X-linked Recessive Disease Research Articles

Phenotypic variability and the gender paradox in the R363C variant of Fabry disease.

Fabry disease is an X-linked lysosomal disease caused by variants in the GLA gene. Although Fabry disease is X-linked, GLA gene variants in females can exhibit a wide range of symptoms, challenging the traditional view of Fabry as an X-linked recessive disease. A family is presented here with a 36-year-old female who is symptomatic with chronic kidney disease and her oligosymptomatic 70-year-old father, both of whom have a heterozygous and hemizygous GLA pathogenic variant, respectively, c.1087C>T (p.R363C). Interestingly, the proband's Lyso-GL-3 levels were lower than her father's despite her more severe clinical presentation. The discordance between clinical severity and Lyso-GL-3 levels, particularly in the context of migalastat therapy, raises questions about the appropriate interpretation and use of this biomarker. The earlier and more severe symptom onset in the female proband suggests the potential role of genetic modifiers or other factors influencing disease expression. This report underscores the complexity of Fabry disease phenotypes and the limitations of current biomarkers in predicting disease severity, particularly in females. The observed paradox between clinical symptoms and biomarker levels suggests the need for a deeper understanding of the underlying mechanisms driving phenotypic variability in Fabry disease.

Beyond the "Dominant" and "Recessive" Patterns of Inheritance.

This study aimed to investigate whether genes with different modes of inheritance differ in the presence of promoter-enriched CGI loci. For each autosomal chromosome, the author searched for variations in the total number of diseases' phenotypes with autosomal dominant (AD) and recessive (AR) inheritance for a list of promoter-poor CGI (CGI-) and promoter-enriched CGI (CGI+) genes using the OMIM database. Then, the CGI- and CGI+ genes displaying random allelic or bi-allelic expression were examined. The author evaluated whether there was a distinct distribution of AD and AR diseases in the groups of chromosomes based on their SNP hotspot density. The same analysis was conducted for the X chromosome. The SPSS statistical package was utilized. The distribution of AD and AR diseases between CGI- and CGI+ bi-allelic genes significantly differed in autosomal chromosomes 6 and 17, which show intermediate SNP hotspot density. Additionally, a statistically significant difference was observed in AD and AR diseases in the remaining autosomal chromosomes with low SNP hotspots between their randomly allelic expressed CGI- and CGI+ genes. Specifically, AD diseases were related to CGI- genes, while AR diseases were associated with CGI+ genes. In the X chromosome, X-linked dominant (XLD) diseases were mainly found in CGI+ genes, and X-linked recessive (XLR) diseases were found in CGI- genes, regardless of the X-inactivation process. It is essential to study inheritance and classify genetic variants in a more stochastic way than the terms "Dominant" and "Recessive," and their derivatives, such as "Codominant" and "Incomplete Dominant," are applied in Mendelian and non-Mendelian inheritance. This concept may further explain the "Reduced Penetrance" and "Variable Expressivity" in certain human diseases. All the above suggests a need to reassess how genetic and epigenetic data are studied and utilized for genetic counseling or precision medicine.

Heart Disease in Mothers of Children with Duchenne Muscular Dystrophy.

Female carriers of Duchenne Muscular Dystrophy (DMD) carry a heterozygous pathogenic variant in the dystrophin gene and can transmit pathogenic variants to their offspring. DMD is an X-linked recessive disease that affects up to 19.8 in every 100,000 male births. Those carriers with symptoms can be referred to as women with dystrophinopathy. Even among asymptomatic carriers, cardiac involvement can be verified in between 2.5% and 75% through echocardiography. The most commonly affected wall of the left ventricle is the inferolateral, with myocardial fibrosis detected by cardiac nuclear resonance. Therefore, screening is recommended for these women carriers due to the risk of cardiomyopathy. There is a lack of longitudinal studies on the evolution of these carriers. In this article, data on clinical presentation, cardiac assessment for female patients with dystrophinopathy and DMD carriers, and approaches for these patients are discussed.

Chinese guidelines for emergency management of bleeding in hemophilia patients (2024)

Hemophilia is a X-linked recessive hemorrhagic disease. Bleeding is the most common complication of hemophilia, and it is also the main cause leading to death and disability or reducing the quality of life of hemophilia patients. Rapid identification and standardized management of the bleeding events is of great significance to improve the prognosis of hemophilia patients. Emergency department is the frontline department for hemophilia patients with bleeding. The emergent management process of hemophilia hemorrhage is complex and often needs multidisciplinary team cooperation. To increase the awareness of the related professionals who may involve in the management of bleeding events of hemophilia patients, in collaboration with the Thrombosis and Hemostasis Group, Chinese Society of Hematology, Chinese Medical Association, Hemophilia Treatment Center Collaborative Network of China issued the Chinese guidelines for emergency management of bleeding in hemophilia patients.

