Search

The article presents the case of a 10-year-old child with a history of X-linked chronic granulomatous disease (CGD) who is experiencing non-productive cough, dysphonia and weight loss for 12 months to discuss chronic granulomatous disease of the upper airway. Also cited are the use of airway endoscopy to confirm friable, edematous mucosa of the supraglottic larynx and the possible causes of CGD like defects in nicotinamide adenine dinucleotide phosphate (NAPH) oxidase subunits.

Aim: X‐linked variants in Filamin A (FLNA) are associated with the Ehlers‐Danlos‐syndrome‐variant form of periventricular heterotopia, and autosomal dominant variants in ubiquitin C‐terminal hydrolase L1 (UCHL1) are associated with a late‐onset spastic ataxia, peripheral neuropathy and optic atrophy. Here we present a rare case involving both a novel heterozygous whole‐gene deletion of UCHL1 and a heterozygous frameshift variant in the FLNA gene resulting in a complex phenotype. Methods: A 67‐year‐old female with a confirmed pathogenic variant in the FLNA gene, resulting in an enlarged aorta and joint pains, presented with a 4‐year history of severe sensory ataxia, upper motor neuron signs, eye movement abnormalities and severe sensory loss. Results: Neurophysiology including Somatosensory‐evoked potentials confirmed the sensory loss as predominantly preganglionic with denervation. Genetic testing revealed a digenic cause of her complex presentation, confirming a pathogenic frameshift variant in the FLNA gene and a heterozygous loss of function deletion in the UCHL1 gene. Conclusions: To the best of our knowledge, this is the first case with concomitant pathogenic variants in the FLNA and UCHL1 genes which explain the complex phenotype. The severe preganglionic sensory loss is also a rare finding and expands the phenotype of UCHL1 variants. [ABSTRACT FROM AUTHOR]

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive genetic disease characterized by clinical symptoms such as eczema, thrombocytopenia with small platelets, immune deficiency, prone to autoimmune diseases, and malignant tumors. This disease is caused by mutations of the WAS gene encoding WASprotein (WASP). The locus and type of mutations of the WAS gene and the expression quantity of WASP were strongly correlated with the clinical manifestations of patients. We found a novel mutation in the WAS gene (c. 931 + 5 G > C), which affected splicing to produce three abnormal mRNA, resulting in an abnormally truncated WASP. This mutation led to a reduction but not the elimination of the normal WASP population, resulting in causes X-linked thrombocytopenia (XLT) with mild clinical manifestations. Our findings revealed the pathogenic mechanism of this mutation. [ABSTRACT FROM AUTHOR]

The N 6-methyladenosine (m6A) modification is a highly conserved RNA modification found in eukaryotic messenger RNAs (mRNAs). It plays a vital role in regulating various biological processes. Dysregulation of m6A modifications has been linked to a range of complex genetic diseases in humans. However, there has been a lack of comprehensive characterization and comparison of m6A modifications at the transcriptome-wide level within families. To address this gap, we profiled transcriptome-wide m6A methylation in 18 individuals across 6 Yoruba trio families. The m6A methylomes of these 18 individuals revealed that m6A modifications in children showed greater similarity to each other than to their parents. This suggests that m6A modifications are influenced by multiple factors rather than solely determined by genetic factors. Additionally, we found that mRNAs exhibiting m6A modifications specific to children were enriched in cell cycle control processes, while those with m6A modifications specific to parents were associated with chromatin modifications. Furthermore, our analysis on the interactions between differentially expressed m6A-related regulatory genes and age-related genes suggested that age might be one of the factors influencing m6A modifications. In summary, our study provided a valuable dataset that highlighted the differences and functional diversity of m6A modifications within and between trio families. [ABSTRACT FROM AUTHOR]

Female carriers of X‐linked inherited retinal diseases (IRDs) are burdened with potentially passing their disease‐causing variant to future generations, as well as exhibiting signs of retinal disease themselves. This study aimed to investigate carriers' experiences of genetic testing, emotions relating to having affected children, and their knowledge regarding genetic testing and gene therapy. An online survey was advertised to self‐identified carriers worldwide. Two hundred and twenty‐eight carriers completed the survey with mean age of 51 years (SD ± 15.0). A majority of respondents resided in the United States of America (51%), Australia (19%), and the United Kingdom (14%). Most carriers identified with feelings of guilt (70%), concern (91%), and anxiety (88%) for their child. Female carriers who had given birth to children had significantly greater gene therapy knowledge compared to carriers who had not (p < 0.05). Respondents agreed that their eyecare provider and general practitioner helped them understand their condition (63%), however, few carriers reported receiving psychological counselling (9%) or family planning advice (5%). Most respondents (78%) agreed that gene therapy should be available to carriers. This study emphasises the importance of providing appropriate counselling to female carriers and illustrates the motivation of many to participate in emerging treatment options, such as gene therapy. [ABSTRACT FROM AUTHOR]

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked genetic disorder characterized by reduced G6PD enzyme levels in the blood. This condition is common in populations exposed to malaria; an acute febrile disease caused by Plasmodium parasites. G6PD-deficient individuals may suffer from acute hemolysis following the prescription of Primaquine, an antimalarial treatment. The population at risk for such a condition includes the Senoi group of Orang Asli, a remote indigenous community in Malaysia. This study aimed to elucidate the G6PD molecular heterogeneity in this subethnic group which is important for malaria elimination. A total of 662 blood samples (369 males and 293 females) from the Senoi subethnic group were screened for G6PD deficiency using a quantitative G6PD assay, OSMMR2000-D kit with Hb normalization. After excluding the family members, the overall prevalence of G6PD deficiency in the studied population was 15.2% (95% CI: 11–19%; 56 of 369), with males (30 of 172; 17.4%) outnumbering females (26 of 197; 13.2%). The adjusted male median (AMM), defined as 100% G6PD activity, was 11.8 IU/gHb. A total of 36 participants (9.6%; 26 male and 10 female) were deficient (<30% of AMM) and 20 participants (5.4%; 4 male and 16 female) were G6PD-intermediate (30–70% of AMM). A total of 87 samples were genotyped, of which 18 showed no mutation. Seven mutations were found among 69 genotyped samples; IVS11 T93C (47.1%; n = 41), rs1050757 (3'UTR +357A>G)(39.1%; n = 34), G6PD Viangchan (c.871G>A)(25.3%; n = 22), G6PD Union (c.1360C>T)(21.8%; n = 19), c.1311C>T(20.7%; n = 18), G6PD Kaiping (c.1388G>A)(8.0%; n = 7), and G6PD Coimbra (c.592C>T)(2.3%; n = 2). Our analysis revealed 27 hemizygote males, 18 heterozygote females, 7 homozygote females, and 2 compound heterozygote females. This study confirms the high prevalence of G6PD deficiency among the Senoi Malaysian Orang Asli, with a significant degree of molecular heterogeneity. More emphasis should be placed on screening for G6PD status and proper and safe use of Primaquine in the elimination of malaria among this indigenous population. [ABSTRACT FROM AUTHOR]

IGSF1 deficiency is a rare X-linked condition characterized by central hypothyroidism and a wide variety of other clinical features with variable prevalence, including a delayed pubertal testosterone rise and growth spurt in the context of normal or accelerated testicular growth, and adult macroorchidism with relatively low serum testosterone concentrations. Other features include increased waist circumference, attention deficit, prolactin deficiency and transient partial growth hormone (GH) deficiency in childhood, contrasting with an increased GH secretion in adulthood. Patients with this disorder are not detected shortly after birth if neonatal screening programs are based on thyroid-stimulating hormone (TSH) concentrations. A 13.2-year-old male patient was referred to pediatric endocrinology for evaluation of short stature. He was born large for gestational age into a nonconsanguineous family. During work-up for short stature, deficiencies of TSH, prolactin and GH were detected, leading to treatment with levothyroxine and GH. At 16.9 years, GH treatment was stopped and during transition to adult care, his insulin-like growth factor 1 level was above the normal range. This prompted an analysis of IGSF1, in which a novel hemizygous variant causing a stop codon at c.3559C>T (p.Q1187*) was found, confirming the diagnosis of IGSF1 deficiency syndrome. In this report, we describe his clinical and hormonal characteristics at presentation and during long-term follow-up. [ABSTRACT FROM AUTHOR]

The article focuses on a case of a 9-day-old infant who initially presented with fast breathing and cough, but later developed severe symptoms, including fever and worsening cough. Topics include the infant's medical history, diagnostic workup, and the identification of an underlying primary immunodeficiency, chronic granulomatous disease (CGD), which was associated with invasive pulmonary Aspergillus infection.

