and exercise routines are essential for managing weight gains . GonzáleSleep difficulties are another prevalent issue among DS children. Choi et al.  conducteThe limitations of the present study are related to the quantity of interventions and any potential bias in the method used to measure muscle tone. Additionally, if other biomechanical factors and various WBVE protocols had been considered, the outcomes might have been different.Another limitation of this case report that should be highlighted is the assessment of cognitive function. Although there is an understanding of the importance of identifying the cognitive potential of DS children, this ability was not considered as a criterion for participation in this protocol, because this evaluation and consideration of its consequences in the development of DS children requires qualified professionals.The strength of this case study is that this is the first one to consider the effect of WBVE on a DS child who underwent total AVSD correction regarding CP, BT, muscle tone, BC, and sleep quality. This case report helps to fill part of the gap in the research field related to the effects of WBVE on CP, BT, tone, BC and sleep quality in DS children.Considering the effects of the WBVE, it is possible to conclude that this type of exercise would promote biological effects with relevant physiological responses in blood pressure, which is an expected effect in the practice of physical exercise. The center temperature, mean, maximum and minimum temperatures verified 15 min after the interventions were also higher, confirming DS-related thermal mis adjustment. In addition, WBVE promoted a small modulation in tone and altered various parameters related to the BC. Moreover, there was also an improvement in the sleep pattern.


Of the 14,615 identified articles, 44 studies provided data on the correlation between cancer risk and the level of circulating sTNFR2. The pooled means comparison showed a consistently significant increase in the levels of sTNFR2 in diverse cancers when compared to healthy controls. These included colorectal cancer, ovarian cancer, breast cancer, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, lung cancer, hepatocarcinoma, and glioblastoma. In a random-effect meta-analysis, the cancer-specific odd ratios (OR) showed significant correlations between increased circulating sTNFR2 levels and the risk of colorectal cancer, non-Hodgkin’s lymphoma, and hepatocarcinoma at 1.59 (95% CI:1.20-2.11), 1.98 (95% CI:1.49-2.64) and 4.32 (95% CI:2.25-8.31) respectively. The overall result showed an association between circulating levels of sTNFR2 and the risk of developing cancer at 1.76 (95% CI:1.53-2.02). This meta-analysis supports sTNFR2 as a potential diagnostic biomarker for cancer, albeit with different predictive strengths for different cancer types. This is consistent with a potential key role for TNFR2 involvement in cancer development.High Tumor Necrosis Factor Receptor 2 (TNFR2) expression is characteristic of diverse malignant cells during tumorigenesis. The protein is also expressed by many immunosuppressive cells during cancer development, allowing cancer immune escape. A growing body of evidence further suggests a correlation between the circulating form of this protein and cancer development. Here we conducted a systematic meta-analysis of cancer studies published up until 1 Cancer remains one of the most lethal diseases and is currently the world’s second most common cause of death . Accordivia its receptor TNFR1 and TNFR2 plays a dual role to suppress or promote cancer proliferation and metastasis (Tumor necrosis factor (TNF) is a cytokine implicated in inflammation and cancer development –6. In thtastasis , 8. TNFRtastasis –11. In mtastasis –11. The + and CD8+ conventional effector T cells (Teffs) necessary to eliminate the neoplastic cells  has been shown to increase in chronic inflammatory conditions such as obesity and Type 2 diabetes (DM2), diabetic kidney disease characterized by increased albuminuria, and juvenile chronic arthritis –35, as wn of TNF , which iof Tregs , 15. In f sTNFR2 , 44. In culation . These sculation , 12, 13.The study was designed to evaluate the utility of sTNFR2 in plasma or serum as a diagnostic biomarker for various cancers and a prognostic biomarker to predict cancer outcome, by performing a meta-analysis on published studies. The literature research was conducted by the authors following the guideline set by the statements provided by “Preferred Reporting Items for Systemic Reviews and Meta-Analysis” (PRISMA) .st October 2022, for studies investigating the associations between circulating sTNFR2 and cancer. The text word search included  and . Duplicates were removed using EndNote20 software , and this software was further used to select articles.The literature was searched systematically in Medline, Embase, and Scopus databases, from inception to 1in vitro studies were excluded. Secondary source articles such as meta-analyses and reviews that do not provide the original data of a study were excluded. No restriction to time or age was applied. Additional search by scanning the reference lists from other related articles was also performed. Relevant articles were then independently reviewed by the three authors  and selected based on the content of the articles, which includes: 1. the study is on cancer, 2. the biomarker of interest is soluble TNFR2 in serum or plasma. The collected articles were sorted and recorded using the PRISMA flow diagram . Case studies, conference papers, animal and  diagram .The article’s quality was assured by noting the author, year, abstract, and number of citations. Importantly, the study fitness was assessed by two authors  in discussion, using the updated Strengthening the Reporting of Observational studies in Epidemiology (STROBE) checklist for diagnostic studies .Three reviewers  recorded data from all studies that met inclusion criteria using a standardized data collection procedure. Data collected was arranged in a table for all the studies  for sTNFR2 and the risk of developing cancer Figure 3We further tested our selected studies comprising various cancer types using a funnel plot, as this plot could indicate study heterogeneity and reporting bias. The funnel plot Figure 4Overall, most cancers still present with a high mortality rate, due to late diagnosis. As such, there is a pressing need for the identification of reliable biomarkers facilitating early detection. It has been frequently proposed that inflammation, orchestrated by various cytokines may promote cancer formation and further its development , 48. CanBased on the calculated pooled mean values, circulating sTNFR2 levels were found to be consistently reported as significantly higher in various cancers in comparison to the healthy controls Figure 5+ Tregs have been associated with poor OS, while ovarian tissue with strong expression of TNFR2 was associated with longer PFS (The increased levels of circulating sTNFR2 do not only correlate with cancer risk but also cancer outcomes such as overall survival and progression-free survival, as has been shown by several studies of various cancers , 107–113nger PFS , 114. Adnger PFS . Moreovenger PFS –119. Thinger PFS .In summary, our meta-analysis study confirms the correlation between increased circulating sTNFR2 levels and increased risk of cancers, albeit the extent of this association varies between different cancers. This indicates circulating sTNFR2 may have utility, perhaps combined with other blood accessible biomarkers, to aid in the diagnosis of cancer. We believe that the easy access to this biomarker through liquid biopsies makes it an ideal candidate to be used alone, or in combination with other markers, as a minimally-invasive cancer screening method, potentially accelerating the implementation of point-of-care devices  for cancThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.AK, MP conceptualized the study. AK designed and directed the study. AK, MR and EC performed literature research and analyzed the data. AK wrote the first draft of the manuscript. EC, MR, CS, CH, AM, MP wrote sections of the manuscript. All authors contributed to the article and approved the submitted version.This research was funded by NHMRC No. 2011747.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Furthermore, the increased CGA recommendation was observed among geriatric patients with: (a) frailty syndrome , (b) high risk of malnutrition or malnutrition , (c) low mental status , (d) low ability to perform basic daily duties , and (e) fall risk . Moreover, homocysteine levels increased with age (p = 0.003) and decreased with sleep duration (p = 0.043). Taken together, all these factors seem to be important when implementing treatment programs adjusted to the individual geriatric patient.In Poland, the elderly population is noticeably increasing every year. Therefore, the current healthcare system has to rise to the challenge of treatment and prevention strategies targeting elderly persons. Based on the Vulnerable Elders Survey , consisting of international and validated scales, we put effort into identifying the factors affecting the increased percentage of CGA (Comprehensive Geriatric Assessment) recommendations by healthcare system physicians. The study group involved 78 patients from the Department of Geriatrics, Wroclaw Medical University, Poland, aged 60–91 (median Me = 81 years old). Of the studied patients, 51 were recommended for CGA . A statistically significant association was observed between CGA recommendation and age ( The Polish population is aging. In 2016, over 6 million patients aged 65+ in Poland constituted approximately 16% of the total population .An accurate estimation of the overall survival (OS) of geriatric patients may be performed by clinical information available from the medical chart or a brief interview with the patient or his/her caregiver. There are also available predictive measures to identify, quantify, and manage the health condition of geriatric patients. The comprehensive geriatric assessment (CGA) is a gold standard to determine a frail older person’s psychological and functional ability to develop a coordinated and integrated plan for treatment and long-term follow-up . This toThe CGA is applied mainly to patients in old age, those with frailty syndrome, and those in critical moments of their life . The crucial elements of the CGA include (1) physical health assessed by medical evaluation and the assessment of disease severity, 2) functional efficiency assessed by Activities of Daily Living , Tinetti Gait and Balance Assessment Tool and activity levels, (3) mental health assessed by cognitive assessment tests and mood disorder rating scales, and (4) social and environmental conditions  [2]. functionFurthermore, there are also geriatric screening tools available that combine all components, as shown in In the present study, we aimed to determine the factors affecting the increased percentage of CGA recommendations by healthcare system physicians. This analysis was mediated using the Vulnerable Elders Survey . Understanding