Safety and efficacy of viltolarsen in ambulatory and nonambulatory males with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease characterized by mutations in the dystrophin gene, causing motor and pulmonary function decline. Viltolarsen is indicated for patients with dystrophin gene mutations amenable to exon 53 skipping. Here, we report safety, motor function, and the first pulmonary function results from the open-label, phase II Galactic53 trial of viltolarsen (NCT04956289). Male participants aged ≥ 8years with DMD received 80mg/kg intravenous viltolarsen once weekly for 48weeks. Results from participants receiving viltolarsen were compared with an external control cohort group-matched for multiple variables. All treatment-emergent adverse events were mild or moderate, 4 were considered treatment-related, and no participants discontinued. Participants receiving viltolarsen experienced clinically meaningful benefits in pulmonary function with higher percent predicted forced vital capacity and higher peak cough flow at Week 49 compared with the control cohort for both ambulatory and nonambulatory participants. Viltolarsen also stabilized upper limb motor function over the Treatment Period. These results support viltolarsen as an important part of the treatment armamentarium for both ambulatory as well as nonambulatory patients with DMD.

Diarylpropionitrile-stimulated ERβ nuclear accumulation promotes MyoD-induced muscle regeneration in mdx mice by interacting with FOXO3A

Duchenne muscular dystrophy (DMD) is an X-linked recessive progressive degenerative disease of skeletal muscle, characterized by intramuscular inflammation, muscle regeneration disorder and replacement of muscle with fibroadipose tissue. DMD is caused by the absence of normal dystrophy. Impaired self-renew ability and limited differentiation capacity of satellite cells are proved as main reasons for muscle regeneration failure. The deficiency of estrogen impedes the process of muscle regeneration. However, the role of estrogen receptor β (ERβ) in muscle regeneration is still unclear. This study aims to investigate the role and the pharmacological effect of ERβ activation on muscle regeneration in mdx mice. This study showed that mRNA levels of ERβ and myogenic-related genes both witnessed increasing trends in dystrophic context. Our results revealed that treatment with selective ERβ agonist (DPN, diarylpropionitrile) significantly increased myogenic differentiation 1 (MyoD-1) level and promoted muscle regeneration in mdx mice. Similarly, in mdx mice with muscle-specific estrogen receptor α (ERα) ablation, DPN treatment still promoted muscle regeneration. Moreover, we demonstrated that myoblasts differentiation was accompanied by raised nuclear accumulation of ERβ. DPN treatment augmented the nuclear accumulation of ERβ and, thus, contributed to myotubes formation. One important finding was that forkhead box O3A (FOXO3A), as a pivotal transcription factor in Myod-1 transcription, participated in the ERβ-promoted muscle regeneration. Overall, we offered an interesting explanation about the crucial role of ERβ during myogenesis.

Hunter’s syndrome: a rare case report

Hunter’s syndrome also known as mucopolysaccridosis-II (MPS-II) is a very rare X-linked recessive disease. It is a chronic progressive metabolic disease. The incidence of this condition is 1 in 1, 62,000 live births, mostly males. There is excessive accumulation of glycosaminoglycan (GAGs) in the lysosome in various parts of body due to the deficiency of enzyme iduronate sulphatase (IDS) and manifests with variety of clinical signs and symptoms. Four novel mutations in IDS gene are reported among families of Hunter syndrome tested by Sanger sequencing of IDS gene.

Aneuploidy rates and likelihood of obtaining a usable embryo for transfer among in vitro fertilization cycles using preimplantation genetic testing for monogenic disorders and aneuploidy compared with in vitro fertilization cycles using preimplantation genetic testing for aneuploidy alone