Background and Aims: X‐linked Charcot–Marie–Tooth disease type 6 (CMTX6) is an extremely rare condition associated with mutations in the PDK3 gene. To date, only three families from different countries have been reported (Australia, South Korea, and Germany). In this study, we sought to provide a comprehensive clinical and electrophysiological characterization of two Brazilian families. Methods: We conducted comprehensive clinical assessments, extensive electrophysiological evaluations, and performed whole‐exome sequencing in the probands to investigate the genetic basis of the disease. Results: Males in the family carrying the Arg162His mutation displayed early‐onset motor and/or sensory axonal neuropathy, absence of tendon jerks, pes cavus, and frequently reported pain. Females in the same family exhibited a milder phenotype of the disease with later onset and some remained asymptomatic into their 50s. In the unrelated family with a single affected male, the clinical presentation was characterized by severe progressive sensorimotor polyneuropathy accompanied by neuropathic pain. Interpretation: We report two Brazilian families with CMTX6 including one harboring a previously unpublished variant in the PDK3 gene, which co‐segregates with the disease as expected in a X‐linked disease. Notably, the clinical presentations across the five families with available descriptions, including our study, share striking similarities. Furthermore, the proximity of the three reported mutations suggests potential functional similarities and common underlying mechanisms. This study contributes to the growing knowledge of CMTX6 and underscores the importance of international collaborations in studying rare genetic disorders. [ABSTRACT FROM AUTHOR]

This paper assesses the judgments of leading radiation geneticists and cancer risk assessment scientists from the mid-1950s to mid-1970s that background radiation has a significant effect on human genetic disease and cancer incidence. This assumption was adopted by the National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) I Genetics Panel for genetic diseases and subsequently applied to cancer risk assessment by other leading individuals/advisory groups (e.g., International Commission on Radiation Protection-ICRP). These recommendations assumed that a sizeable proportion of human mutations originated from background radiation due to cumulative exposure over prolonged reproductive periods and the linear nature of the dose-response. This paper shows that the assumption that background radiation is a significant cause of spontaneous mutation, genetic diseases, and cancer incidence is not supported by experimental and epidemiological findings, and discredits erroneous risk assessments that improperly influenced the recommendations of national and international advisory committees, risk assessment policies, and beliefs worldwide. [ABSTRACT FROM AUTHOR]

A new electrochemical biosensor based on the sequence of chromosome Y (SRY) has been introduced to determine the gender of the fetus. At first, the DNA probe was designed based on the SRY gene sequence on chromosome Y. Then, a suitable functional group was added to the DNA probe, and it has been immobilized on the surface of the electrode modified with a nanocomposite containing Cu(OH)2 @N–C n-boxes. This substrate causes more DNA probes to connect to the electrode surface by increasing the effective surface area. The presence of the SRY sequence in the DNA sample extracted from blood was detected by the electrochemical signal of the bio-sensor. After optimizing the parameters, the fabricated genosensor showed linear responses in the two concentration ranges containing 0.5 fM to 50 pM and 50 pM to 500 nM. The limit of detection (LOD) for the proposed method was 0.16 fM. The proposed genosensor has been successfully used to determine the gender of the fetus using cell-free fetal DNA (cffDNA) in the blood plasma of several pregnant mothers. This method has advantages such as being simple, portable, accurate, and non-invasive for early determination of the gender of the fetus and early diagnosis of X-linked genetic disorders. [ABSTRACT FROM AUTHOR]

Background: Cystic fibrosis (CF) is a rare genetic disease affecting approximately 30,000 people in the United States (US). African American persons with CF are even rarer, comprising approximately 5% of this population. Purpose: The purpose of this study was to explore the lived experiences of African American persons with CF to identify potential disparities in health care. Methods: Descriptive phenomenology was used to explore lived experiences of African American persons with CF over age 18 recruited from CF Foundation-accredited Centers in the US, CF-specific social media, and via snowball sampling. Study data was obtained through telephone interviews that were audio-recorded, transcribed verbatim, and analyzed using Colaizzi's method of thematic analysis. Results: Six men and six women (ages 23–45) completed the study. Interviews revealed three themes: (1) Accepting a Diagnosis of CF; (2) Desiring a Normal Life while Living with an Invisible Disease; and 3) A Slippery Slope of Subtle Racism. Each theme had 2–3 subthemes. Conclusions: It is critical to explore the unique challenges faced by African American persons with CF in order to develop interventions that improve their daily lives and create better futures. Implications for Practice: Findings highlight the unique challenges faced by underrepresented groups with CF and the need to address health inequities to improve care delivery. [ABSTRACT FROM AUTHOR]

Cytopenia due to the abnormal regulation of GATA1 could manifest as varying degrees of thrombocytopenia and/or anemia and more severely in male children than in female children. Here, we describe the case of pancytopenic and transfusion-dependent twin brothers at our center whose bone marrow puncture revealed low bone marrow hyperplasia. Whole-exome sequencing revealed that the twins had a new germline GATA1 mutation (nm_002049: exon 3:c.515 T >C:p.F172S), which confirmed the diagnosis of GATA1 mutation–related pancytopenia. The mutation was inherited from their mother, who was heterozygous for the mutation. Sanger sequencing verified the pathogenicity of the mutation. Further family morbidity survey confirmed that GATA1 mutation–related pancytopenia is an X-linked recessive genetic disorder. We developed haploid hematopoietic stem cell transplantation programs for twins, with the father as the only donor, and finally, the hematopoietic reconstruction was successful. Although they experienced acute graft-versus-host disease, hemorrhagic cystitis, and a viral infection in the early stage, no abnormal manifestations or transplant-related complications were observed 3 months after transplantation. Through hematopoietic stem cell transplantation technology for one donor and two receptors, we eventually cured the twins. The p.F172S variant in the new germline GATA1 mutation may play an essential role in the pathogenesis of GATA1 mutation–related cytopenia. [ABSTRACT FROM AUTHOR]

As the most common type of inherited retinal degenerative disease, retinitis pigmentosa (RP) has taken clinical and prenatal attention. Considering the clinical importance of consanguineous marriages, new mutations in this type of pregnancy have a high risk and increase the importance of Prenatal Diagnosis (PND). In vitro analysis was done through Whole Exome Sequencing (WES) for a 36-year-old woman who was referred to a genetic laboratory in Kermanshah in 2021 for PND. The woman had consanguineous marriage and was pregnant with twins (a boy and a girl). Mutation confirmation tests were also performed on her husband and both fetuses to find mutations. Moreover, in silico analyses were performed by SWISS-MODEL, ProSA, Molprobity, Swiss-Pdb Viewer, and ERRAT. The WES analysis showed a novel mutation of the RP2 gene (exon2:c. 359G>C: p.R120P) in the 36-year-old pregnant woman. Mutations identified in her husband and her twins revealed changes in protein conformations. Further modeling and validation evaluations showed the replacement of Arg by Pro at the 120th residue site of the cognate protein. For the first time, our report introduced a novel missense mutation in the RP2 gene associated with severe signs of RP in an Iranian family based on an X-linked recessive pattern of genetic inheritance. These findings may pave the way for a better diagnosis of RP in genetic counseling and PND. [ABSTRACT FROM AUTHOR]