the factors increasing the percentage of CGA recommendations among geriatric patients seems to be crucial for health professionals, whose role is to control the aging processes and implement treatment strategies for comorbid diseases, as well as to encourage geriatric patients to change their lifestyle and nutrition habits.The study group involved 78 patients from the Department of Geriatrics, Wroclaw Medical University, Poland, including 65 women  aged 60–91 years old  . The incThe characteristics of all studied patients are presented in The VES-13 (Vulnerable Elders Survey) scale was used to identify patients requiring a CGA recommendation. If the result of the VES-13 scale shows more than three points, it is very likely to signify a significant deterioration in health, functional capacity, or death within the next two years. The CGA procedure consisted of (1) the risk of pressure ulcers by the Norton scale, (2) the risk of malnutrition by MNA or NRS scales, (3) the Geriatric Depression Scale (GDS), (4) the mini-mental state examination (MMSE), (5) the Clock-Drawing Test, (6) frailty syndrome assessment (TFI), (7) fall risk by the Tinetti test, (8) the Activities of Daily Living , (9) the Lawton Instrumental Activities of Daily Living Scale (IADL), and (10) the Barthel scale.Of the 78 patients studied, 51 were recommended for CGA . The correlation between the assessment of the necessity to carry out a CGA and gender, age, and patient status are summarized in p < 0.001); the likelihood of a CGA recommendation increases with age. Based on the ROC curve analysis, the age of 79 years is a cut-off value ; OR = 15.0, p < 0.05 was observed only between the recommendation for CGA and the level of the frailty syndrome ; therefore, not all patients were assessed with the use of subsequent scales. p < 0.2, a dichotomous division was performed , a mini-mental status test (MMST) < 27 points , and an assessment of frailty syndrome ≥ 4 points . Furthermore, patients for whom the ADL and IADL scales were detected as less than 6 points and less than 27 points, respectively, were more likely to be recommended for CGA . A significant statistical correlation was also determined among patients with a fall risk assessed as less than 8 points  and a Barthel scale with less than 100 points ; the likelihood of a CGA recommendation increases with age. Among patients aged 79+, the chance of obtaining a recommendation for CGA is fifteen times higher compared to patients under 79 years old (95% CI (4.67–48.3); OR = 15.0, p < 0.001, Over the last hundred years, life expectancy has increased linearly by three months per year , leadingp < 0.05 between the recommendation for CGA and the level of the frailty syndrome   occurring substantially in advancing age, frailty syndrome became a key topic of interest, both in terms of clinical practice and scientific research. It is a physiological syndrome characterized by reduced immunological reserves and resistance to stressors. It is associated with an increased risk of complications, such as loss of independence, the need for more frequent hospitalization, susceptibility to more frequent illness, or even death. Increased levels of inflammatory markers, age-related coagulation disorders, changes in the endocrine system, and loss of muscle mass or sarcopenia appear to be closely related to the development of this syndrome. The clinical criteria for diagnosis are weight loss, asthenia, exhaustion, slower walking, and decreased physical activity ,33,34,35p = 0.04). This condition leads to an impairment of physical and mental health and adversely affects the treatment outcome of underlying disease treatment. Consistently, Cailett et al. identified the factors associated with changes in cancer treatment, including lower ADL scores ((OR), 1.25 per 0.5-point decrease; CI, 1.04 to 1.49; p = 0.016) and malnutrition . Our study also revealed this association between low ADL scores, and hence functional impairment and more frequent CGA recommendations  [p = 0.01) than those without malnutrition [It is well known that frailty syndrome is a manageable condition that can be targeted for intervention ,34,35. Tp = 0.003, p = 0.004, With age, the correct function of many organs, including the kidneys, declines. This leads to a decrease in homocysteine secretion and hence its rise in the plasma. Such a result was found in our study. The level of homocysteine increases with age . It is also worth considering the group sizes for which the statistical significance has been noticed. Due to the small size of some groups, it is possible to obtain a false positive result. It is also quite challenging to assess the definition of frailty; for each study investigator, frailty may be interpreted slightly differently.This study revealed, for the first time in Poland, the factors increasing the likelihood of recommending the CGA: (1) the presence of frailty syndrome, (2) older age, (3) malnutrition and risk of malnutrition, (4) low mental status, (5) problems with performing daily duties , and (6) a high level of homocysteine. Therefore, we suggest taking into account the scales and screening tools that allow clinicians to determine patients’ CGA components, as mentioned above, and assess their health status. The current literature focuses on patients with cancer treatments; our study revealed a broader spectrum, including patients with different diseases and health impairments. Furthermore, our findings show that the implementation of mandatory CGA assessment among patients older than 79 should be considered in Poland.