ObjectiveTo compare aneuploidy rates among IVF cycles using preimplantation genetic testing for monogenic disorders (PGT-M) and aneuploidy (PGT-A) compared to IVF cycles using PGT-A alone, and to determine the likelihood of obtaining at least one usable embryo in cycles using PGT-M+PGT-A compared with cycles using PGT-A alone. DesignRetrospective cohort study SubjectsAll IVF cycles for patients aged 18-45 undergoing PGT-A with or without concurrent PGT-M at a single genetics laboratory from November 2019 to March 2023. ExposureUse of PGT-M+PGT-A versus use of PGT-A alone Main Outcome MeasuresPer-cycle aneuploidy rate stratified by age, and per-cycle likelihood of obtaining at least one usable embryo stratified by age and inheritance pattern of monogenic disease ResultsA total of 72,522 IVF cycles were included; 4,255 cycles (5.9%) using PGT-M+PGT-A and 68,267 cycles (94.1%) using PGT-A alone. The PGT-M+PGT-A group was younger than the PGT-A alone group (<35 years old: 56.1% vs 30.5%, p<0.001). The majority of PGT-M cycles were performed for autosomal dominant pathogenic variants (42.4%), followed by autosomal recessive (36.5%), X-linked dominant (13.3%), and X-linked recessive (7.5%). The median number of embryos biopsied was higher in PGT-A alone compared to PGT-M+PGT-A cycles for patients aged <35, but it was equivalent in all other age groups. Age stratified aneuploidy rates did not significantly differ between PGT-M+PGT-A compared with PGT-A alone cycles. The probability of having a usable embryo declined with increasing age across all inheritance patterns. Compared with PGT-A alone, PGT-M+PGT-A cycles for patients aged ≤40 across all inheritance patterns were significantly less likely to yield a usable embryo (p<0.01), except in cycles for autosomal recessive diseases in the 38-40 age group and X-linked recessive diseases in the 35-37 age group. There were no consistent differences seen between groups in patients over 40. Cycles for patients with autosomal dominant diseases had the lowest likelihood of yielding a usable embryo for patients aged <43. ConclusionIVF cycles using PGT-M+PGT-A have similar age-specific aneuploidy rates to those using PGT-A alone. Cycles for patients ≤ 40 using PGT-M+PGT-A are significantly less likely to yield a usable embryo compared to those using PGT-A alone.

Muscular Dystrophies: An Update Review

A broad group of illnesses known as muscular dystrophies are defined by pathologic alterations found in muscle tissue following biopsy. A progressive weakening of the skeletal muscles characterises the clinical appearance of these disorders. The most common type of muscular dystrophy is Duchenne Muscular Dystrophy, an X-linked recessive disease. Distal muscular dystrophy is most common in people between the ages of 40 and 60 and primarily affects the lower limbs, such as the hands, feet, arms, and legs. The development of muscle weakness during infancy or early childhood, usually before the age of two, is a common symptom of congenital muscular dystrophy. The majority of MD types frequently result in respiratory issues that affect the diaphragm and other breathing muscles. Several MD subtypes are linked to cardiac arrhythmias or cardiomyopathy. This class of disorders is the main target of gene transfer and gene repair therapies.

Cognition trajectory in Duchenne muscular dystrophy

BackgroundDuchenne muscular dystrophy (DMD) is an X-linked recessive disease brought on by genetic changes that alter the dystrophin (DYS) protein. There has been growing evidence that children with DMD have been at higher risk of developing symptoms of neurodevelopmental disorders. We aimed at defining the cognitive difficulties and their categories in patients with DMD, compared to healthy controls, and assessing their relation with the functional severity. This work was a multi-center, observational, case–control study conducted on DMD patients. Age and sex-matched healthy subjects with no neurologic, psychiatric, or medical comorbidities were included as normal controls.ResultsThere was a statistically significant difference in cognitive patterns between the studied groups. We have observed a significant relationship between cognitive difficulties and functional severity assessment in our patients. There was a statistically significant difference between the studied cases regarding basic characteristics and correlation between cognitive functions and demographic data.ConclusionsThe decline in cognitive functions in DMD patients compared to healthy controls was established. Education was the most affected domain in patients, with more speech delay and dropping out of school. Therefore, it was recommended to establish cognitive screening as a routine in the evaluation and follow-up of DMD children.

Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked: IPEX syndrome in pediatrics

Immune dysregulation, polyendocrinopathy, X-linked enteropathy (IPEX) is a rare genodermatosis associating dermatitis, enteropathy, type 1 diabetes, thyroiditis, hemolytic anemia and thrombocytopenia. It is an X-linked recessive disease affecting regulatory T lymphocytes. It is diagnosed in early childhood and can be quickly fatal. Malabsorption and associated problems cause affected individuals to die early in their lives. IPEX is caused by mutations in the FOXP3 gene on X chromosome, which encodes a DNA-binding protein required for regulatory T cell development. Treatment choices are restricted and primarily rely on the combination of immunosuppressive medicines such as prednisolone, tacrolimus, or sirolimus, or, when possible, hematopoietic stem cell transplantation. Here we present this pathology in a 3-year old boy who received an allogeneic bone marrow transplant from an HLA-identical family member.