Perrault syndrome (PRLTS) is a rare autosomal recessive disorder which is associated with pathogenic variants in HSD17B4, HARS2, CLPP, LARS2, GGPS1, RMND1, TWNK, ERAL1, and PRORP genes. The disease is characterized by sensorineural hearing loss, sometimes with neurological signs, including progressive sensory and motor peripheral neuropathy, cerebellar ataxia, mild mental retardation, and ovarian dysgenesis in females. In this article, we report a case of a child diagnosed with spastic diplegic cerebral palsy. Determination of the segregation status of the parents of a proband with a rare compound heterozygote in the gene HSD17B4 will help the genetic counselling for the prognosis of Perrault syndrome in the family. [ABSTRACT FROM AUTHOR]

Background: The severity of X-linked hypophosphataemic rickets (XLH) may be affected by genotype and sex. However, burosumab, a fully humanized monoclonal antibody against fibroblast growth factor 23, has the same pediatric dose recommendation for both sexes (0.8 mg/kg every 2 weeks). Patients and methods: In a retrospective cohort study, we describe the burosumab response differences by sex in children with XLH. Results: We treated 10 children (5 females, mean age at initiation 4.2 ± 3.5 years) with XLH with burosumab. Initial mean serum phosphate was 0.69 ± 0.18 mmol/L in males and 0.86 ± 0.22 mmol/L in females (p = 0.108). The mean ratio of tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) was 0.55 ± 0.11 mmol/L in males and 0.76 ± 0.23 mmol/L in females (p = 0.06). The mean starting dose of burosumab was 0.83 ± 0.19 mg/kg subcutaneously every 14 days (males: 0.79 ± 0.19 mg/kg; females: 0.87 ± 0.21 mg/kg, n.s.). Two weeks after starting burosumab, serum phosphate differed significantly between males (0.90 ± 0.21 mmol/L) and females (1.27 ± 0.25 mmol/L) (p = 0.018). All males required a dose increase to try to normalize serum phosphate. On day 140 after starting, the average dose in males increased further to 1.24 ± 0.41 mg/kg to achieve a phosphate of 0.87 ± 0.11 mmol/L while females had a normal phosphate and alkaline phosphatase on the starting dose. After a mean of 458 ± 79 days, the mean burosumab dose/kg in males was 1.68 ± 0.61 mg/kg, mean serum phosphate was 1.08 ± 0.23 mmol/L, mean TmP/GFR was 1.01 ± 0.20, mean alkaline phosphatase had normalized to 303.6 ± 40.7U/L, and mean 1.25(OH)2 vitamin D level was 186.4 ± 16.6 nmol/L. Conclusions: Our findings may suggest a sex difference in response to burosumab in XLH patients. Our data suggest that males may require higher doses. [ABSTRACT FROM AUTHOR]

Barth syndrome (BTHS) is an X-linked recessive genetic disorder due to mutations in the Tafazzin (TAFAZZIN) gene that lead to cardiac and skeletal muscle mitochondrial dysfunction. Previous studies in humans with BTHS demonstrate that the defects in muscle mitochondrial oxidative metabolism result in an enhanced reliance on anaerobic metabolism during exercise to meet energy demands of muscular work. During exercise, the liver normally increases glucose production via glycogenolysis and gluconeogenesis to match the elevated rate of muscle glucose uptake and meet the ATP requirements of working muscle. However, the impact of Tafazzin deficiency on hepatic glucose production and the pathways contributing to hepatic glucose production during exercise is unknown. Therefore, the purpose of this study was to quantify in vivo liver gluconeogenesis and glycogenolysis in Tafazzin knockdown mice at rest and during acute exercise. METHODS: Male TAFAZZIN shRNA transgenic (TG) and wild-type (WT) mice completed exhaustive treadmill running protocols to test exercise tolerance. Mice underwent 2H- and 13C-stable isotope infusions at rest and during a 30-minute treadmill running bout to quantify hepatic glucose production and associated nutrient fluxes under sedentary conditions and during acute exercise. Circulating and tissue (skeletal muscle and liver) samples were obtained during and following exercise to assess static metabolite levels. RESULTS: TG mice reached exhaustion sooner during exhaustive treadmill running protocols and exhibited higher plasma lactate concentrations after exhaustive exercise compared to WT mice. Arterial glucose levels were comparable between genotypes at rest, but higher in TG mice compared to WT mice during exercise. Consistent with the higher blood glucose, TG mice showed increased endogenous glucose production owing to elevated glycogenolysis compared to WT mice during exercise. Total gluconeogenesis, gluconeogenesis from glycerol, gluconeogenesis from phosphoenolpyruvate, pyruvate cycling, total cataplerosis, and anaplerotic fluxes were similar between TG and WT mice at rest and during exercise. However, lactate dehydrogenase flux and TCA cycle fluxes trended higher in TG mice during exercise. Liver glycogen content in TG was higher in TG vs. controls. CONCLUSION: Our data in the Tafazzin knockdown mouse suggest that elevated anaerobic metabolism during rest and exercise previously reported in humans with BTHS are supported by the finding of higher hepatic glycogenolysis. [ABSTRACT FROM AUTHOR]

Interestingly, although both patients showed a complete LAMP2 protein deficiency, vacuoles were not visible on light microscopy in the muscle of patient I. This may be due to his young age because the formation of vacuoles and the development of a full picture of DD is a time-dependent process. X-axis shows fold change of mRNA abundance [FPKM] in DD-patients while Y-axis shows fold change of protein abundance (arbitrary units) in patients suffering from DD. Keywords: Danon disease; LAMP2; mitophagy; proteomics; transcriptomics EN Danon disease LAMP2 mitophagy proteomics transcriptomics 1 7 7 09/01/23 20230801 NES 230801 Key points Danon disease is characterised by both vacuolar myopathy and impaired mitochondrial turnover, evident at the morphological, mRNA and protein levels. 184 rows, 5 columns, T-test between DD-patients and Controls p < 0.05 (B) mRNA investigation: DD-patients (n = 2) versus Controls (n = 4) => 14,334 mRNA species included. [Extracted from the article]

Introduction: Incontinentia pigmenti (IP) is a rare X‐linked dominant genetic disease affecting ectodermal tissue and often misdiagnosed in the neonatal period. The aim of this study was to highlight sequential clinical features and evaluate prognosis of the 32 neonatal IP patients. Material and methods: A retrospective descriptive analysis was performed, using the clinical, blood analytical, pathological, radiological, genetic, and followed‐up data of neonatal patients diagnosed with IP from 2010 to 2021, in Xi'an, China. Results: Of the 32 patients, two (6.25%) were male. Thirty babies (93.75%) had eosinophilia (eosinophilic granulocyte count: 0.31–19.9 × 109, mean proportion of white blood cells: 20.98 ± 15.21%). Twenty babies (62.5%) had thrombocytosis (thrombocyte count: 139–975 × 109, mean count: 416.76 ± 176.82). Thirty‐one babies (96.88%) exhibited the first three cutaneous lesion stages characterized by erythema and superficial vesicles on inflammatory bases in a linear distribution in the first week of age. Thirteen babies (40%) combined nervous system abnormalities, and nine babies (28.13%) had retinopathy. Two types of genetic mutations were detected in the NEMO gene. Nineteen babies were followed up. According to the follow‐up, four babies displayed psychomotor retardation, and five babies developed a decrease in vision with astigmatism and amblyopia. Conclusion: It is important that 30 babies (93.75%) had eosinophilia and 20 babies (62.5%) had thrombocytosis. Therefore, we speculate that the mechanism of the injury may be related to the platelet aggregation on the basis of the increase in eosinophil cells and the release of inflammatory factors. [ABSTRACT FROM AUTHOR]