GRM1 gene is expressed mainly in the brain, with the highest expression in the cerebellum. Mutations in the GRM1 gene have previously been known to cause autosomal recessive and autosomal dominant spinocerebellar ataxias. In this study, whole-exome sequencing of a patient from a family of Azerbaijani origin with a diagnosis of congenital cerebellar ataxia was performed, and a new homozygous missense mutation in the GRM1 gene was identified. The mutation leads to the homozygous amino acid substitution of p.Thr824Arg in an evolutionarily highly conserved region encoding the transmembrane domain 7, which is critical for ligand binding and modulating of receptor activity. This is the first report in which a mutation has been identified in the last transmembrane domain of the mGluR1, causing a congenital autosomal recessive form of cerebellar ataxia with no obvious intellectual disability. Additionally, we summarized all known presumable pathogenic genetic variants in the GRM1 gene to date. We demonstrated that multiple rare variants in the GRM1 underlie a broad diversity of clinical neurological and behavioral phenotypes depending on the nature and protein topology of the mutation. Metabotropic glutamate receptor 1 (mGluR1) plays a crucial role in slow excitatory postsynaptic conductance, synapse formation, synaptic plasticity, and motor control. The  GRM1 gene, which has the highest expression level in the cerebellum from early development and during ontogenesis [GRM1 gene is also expressed in the cerebral cortex, basal ganglion, medulla oblongata, spinal cord, heart, bone marrow, and kidney. Alternative splicing of the GRM1 gene transcript results in the formation of four mGluR1 isoforms. These isoforms have identical extracellular regions, consisting of a venus flytrap domain and cysteine-rich domain, seven transmembrane domains, and differ by distinct C-termini [Glutamate is the essential neurotransmitter in certain parts of the central nervous system, one of which is the cerebellum. There are several types of glutamate receptors: ionotropic glutamate receptors (iGluRs) mediated fast synaptic transmission and metabotropic glutamate receptors (mGluRs), which are coupled to G proteins and produce a more complex postsynaptic response consisting of both internal calcium release and a slow excitatory postsynaptic potential . mGluRs ogenesis ,5. Howev-termini ,7. In Pu-termini . Purkinj-termini . As the -termini . Impaire-termini . ABCB7 gene was identified in a large Buryat family, which led to X-linked recessive cerebellar hypoplasia [LRCH2 gene, the role of which is not clearly known, but it is highly expressed in the embryonic brain, especially in the cerebellum and brain regions involved in motor functions [CSMD1 gene, which is involved in brain development and the growth of neuronal processes, has a founder effect [Cerebellar hypoplasia is a rare brain pathology that results in a severe disorder, most often from birth, characterized by psychomotor developmental delay, ataxia, and in most cases, accompanied by intellectual disability ,13. Casepoplasia ,15. In tunctions . Furtherr effect . GRM1) that plays an important role in the development of the brain during the embryonic period. Mutations in the GRM1 gene are extremely rare. The discovered mutation expanded the range of genetic defects in the GRM1 gene underlying a variety of clinical manifestations.In this study, we performed a genetic analysis in the case of autosomal recessive cerebellar ataxia with no obvious intellectual disability. A novel mutation has been identified in the metabotropic glutamate receptor 1 gene (The disease in a patient from an Azerbaijani family (AIV-1) was diagnosed from birth. The patient’s parents were healthy. From infancy and early childhood, there was a delay in physical development. He began to walk at around the age of 4–4.5 years, but from the beginning, walking was awkward, and he often stumbled. From about 6–7 years of age, the condition remained relatively stable. The patient studied at a special boarding school. Medical examination at the Research Center of Neurology was carried out in the third decade of life. The following neurological symptoms were revealed: dysarthria, truncal ataxia during standing and