Investigation of genotype-phenotype and familial features of Turkish dystrophinopathy patients.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive allelic muscle diseases caused by dystrophin gene mutations. Eight hundred thirty-seven patients admitted between 1997 and 2022 were included in the study. Two hundred twenty patients were analyzed by multiplex PCR (mPCR) alone. Five hundred ninety-five patients were investigated by multiplex ligation-dependent probe amplification (MLPA), and 54 patients were examined by sequencing. Deletion was detected in 60% (132/220) of the cases in the mPCR group only and in 58.3% (347/595) of the cases with MLPA analysis. The rates of deletion and duplication were 87.7% and 12.3%, respectively, in the MLPA analysis. Single exon deletions were the most common mutation type. The introns 43-55 (81.8%) and exons 2-21 (13.1%) regions were detected as hot spots in deletions. It was determined that 89% of the mutations were suitable for exon skipping therapy. The reading frame rule did not hold in 7.6% of D/BMD cases (17/224). We detected twenty-five pathogenic/likely pathogenic variants in sequencing, five of which were novel variants. Nonsense mutation was the most common small mutation (44%). 21% of DMD patients were familial. We detected germline mosaicism in four families (4.3%) in the large rearrangement group and one gonosomal mosaicism in a family with a nonsense mutation. This is the largest study examining genotype and phenotype data in Turkish D/BMD families investigated by MLPA analysis. The reading frame hypothesis is not valid in all cases. Sharing the genotype and phenotype characteristics of these cases in the literature will shed light on the molecular structure of DMD and guide gene therapy research. In genetic counseling, carrier screening in the family and possible gonadal mosaicism should be emphasized.

Creatine Kinase-MM/Proto-oncogene Tyrosine-Protein Kinase Receptor as a Sensitive Indicator for Duchenne Muscular Dystrophy Carriers.

Duchenne muscular dystrophy (DMD), a lethal X-linked recessive genetic disease, is characterized by progressive muscle wasting which will lead to premature death by cardiorespiratory complications in their late twenties. And 2.5-19% DMD carriers that also suffer from skeletal muscle damage or dilated cardiomyopathy when diagnosed as soon as possible is meaningful for prenatal diagnosis and advance warning for self-health. The current DMD carrier screening mainly relies on detecting serum creatine kinase activity, covering only 50-70% DMD carriers which will cause many false negatives and require the discovery of highly effective biomarker and simple detection procedure for DMD carriers. In this article, we have compiled a comprehensive summary of all documented biomarkers associated with DMD and categorized them based on their expression patterns. We specifically pinpointed novel DMD biomarkers, previously unreported in DMD carriers, and conducted further investigations to explore their potential. Compared to creatine kinase activity alone in DMD carriers, creatine kinase-MM can improve the specificity from 73 to 81%. And our investigation revealed another promising protein: proto-oncogene tyrosine-protein kinase receptor (RET). When combined with creatine kinase-MM (creatine kinase-MM/RET ratio), it significantly enhances the specificity (from 81 to 83%) and sensitivity (from71.4 to 93%) of detecting DMD carriers in serum. Moreover, we successfully devised an efficient method for extracting RET from dried blood spots. This breakthrough allowed us to detect both creatine kinase-MM and RET using dried blood spots without compromising the detection rate.

An Ayurvedic Perspective About Duchenne Muscular Dystrophy

Duchenne muscular dystrophy is a neuromuscular disease. This is an X-linked recessive disease caused by mutations in the dystrophin protein gene located on the short arm of the X chromosome, in the Xp21 region. It causes progressive muscle weakness due to wasting of muscle fibers. It causes loss of ability to stand, walk, and move before age 10; most patients die in their 20s. Since there is no specific treatment in any medical system and the prognosis of the disease is uncertain, if we start treatment at an early stage, children with DMD can walk, it can slow or stop progressive muscle degeneration. DMD cannot be directly related to a single disease in Ayurveda. Most major neuromuscular disorders are determined by Vata dosha. In Ayurveda, this pathogenesis can be clearly understood by the concept of Adibala Pravrutta Vyadhi (genetic disease). Here the pathogenesis is due to Beeja Bhagavayava Dusti (partial chromosomal defect) leading to Mamsa Vata Dushti.