Background: Chronic Granulomatous Disease (CGD) is a primary immunodeficiency that causes susceptibility to recurrent fungal and bacterial infections. The CYBB gene encodes gp91phox component of the Phagocytic Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and specifically, X-linked CGD is caused by mutations in the CYBB gene, located on the X chromosome. The aim of the study was to characterize functional and genetic mutations in X-linked CGD. Methods: Functional analysis was conducted on the whole blood of seventeen male individuals who were suspected to have X-linked chronic granulomatous disease (CGD). Flow cytometry was employed to assess the capacity of NADPH oxidase, measuring both H2O2 production and gp91phox protein expression in neutrophils. Additionally, DNA Sanger sequencing was performed for genetic analysis. The pathogenicity of novel mutations was assessed by pathogenicity prediction tools. Result: Among the seventeen patients evaluated, five patients (P1, P2, P3, P4, and P5) displayed impaired H2O2 production by their neutrophils upon stimulation with Phorbol myristate acetate (PMA), accompanied by abnormal gp91phox expression. DNA sequencing of the CYBB gene identified specific mutations in each patient. In P1 and P2 (previously reported cases), a hemizygous missense mutation, c.925G > A/p.E309K was identified. In P3 and P4 (novel cases), hemizygous nonsense mutations, c.216T > A/p.C72X were found. Lastly, in P5 (also a novel case), a hemizygous missense mutation, c.732T > G/p.C244W was detected. These mutations reside in exons 9,3 and 7 of the CYBB gene, respectively. Conclusions: The current study contributes to the understanding of the clinical and genetic spectrum associated with X-linked chronic granulomatous disease (CGD). It highlights the significance of early diagnosis in CGD and emphasizes the importance of lifelong prophylaxis to prevent severe infections. [ABSTRACT FROM AUTHOR]

The article presents answers to a clinical quiz about low molecular weight proteinuria, congenital myopia and hearing loss in a ten-year-old boy.

Background: Wiskott–Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by thrombocytopenia and eczema and is caused by a mutation in the WAS gene. WAS has heterogeneous clinical manifestations, and its clinically milder form is called X-linked thrombocytopenia (XLT). Patients with WAS/XLT sometimes have kidney complications, the most common of which is immunoglobulin (Ig)A nephropathy associated with aberrant glycosylation of IgA. Case diagnosis/treatment: The patient was a 6-year-old girl who was diagnosed with female XLT at the age of 4 years; she presented with microscopic hematuria and proteinuria at a school urinalysis. Her father had thrombocytopenia and IgA nephropathy while in his 20 s. The patient and her father had the same WAS gene mutations. A kidney biopsy was performed, and no abnormal findings were observed by light microscopy. Immunofluorescence analysis revealed a granular pattern of IgG staining along the capillary wall. Electron microscopy revealed small electron-dense deposits in subepithelial lesions. Consequently, we diagnosed her with membranous nephropathy (MN). Tissue PLA2R and THSD7A were negative, and she was judged unlikely to have secondary MN on the basis of blood test findings and IgG staining. We started the administration of angiotensin-converting enzyme inhibitors, and her proteinuria gradually decreased. Conclusion: To our knowledge, this is the first report of MN in a female WAS/XLT patient. WAS protein expression defects affect all immune system cells; however, the mechanisms underlying the occurrence of autoimmunity are not completely understood. In WAS/XLT patients, MN may develop as a result of increased autoantibody production, similar to other types of immunodeficiency. [ABSTRACT FROM AUTHOR]

Background: Ornithine transcarbamylase deficiency is an X‐linked genetic disorder that induces accumulation of ammonia in the liver and is the most common urea cycle disorder. The clinical manifestation of ornithine transcarbamylase deficiency is hyperammonemia that causes irreversible neurological damage. Liver transplantation is a curative therapy for ornithine transcarbamylase deficiency. The aim of this study is to suggest, from our previous experience, an anesthesia management protocol of liver transplantation for ornithine transcarbamylase deficiency, particularly focused on liver transplantation for cases with uncontrolled hyperammonemia. Method: We retrospectively reviewed our anesthesia‐related experience in all cases of liver transplantation for ornithine transcarbamylase deficiency in our center. Results: Twenty‐nine liver transplantation cases for ornithine transcarbamylase deficiency were found between November 2005 and March 2021 in our center. Of these, 25 cases were stable through the perioperative period. However, 2 cases with carrier donor graft had hyperammonemia after liver transplantation. Another two cases had uncontrolled hyperammonemia before liver transplantation, even with continuous hemodialysis. They underwent life‐saving liver transplantation. Their metabolic status stabilized after the anhepatic phase. Conclusion: Liver transplantation for cases with uncontrolled hyperammonemia can be performed with proper management. Second, liver transplantation with carrier donors should be avoided because of the risk of postoperative recurrence. [ABSTRACT FROM AUTHOR]

Couple screening aims to identify couples with an increased risk of having a child affected with an autosomal recessive or X-linked disorder, in order to facilitate informed reproductive decision making. Both expectant parents should be screened as a single entity, instead of individual testing. Carrier testing was typically performed for a few relatively common recessive disorders associated with significant morbidity, reduced life expectancy and often because of a considerably higher carrier frequency in a specific population for certain diseases. However, new genetic testing technologies enable the expansion of screening to multiple conditions, genes and sequence variants. There are multiple reproductive options for screening couples at risk, particularly when genetic traits are detected in the preconception period. [ABSTRACT FROM AUTHOR]

Purpose: To describe outcomes from the first-in-human study of dersimelagon, an investigational oral selective MC1R agonist, under development for the treatment of erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). Methods: In this double-blind, placebo-controlled phase 1 study, the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending oral doses of dersimelagon in healthy participants were evaluated. Results: Dersimelagon was generally well tolerated in healthy participants, with the most common TEAEs being lentigo (52.8%) and skin hyperpigmentation (50.0%) after multiple doses. Systemic exposure to dersimelagon in plasma (based on AUC0-∞ and Cmax) increased in a slightly more than dose-proportional manner over the 1- to 600-mg single-dose range. Following multiple doses, dersimelagon was rapidly absorbed (median Tmax ranging from 4 to 5 h postdose on days 1 and 14). Mean t1/2 ranged from 10.56 to 18.97 h on day 14, and the steady state of plasma concentration was generally reached by 5 days of multiple dosing. There were no observable effects of age or race on the PK profile of dersimelagon or its metabolite dersimelagon glucuronide. No treatment-related effects on melanin density (MD) were observed following single doses of dersimelagon; however, after multiple doses, increases in MD were observed in participants receiving 150 and 300 mg dersimelagon. Conclusion: Our study results indicate that dersimelagon is generally well tolerated and demonstrates a generally consistent PK profile across diverse subgroups. Treatment-related increases in MD warrant further investigation in a larger study population and in patients with EPP and XLP. Trial registration: A Study to Investigate the Safety, Tolerability and Pharmacokinetics of MT-7117 in Healthy Subjects, NCT02834442, https://clinicaltrials.gov/ct2/show/NCT02834442, registration began July 2016. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD), the most common muscle degenerative disease, is an X‐linked genetic disorder caused by the loss or reduction of dystrophin protein, resulting in progressive muscle wasting, and involving skeletal, cardiac, and respiratory muscles. There is currently no cure for DMD, and an anti‐inflammatory steroid is the conventional treatment to delay disease progression. Recently, several therapeutic approaches have been developed to improve patient quality of life and even to treat the underlying cause of the disease. These approaches include exon‐skipping, stop‐codon read‐through, vector‐mediated gene therapy, and stem cell transplantation. Exon‐skipping is one of the most promising techniques, and four exon‐skipping drugs have received approval, including NS‐065/NCNP‐01 (viltolarsen) in Japan and the USA. The read‐through drug, Ataluren, has received approval in the EU. Vector‐mediated therapy and cell transplantation are also attractive approaches, and currently, clinical trials are ongoing for some drugs. Furthermore, several studies have developed innovative approaches for DMD treatment, such as multiple exon skipping, gene editing using the CRISPR/Cas9 system, and mesenchymal stromal cell (MSC)‐ or inducible pluripotent stem cell (iPSC)‐based cell transplantation. In this review, we summarize current therapeutic approaches for DMD treatment. [ABSTRACT FROM AUTHOR]