walking, and coarse discoordination when performing dynamic tests in the hands. MRI showed hypoplastic and underdeveloped cerebellar hemispheres, enlarged fourth ventricle, and cisterna magna due to hypoplasia of the caudal vermis and paramedian zones of the cerebellar hemispheres, with normal corpus callosum, basis pontis, and medulla. The patient was diagnosed with congenital cerebellar hypoplasia. According to the results of a general examination and a survey of relatives, no obvious intellectual disability has been observed from early development to the present. When tested with the Mini-Mental State Examination (MMSE) scale, the patient scored 27 points, which formally fits into the category of “mild cognitive decline.” However, it should be noted that due to certain difficulties with the Russian language , cognitive testing was carried out by Russian-speaking medical personal with the participation and help of a Russian-speaking adult relative. Such examination conditions made it difficult to communicate and correctly evaluate the test results. On repeated testing, the performance was better, which was in line with the norm. These results were strikingly different from those observed in other patients with cerebellar hypoplasia and intellectual disability described in the literature. In those cases, there was usually a pronounced cognitive defect with a decrease in the patient’s adaptation to everyday life and the need for outside help ,13. ThusGRM1 gene was identified in patient, AIV-1  and spinocerebellar ataxia autosomal recessive 13, SCAR13, (OMIM 614831). The found mutation is located in an evolutionarily highly conservative region; the PhyloP score of this site is 7.7842. SIFT and PolyPhen2 programs predicted that this variant is “deleterious” (0.01) and “probably damaging” (0.999) [GRM1 gene was confirmed by Sanger sequencing  in the 1000 Genomes Project and gnomAD databases were selected ,18. Addit, AIV-1 A. We con (0.999) ,26. CADD (0.999) ,28. The quencing B.GRM1 gene leads to a change in the polar uncharged amino acid threonine with an electrically positively charged amino acid arginine at position 824 (p.Thr824Arg) in both long  and short (beta) isoforms of the glutamate metabotropic receptor 1 (mGluR1) protein. The amino acid threonine is located in a large, evolutionarily highly conserved region and is present in all analyzed orthologues from cyclostomes to primates  and autosomal recessive spinocerebellar ataxia type 13 . In the case of an autosomal recessive form, the course of the disease is severe, characterized by psychomotor developmental delay, intellectual disability, short stature, muscle hypotension, and severe impairment of motor functions throughout life; some patients are unable to move independently and speak [GRM1 gene in two of the three published cases with autosomal recessive inheritance led to a disruption of the reading frame and truncation of the receptor [GRM1 gene [GRM1 gene is an interesting example of the pleiotropic effects of mutations in one gene linked to both rare neurological and presumable neuropsychiatric disorders.Variants in the explored ,37,38,39n domain . The clind speak ,41,42,43receptor ,41. Addireceptor . In addiRM1 gene ,48,49,50The study was approved by the Ethics Committee of the Research Center of Neurology with appropriate informed consent. Blood samples were collected from the patient, and DNA was extracted using a QIAamp DNA Blood Mini Kit . The exome library was prepared using a TruSeq Exome kit , and sequencing was performed using a NovaSeq 6000 System  by Genetico . Bwa mem software was used to align raw reads to the human reference genome GRCh37/hg19 . The meaGRM1 gene contribute to a wide diversity of neurological phenotypes and may even be related to common neuropsychiatric illnesses.The new homozygous mutation is located in a highly conserved region in one of the transmembrane domains of the mGluR1 receptor and, in contrast to the previously described syndromes, has resulted in an autosomal recessive form of the congenital cerebellar ataxia, characterized by early-onset of the disease, delayed motor development, cerebellar hypoplasia, dysarthria, and ataxia with no obvious intellectual disability. In conclusion, the rare mutations in the