Glucose-5-phosphate dehydrogenase (G6PD) deficiency is an X-linked genetic disorder that affects red blood cells' metabolism. This retrospective study aimed to investigate the prevalence and characteristics of G6PD testing in Korea. Data were collected from laboratory information systems between July 2021 and June 2022. A total of 5193 patients (1722 males and 3471 females) with a median age of 55.1 years (interquartile range, IQR 44.6 to 64.5) were tested for whole blood G6PD, with 1.6% of tests performed on patients of non-Korean ethnicity. The majority of tests were performed in hospitals (37.7%) or local clinics (34.5%). Interestingly, no female children were tested for whole blood G6PD during the study period. The prevalence of decreased G6PD activity (<7.9 U/g Hb) was 0.4% (19/5111 Koreans and 2/82 non-Koreans), and only seven male patients with G6PD deficiency (<30% of the male median) were identified, with ages ranging from 4.8 months to 50.2 years. No female patients with G6PD deficiency were found. Further research is necessary to determine the clinical significance of G6PD test results and monitor their use. [ABSTRACT FROM AUTHOR]

Simple Summary: Barth Syndrome (BTHS) is a rare X-linked genetic disease in which some patients suffer from severe infections due to neutrophil dysfunction. B cells produce cytokines that attract neutrophils to sites of infection. Here, we examined if B cells from BTHS patients exhibited a reduced ability to express chemokine (C-X-C motif) ligand 1 (CXCL1), a known chemoattractant for neutrophils. We show that B cells from BTHS patients exhibit lowered expression of CXCL1 when stimulated with bacteria compared to control cells. Our findings suggest that an impaired ability of B cells to produce cytokines might contribute to infections in some BTHS patients. Barth Syndrome (BTHS) is a rare X-linked genetic disease caused by a mutation in the TAFAZZIN gene, which codes for the protein tafazzin involved in cardiolipin remodeling. Approximately 70% of patients with BTHS exhibit severe infections due to neutropenia. However, neutrophils from BTHS patients have been shown to exhibit normal phagocytosis and killing activity. B lymphocytes play a crucial role in the regulation of the immune system and, when activated, secrete cytokines known to attract neutrophils to sites of infection. We examined the expression of chemokine (C-X-C motif) ligand 1 (CXCL1), a known chemotactic for neutrophils, in Epstein–Barr virus transformed control and BTHS B lymphoblasts. Age-matched control and BTHS B lymphoblasts were incubated with Pseudomonas aeruginosa for 24 h and then cell viability, CD27+, CD24+, CD38+, CD138+ and PD1+ surface marker expression and CXCL1 mRNA expression determined. Cell viability was maintained in lymphoblasts incubated in a ratio of 50:1 bacteria:B cells. Surface marker expression was unaltered between control and BTHS B lymphoblasts. In contrast, CXCL1 mRNA expression was reduced approximately 70% (p < 0.05) in untreated BTHS B lymphoblasts compared to control and approximately 90% (p < 0.05) in bacterial treated BTHS B lymphoblasts compared to the control. Thus, naïve and bacterial-activated BTHS B lymphoblasts exhibit reduced mRNA expression of the neutrophil chemoattractant factor CXCL1. We suggest that impaired bacterial activation of B cells in some BTHS patients could influence neutrophil function via impairing neutrophil recruitment to sites of infection and this could potentially contribute to these infections. [ABSTRACT FROM AUTHOR]

Simple Summary: Lateralized overgrowth may be isolated or accompany syndromes. Recently, international BWS consensus proposed that the patients with isolated lateralized overgrowth and epigenetic change related to this syndrome should be evaluated within the Beckwith–Wiedemann spectrum. The risk of cancer is high in patients with lateralized overgrowth, some patients also may be admitted presenting with a tumor. The aim of this study was to classify patients with lateralized overgrowth into isolated, atypical, and classic phenotypes according to consensus scoring, to investigate epigenetic alterations on chromosome 11p15.5, and to raise awareness for early detection and prevention of cancer. The Beckwith–Wiedemann spectrum (BWSp) ranges from isolated lateralized overgrowth (ILO) to classic phenotypes. In this broad clinical spectrum, an epigenetic alteration on chromosome 11p15.5 can be detected. The risk for embryonal tumors is high, especially in patients with lateralized overgrowth (LO). The aim of this study is to investigate epigenetic alterations in 11p15.5 and tumor risk in 87 children with LO. The methylation level of 11p15.5 was examined in the blood of all patients and in skin samples or buccal swabs from 40 patients with negative blood tests; 63.2% of patients were compatible with the ILO phenotype, 18.4% were atypical, and 18.4% were classic. The molecular diagnosis rate was 81.2% for the atypical and classic phenotypes, and 10.9% for the ILO phenotype. In patients with epigenetic alterations, LO was statistically significantly more severe than in test negatives. Tumors developed in six (6.9%) of the total 87 patients with LO; four belonged to the atypical or classical phenotype (12.5%) and two to ILO (3.5%). Three of the four patients with atypical/classical phenotypes had pUPD11, one had IC1-GOM alteration, and two ILO patients were negative. We conclude that LO patients should be monitored for tumor risk even if their epigenetic tests are negative. [ABSTRACT FROM AUTHOR]

Background: Haemophilia is an X-linked recessive genetic disorder characterised by bleeding within soft tissue and joints. The ankle is disproportionally affected by haemarthropathy when compared to the elbows and knees; reported as the most affected joints in patients with haemophilia. Despite advances in treatment, patients still report ongoing pain and disability, however, the impact has not been evaluated, nor has the effect on health-related quality of life (HRQoL) or foot and ankle patient-reported outcome measures (PROMs). The primary aim of this study was to establish the impact of ankle haemarthropathy in patients with severe and moderate haemophilia A and B. Secondly to identify the clinical outcomes associated with a decline in HRQoL and foot and ankle PROMs. Methods: A cross-sectional multi-centre questionnaire study was conducted across 18 haemophilia centres in England, Scotland and Wales with a recruitment target of 245 participants. The HAEMO-QoL-A and Manchester-Oxford Foot Questionnaire (MOXFQ) (foot and ankle) with total and domain scores measured impact on HRQOL and foot and ankle outcomes. Demographics, clinical characteristics, ankle haemophilia joint health scores, multi-joint haemarthropathy and Numerical Pain Rating Scales (NPRS) of "ankle pain over the past six months" were collected as a measure of chronic ankle pain. Results: A total of 243 of 250 participants provided complete data. HAEMO-QoL-A and MOXFQ (foot and ankle) total and index scores indicated worse HRQoL with total scores ranging from a mean of 35.3 to 35.8 (100 best-health) and 50.5 to 45.8 (0 best-health) respectively. NPRS (mean (SD)) ranged from 5.0 (2.6) to 5.5 (2.5), with median (IQR) ankle haemophilia joint health score of 4.5 (1 to 12.5) to 6.0 (3.0 to 10.0) indicating moderate to severe levels of ankle haemarthropathy. Ankle NPRS over six months and inhibitor status were associated with decline in outcome. Conclusions: HRQoL and foot and ankle PROMs were poor in participants with moderate to severe levels of ankle haemarthropathy. Pain was a major driver for decline in HRQoL and foot and ankle PROMs and use of NPRS has the potential to predict worsening HRQoL and PROMs at the ankle and other affected joints. [ABSTRACT FROM AUTHOR]

Background: The underlying mechanisms of obesity in X-linked hypophosphatemia (XLH) are not known. We aimed to evaluate whether FGF21, an endocrine FGF involved in the regulation of carbohydrate–lipid metabolism, could be involved. Methods: We performed a prospective multicenter cross-sectional study comparing FGF23, Klotho, and FGF21 levels in teenagers with XLH compared to healthy controls (VITADOS cohort) after matching for age, gender, and puberty. Non-parametric tests were performed (results presented as median (min–max)). Results: A total of 40 XLH teenagers (n = 20 Standard Of Care, SOC, n = 20 burosumab) were included. While patients receiving burosumab displayed increased BMI as compared to patients receiving SOC, systolic blood pressure expressed as percentile was progressively and significantly lower when comparing the three groups: 77 (4–99) in SOC, 47 (9–98) in burosumab, and 28 (1–94) in controls (p = 0.007). When compared to patients receiving SOC, patients receiving burosumab displayed significantly increased phosphate and 1,25(OH)2D levels. We found increased Klotho levels in patients receiving burosumab. No differences were found for either carbohydrate–lipid biomarkers or FGF21 between the three groups. A total of 21 XLH patients (53%) had insulin resistance (HOMA > 2.4, N = 10 SOC, N = 11 burosumab). Conclusion: FGF21 does not explain obesity/overweight in XLH. Of note, this study was performed in France in 2018–2019, early after the approval authorizing burosumab only in case of severe XLH despite SOC. As such, the data on systolic blood pressure highlighting a possible impact of burosumab to decrease blood pressure as well as increase Klotho levels deserve further studies given their potential effect on long-term cardiovascular risk. A higher resolution version of the Graphical abstract is available as Supplementary information [ABSTRACT FROM AUTHOR]

Transposable elements (TEs) have been implicated in autism spectrum disorder (ASD). However, our understanding of their roles is far from complete. Herein, we explored de novo TE insertions (dnTEIs) and de novo variants (DNVs) across the genomes of dizygotic twins with ASD and their parents. The neuronal regulatory elements had a tendency to harbor dnTEIs that were shared between twins, but ASD-risk genes had dnTEIs that were unique to each twin. The dnTEIs were 4.6-fold enriched in enhancers that are active in embryonic stem cell (ESC)-neurons (p < 0.001), but DNVs were 1.5-fold enriched in active enhancers of astrocytes (p = 0.0051). Our findings suggest that dnTEIs and DNVs play a role in ASD etiology by disrupting enhancers of neurons and astrocytes. [ABSTRACT FROM AUTHOR]

X-linked hypophosphatemia (XLH) is characterized by mutations in the PHEX gene, leading to elevated serum levels of FGF23, decreased production of 1,25 dihydroxyvitamin D3 (1,25D), and hypophosphatemia. Those affected with XLH manifest impaired growth and skeletal and dentoalveolar mineralization as well as increased mineralization of the tendon–bone attachment site (enthesopathy), all of which lead to decreased quality of life. Many molecular and murine studies have detailed the role of mineral ions and hormones in regulating complications of XLH, including how they modulate growth and growth plate maturation, bone mineralization and structure, osteocyte-mediated mineral matrix resorption and canalicular organization, and enthesopathy development. While these studies have provided insight into the molecular underpinnings of these skeletal processes, current therapies available for XLH do not fully prevent or treat these complications. Therefore, further investigations are needed to determine the molecular pathophysiology underlying the complications of XLH. [ABSTRACT FROM AUTHOR]

X-linked hypophosphatemia (XLH) is a rare type of hereditary hypophosphatemic rickets. Patients with XLH have various symptoms that lower their QOL as defined by HAQ, RAPID3, SF36-PCS, and SF36-MCS in adult patients and SF-10 and PDCOI in pediatric patients. Early diagnosis and treatment are needed to reduce the burden, but the condition is often diagnosed late in childhood. The present review aims to summarize the symptoms, radiological and biological characteristics, and long-term prognosis of pediatric XLH. Typical symptoms of XLH are lower leg deformities (age six months or later), growth impairment (first year of life or later), and delayed gross motor development with progressive lower limb deformities (second year of life or later). Other symptoms include dental abscess, bone pain, hearing impairment, and Chiari type 1 malformation. Critical, radiological findings of rickets are metaphyseal widening, cupping, and fraying, which tend to occur in the load-bearing bones. The Rickets Severity Score, validated for XLH, is useful for assessing the severity of rickets. The biochemical features of XLH include elevated FGF23, hypophosphatemia, low 1,25(OH)2D, and elevated urine phosphate. Renal phosphate wasting can be assessed using the tubular maximum reabsorption of phosphate per glomerular filtration rate (TmP/GFR), which yields low values in patients with XLH. XLH should be diagnosed early because the multisystem symptoms often worsen over time. The present review aims to help physicians diagnose XLH at an early stage. [ABSTRACT FROM AUTHOR]

Highlights: What are the main findings? Adherence to conventional treatment is essential but challenging for patients with XLH. Conventional treatment should continue even after XLH-children have stopped their growth. What is the implication of the main findings? Burosumab is a novel treatment strategy for pediatric patients with poor adherence to conventional treatment. X-linked hypophosphatemic rickets/osteomalacia is an inherited disease caused by the loss of function in PHEX. Elevated plasma FGF23 in patients with XLH leads to hypophosphatemia. The conventional treatment for XLH, consisting of oral phosphate and active vitamin D, is often poorly adhered to for various reasons, such as the requirement to take multiple daily doses of phosphate. Burosumab, an anti-FGF23 antibody, is a new drug that directly targets the mechanism underlying XLH. We report herein three adult patients with poor adherence to the conventional treatment. In Patient 1, adherence was poor throughout childhood and adolescence. The treatment of Patients 2 and 3 became insufficient after adolescence. All of the patients suffered from gait disturbance caused by pain, fractures, and lower extremity deformities early in life. We prescribed burosumab for the latter two patients, and their symptoms, which were unaffected by resuming conventional treatment, dramatically improved with burosumab. Maintaining adherence to the conventional treatment is crucial but challenging for patients with XLH. Starting burosumab therapy from childhood or adolescence in pediatric patients with poor adherence may help prevent the early onset of complications. [ABSTRACT FROM AUTHOR]

Objective The aim of the study is to examine the impact of maternal interpregnancy body mass index (BMI) change on subsequent offspring mortality risk. Study Design This is a retrospective cohort study of women who had two consecutive live singleton deliveries of at least 20 weeks' gestation from the Utah Population Database. Our exposure was defined as interpregnancy BMI change from the date of first delivery to the conception date of subsequent pregnancy. We categorized BMI change as: < − 1, −1 to 0, 0 to <1 (reference), 1 to 2, 2 to 4, ≥4 kg/m 2. Our primary outcome was all-cause age-specific mortality during four time periods: neonatal (≤28 days), infant (29 days to <1 year old), childhood ((≥1 to <5 years old), and late childhood (5 to <18 years old). We also examined mortality specifically attributed to congenital anomalies. Analyses used Cox proportional hazard models stratified by full term (≥37 weeks) and preterm (<37 weeks) deliveries. All models were adjusted for relevant confounders. Results Of 266,752 women, among full-term deliveries, women with a BMI increase of 4 kg/m 2 or more had an increased risk of neonatal mortality in their subsequent pregnancy (hazard ratio or HR = 1.72, 95% confidence interval or CI: 1.23–2.41) Women who lost 1 kg/m 2 or more between deliveries also had increased neonatal mortality (HR = 1.46, 95% CI: 1.04–2.05). There were no differences in infant, early, or late childhood mortality by interpregnancy BMI change. Maternal interpregnancy interval weight loss of 1 kg/m 2 or more and weight gain of ≥4 kg/m 2 also had increased risk of mortality associated with congenital anomalies or conditions arising during the neonatal period following their subsequent delivery. Conclusion Women with significant interpregnancy weight gain and modest weight loss have a significant increased risk of neonatal mortality following their subsequent pregnancy. Key Points Significant weight gain between deliveries increases the risk of neonatal death. Modest weight loss between deliveries increases the risk of neonatal death. This risk may be partially explained by increased risk of congenital malformations. [ABSTRACT FROM AUTHOR]

BACKGROUND: Evidence for a potential link between air pollution and rheumatoid arthritis (RA) is inconsistent, and the modified effect of genetic susceptibility on the relationship between air pollution and RA has not been well studied. OBJECTIVE: Using a general population cohort from the UK Biobank, this study aimed to investigate the associations between various air pollutants and the risk of incident RA and to further estimate the impact of combined exposure to ambient air pollutants on the risk of developing RA under the modification effect of genetic predisposition. METHODS: A total of 342,973 participants with completed genotyping data and who were free of RA at baseline were included in the study. An air pollution score was constructed by summing the concentrations of each pollutant weighted by the regression coefficients with RA from single-pollutant models to assess the combined effect of air pollutants, including particulate matter (PM) with diameters ≤ 2.5 µm (PM2.5), between 2.5 and 10 µm (PM2.5–10), and ≤ 10 µm (PM10), as well as nitrogen dioxide (NO2) and nitrogen oxides (NOx). In addition, the polygenic risk score (PRS) of RA was calculated to characterize individual genetic risk. The Cox proportional hazard model was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of associations of single air pollutant, air pollution score, or PRS with incident RA. RESULTS: During a median follow-up time of 8.1 y, 2,034 incident events of RA were recorded. The HRs (95% CIs) of incident RA per interquartile range increment in PM2.5, PM2.5-10, PM10, NO2, and NOx were 1.07 (1.01, 1.13), 1.00 (0.96, 1.04), 1.01 (0.96, 1.07), 1.03 (0.98, 1.09), and 1.07 (1.02, 1.12), respectively. We also found a positive exposure-response relationship between air pollution score and RA risk (푝Trend = 0.000053). The HR(95% CI) of incident RA was 1.14 (1.00, 1.29) in the highest quartile group compared with the lowest quartile group of the air pollution score. Furthermore, the results of the combined effect of air pollution score and PRS on the RA risk showed that the risk of RA incidence in the highest genetic risk and air pollution score group was almost twice that of the lowest genetic risk and air pollution score group [incidence rate (IR) per 100,000 person-years: 98.46 vs. 51.19, and HR= 1.73 (95% CI: 1.39, 2.17) vs. 1 (reference)], although no statistically significant interaction between the air pollution and genetic risk for incident RA was found (푝Interaction >0.05). DISCUSSION: The results revealed that long-term combined exposure to ambient air pollutants might increase the risk of RA, particularly in those with high genetic risk. [ABSTRACT FROM AUTHOR]

A personal narrative is presented which explores the author's experience of dealing with a 50 percent risk of developing cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an inherited genetic condition with no known treatment.

Background: Wiedemann–Steiner syndrome (WSS) is a rare genetic disorder caused by heterozygous variants in KMT2A. To date, the cognitive profile associated with WSS remains largely unknown, although emergent case series implicate increased risk of non‐verbal reasoning and visual processing deficits. This study examines the academic and learning concerns associated with WSS based on a parent‐report screening measure. Participants and Methods: A total of 25 parents of children/adults with a molecularly‐confirmed diagnosis of WSS (mean age = 12.85 years, SD = 7.82) completed the Colorado Learning Difficulties Questionnaire (CLDQ), a parent‐screening measure of learning and academic difficulties. Parent ratings were compared to those from a normative community sample to determine focal areas in Math, Reading and Spatial skills that may be weaker within this clinical population. Results: On average, parent ratings on the Math (mean Z = ‐3.08, SD = 0.87) and Spatial scales (mean Z = ‐2.52, SD = 0.85) were significantly more elevated than that of Reading (mean Z = ‐1.31, SD = 1.46) (Wilcoxon sign rank test Z < −3.83, P < 0.001), reflecting relatively more challenges observed in these areas. Distribution of parent ratings in Math items largely reflect a positively skewed distribution with most endorsing over three standard deviations below a community sample. In contrast, distributions of parent ratings in Reading and Spatial domains were more symmetric but flat. Ratings for Reading items yielded much larger variance than the other two domains, reflecting a wider range of performance variability. Conclusions: Parent ratings on the CLDQ suggest more difficulties with Math and Spatial skills among those with WSS within group and relative to a community sample. Study results are consistent with recent case reports on the neuropsychological profile associated with WSS and with Kabuki syndrome, which is caused by variants in the related gene KMT2D. Findings lend support for overlapping cognitive patterns across syndromes, implicating potential common disease pathogenesis. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder manifesting in early childhood with progressive muscular weakness and atrophy, and resulting in early loss of ambulation. The collection and evaluation of epidemiological data for this disease is crucial for an early diagnosis and disease management. In Germany, data are collected via the TREAT-NMD DMD patient registry (www.dmd-register.de). In contrast, data collection in Austria has not yet been performed systematically. For collecting data from Austrian DMD patients, an online survey of the patient's caregivers was conducted. Data of 57 patients were collected entailing initial symptoms, diagnosis and therapeutic measures. Comparable data has been collected for Germany via the TREAT-NMD DMD patient registry. 57 DMD patients aged 4–34 years completed the Austrian survey. On average, first symptoms of the disease appeared at the age of 3.1 years. As the most frequent first symptom, 46% of the patients described problems in climbing stairs. In 40% of the patients, DMD was diagnosed early due to an accidentally detected hyperCKemia in infancy or early childhood. Corticosteroids represented the main therapeutic option in our cohort. At the time of the survey, only 52% of the patients were treated with corticosteroids. Patients from Germany reported that first symptoms appeared at the age of 3.06 years. Diagnosis was established by genetic testing or muscle biopsy. 47% of the patients were treated with corticosteroids. Time between first symptoms and diagnosis was 7 months in Austria, and 4.7 months in Germany, respectively. Compared to earlier international studies, the Austrian data show encouraging results regarding earlier start of corticosteroid therapy in a larger percentage of patients. Austrian and German data show a trend towards an earlier diagnosis of DMD, while the age at symptom onset was similar to previous studies. The collection and evaluation of epidemiological data of DMD patients is important and will hopefully contribute to accelerate DMD diagnosis and treatment access for the patients. [ABSTRACT FROM AUTHOR]

Objective: The classic triad, which defines IFAP syndrome, is ichthyosis follicularis, alopecia, and photophobia. It is a rare X-linked genetic disorder characterized by multiple congenital anomalies with variable severity, caused by pathogenic variants in the MBTPS2 gene, which encodes a zinc metalloprotease that is essential for normal development. This study aimed to report a case of a Brazilian patient with IFAP syndrome presenting skeletal anomalies, which is a rare finding among patients from different families. Case description: We describe a male proband with IFAP syndrome showing severe ichthyosis congenita, cryptorchidism, limb malformation, and comprising the BRESHECK syndrome features. Using whole-exome sequencing, we identified a rare missense variant in hemizygosity in the MBTPS2 gene, which had not been identified in other family members. Comments: This is the first diagnosis of IFAP syndrome in Brazil with a molecular investigation. The present case study thus expands our knowledge on the mutational spectrum of MBPTS2 associated with IFAP syndrome. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is a severe, progressive and incurable X-linked genetic disorder. The article presents 18 children with DMD admitted between 2016-2022 in the Pediatric Clinic II, Emergency County Hospital in Craiova. The study looked at: the distribution according to residence, the average age when they walked, when they were diagnosed and when they walked in a wheelchair, heredocollateral and pathological antecedents, clinical manifestations, nutritional status, genetic tests and the evolution of these patients. [ABSTRACT FROM AUTHOR]

The region of the duplication contained the I HPS3 i gene, which appears to be the only known gene in this duplication to be involved in the pigmentary pathway.2 In our patient, this mosaic genetic anomaly did not result in any additional developmental abnormalities. As fibroblast culture was not possible from the skin biopsy, it remains unconfirmed whether this extra material is present as an interstitial duplication or as a supernumerary marker chromosome. An array comparative genomic hybridization on DNA extracted from a skin biopsy revealed a 63.63-Mb duplication, arr[GRCh37] 3q22.2q29(134212001 197837069)x3, on the long arm of chromosome 3. [Extracted from the article]

Barth syndrome (BTHS) is a rare X-linked genetic disease caused by mutations in TAFAZZIN. The tafazzin (Taz) protein is a cardiolipin remodeling enzyme required for maintaining mitochondrial function. Patients with BTHS exhibit impaired mitochondrial respiratory chain and metabolic function and are susceptible to serious infections. B lymphocytes (B cells) play a vital role in humoral immunity required to eradicate circulating antigens from pathogens. Intact mitochondrial respiration is required for proper B-cell function. We investigated whether Taz deficiency in mouse B cells altered their response to activation by anti-cluster of differentiation 40 (anti-CD40) + interleukin-4 (IL-4). B cells were isolated from 3–4-month-old wild type (WT) or tafazzin knockdown (TazKD) mice and were stimulated with anti-CD40 + IL-4 for 24 h and cellular bioenergetics, surface marker expression, proliferation, antibody production, and proteasome and immunoproteasome activities determined. TazKD B cells exhibited reduced mRNA expression of Taz, lowered levels of cardiolipin, and impairment in both oxidative phosphorylation and glycolysis compared to WT B cells. In addition, anti-CD40 + IL-4 stimulated TazKD B cells expressed lower levels of the immunogenic surface markers, cluster of differentiation 86 (CD86) and cluster of differentiation 69 (CD69), exhibited a lower proliferation rate, reduced production of immunoglobulin M and immunoglobulin G, and reduced proteasome and immunoproteasome proteolytic activities compared to WT B cells stimulated with anti-CD40 + IL-4. The results indicate that Taz is required to support T-cell-dependent signaling activation of mouse B cells. [ABSTRACT FROM AUTHOR]

The blood and its components are involved in a wide range of processes to support life, including fighting infection and providing the body's tissues with oxygen and nutrients. If any stage in the development of blood cells is disrupted, for example by genetic abnormalities or a lack of nutrients, disease may result. This article provides an overview of some of the blood's key components, blood cells and their formation and functions, blood groups and some of the problems that can arise from malfunctions. A case study on haemophilia A as a blood disorder is presented to consolidate knowledge. [ABSTRACT FROM AUTHOR]

Background: X-linked hypophosphatemic rickets (XLH) is the most common cause of inherited rickets. Historically, XLH was treated with oral phosphate and calcitriol (conventional treatment). Burosumab, a fibroblast growth factor 23 (FGF-23) monoclonal antibody, was approved by the United States Food and Drug Administration (FDA) in 2018 for XLH treatment. Nevertheless, conventional treatment of XLH continues to be recommended by some specialists due to lack of published experience with burosumab in the clinical setting. We compared laboratory and radiographic changes observed following transition from conventional therapy to burosumab in pediatric XLH patients as part of routine care. Methods: This retrospective single-center study identified and retroactively studied twelve patients aged 1–18 years old with XLH previously treated with conventional therapy and transitioned to burosumab. Laboratory studies and radiographs were obtained routinely as standard of care during two treatment periods: (1) conventional therapy and (2) burosumab treatment. Laboratory values and radiologic rickets severity scores were compared between periods. Results: All laboratory values demonstrated improvement following 1 month of burosumab treatment, findings which were sustained over the 2-year study period. Rickets severity scores and height z-scores also improved with burosumab. There were no serious adverse events with burosumab, and adverse events overall were very infrequent and mild. One patient developed an asymptomatic mild elevation of serum phosphate while taking burosumab resulting in a temporary pause in therapy. Conclusions: Safety and effectiveness of burosumab in treatment of XLH were demonstrated as burosumab yielded statistically significant improvement in laboratory and radiographic markers of rickets and height compared to conventional therapy. A higher resolution version of the Graphical abstract is available as Supplementary information. [ABSTRACT FROM AUTHOR]

The article offers information about the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome and disease taxonomy in rheumatology. It mentions that VEXAS syndrome, discovered through the use of a genotype-first approach, whereby a large genetic database was analyzed for commonalities among patients, with minimal consideration of clinical phenotype.

A clinical quiz on a case of a pediatric male patient with gross hematuria, edema, and hypocomplementemia is presented.

The last decade has been revolutionary regarding the management of rare bone diseases caused by impaired calcium and phosphate metabolism. Elucidation of the underlying genetic basis and pathophysiologic alterations has been the determinant factor for the development of new, disease-specific treatment agents. The phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) possesses a critical role in the pathogenesis of various hypophosphatemic disorders. Among them, the genetic disorder of X-linked hypophosphatemia and the acquired syndrome of tumor-induced osteomalacia, although very rare, have attracted the scientific community's attention towards designing an FGF23-inhibitor as a potential specific therapy. The monoclonal antibody burosumab was approved for the treatment of children and adult patients with X-linked hypophosphatemia and recently for tumor-induced osteomalacia patients, demonstrating benefits regarding their symptoms, biochemical profile and bone mineralization status. Asfotase alfa is a hydroxyapatite-targeted recombinant alkaline phosphatase, an enzymatic replacement therapy, substituting the defective activity of tissue non-specific alkaline phosphatase, in patients suffering from hypophosphatasia. Promising data regarding its favorable effect on survival rate, bone quality, fracture healing, muscle strength, mobility, respiratory function, and general quality of life have led to the approval of the drug for the treatment of childhood-onset hypophosphatasia. Given the high costs of treatment for both agents and their limited clinical use until now, more data are needed to define patients' characteristics that make them ideal candidates for therapy. Long-term safety issues also need to be clarified. [ABSTRACT FROM AUTHOR]

Keywords: XIAP deficiency; Gonosomal mosaicism; Droplet digital PCR EN XIAP deficiency Gonosomal mosaicism Droplet digital PCR 525 527 3 02/28/23 20230401 NES 230401 Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s10875-022-01414-2. Gonosomal mosaicism, caused by somatic mutations in the early stages of embryonal development, results in both germline and somatic mosaicism. [Extracted from the article]