Клинический случай ингибиторной формы гемофилии В у ребенка

Hemophilia B is a hereditary, X-linked recessive disease caused by a violation of plasma homeostasis, resulting from a deficiency or absence of coagulation factor IX (FIX). The cause is a mutation of the Xq27 gene encoding FIX. A serious complication of this pathology is the inhibitory form, clinically manifested by the presence of IgG allo-antibodies neutralizing exogenous FIX. The article describes a clinical case of an inhibitory form of hemophilia B in a 12-year-old child.

A Novel Splicing Mutation Leading to Wiskott-Aldrich Syndrome from a Family.

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 + 5G > 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.

Prenatal diagnosis of dent disease type I with a nonsense pathogenic variant in CLCN5: a case study

IntroductionDent disease type I is a rare X-linked recessive renal tubular disease resulting from pathogenic variants in the CLCN5 gene. Due to the rarity of Dent disease type I and the diversity of its phenotypes, its clinical diagnosis is complex and poses a challenge to clinicians.MethodsA foetus and a child from a 36-year-old pregnant woman with a birth history of abnormal children were enrolled in this study. Pregnant women undergo amniocentesis for prenatal diagnosis at the gestational age of 12+ 3 weeks. Chromosomal microarray (CMA) analysis and whole-exome sequencing (WES) were employed to investigate the chromosomal copy number and single gene variants. Literature retrieval and data analysis were performed for genotype and phenotype collection analysis.ResultsNo chromosomal abnormalities or CNVs were detected in the entire family through karyotype and familial CMA analyses. WES identified a nonsense pathogenic variant in CLCN5 of the X chromosome, c.1942 C > T (exon 11, NM_000084), which was inherited from his mother, who exhibited regular clinical features.ConclusionThis study suggests that children with low-molecular-weight proteinuria and hypercalciuria should undergo prompt genetic testing to exclude Dent disease.

Duchenne muscular dystrophy treatment with lentiviral vector containing mini-dystrophin gene in vivo.

Duchenne muscular dystrophy (DMD) is an incurable X-linked recessive genetic disease caused by mutations in the dystrophin gene. Many researchers aim to restore truncated dystrophin via viral vectors. However, the low packaging capacity and immunogenicity of vectors have hampered their clinical application. Herein, we constructed four lentiviral vectors with truncated and sequence-optimized dystrophin genes driven by muscle-specific promoters. The four lentiviral vectors stably expressed mini-dystrophin in C2C12 muscle cells in vitro. To estimate the treatment effect in vivo, we transferred the lentiviral vectors into neonatal C57BL/10ScSn-Dmdmdx mice through local injection. The levels of modified dystrophin expression increased, and their distribution was also restored in treated mice. At the same time, they exhibited the restoration of pull force and a decrease in the number of mononuclear cells. The remissions lasted 3-6 months in vivo. Moreover, no integration sites of vectors were distributed into the oncogenes. In summary, this study preliminarily demonstrated the feasibility and safety of lentiviral vectors with mini-dystrophin for DMD gene therapy and provided a new strategy to restore truncated dystrophin.

Adherence tool for prophylactic haemophilia treatment in adult and adolescent patients: A systematic review and meta-analysis protocol

Hemophilia is a congenital bleeding disorder resulting from a low level or deficiency of clotting factors. It is an x-linked recessive disease and happens almost exclusively in males whereas females are the carrier of the affected gene. The most common types of hemophilia are hemophilia A and Hemophilia B. Hemophilia is classified into mild, moderate and severe. Prophylaxis treatment has more advantages clinically compare to on-demand therapy. It may reduce the bleeding frequency, gives protection from joint damage, may lower the number of total bleeding episodes per year, and may reduce annualised spontaneous and trauma related bleeding events. However, prophylaxis treatment needs regular weekly infusions therefore it is painful to administer especially if the vein is difficult to access. It may cause pain at the site of injections and may lead to non-adherence to treatment. Non-adherence to a regimen will result in insufficient clotting factor levels in the body. The efficacy of the medication is reduced and may lead to a high bleeding tendency. Thus far, the study on adult haemophilic patient adherence tool is scarce and limited; and therefore this review is warranted. The study protocol is conducted as per the PRISMA-P guideline. There are 4 concepts in this systematic review which are Haemophilia, adult and adolescence, preventive treatment and adherence. Articles will be sought from electronic databases PUBMED, Ovid EMBASE, CINAHL, and SCOPUS using the MeSH term, synonym free-text word, truncation, and proximity operators as per each database. The proposed keywords within each concept will be joined using the Boolean operator “OR “and the 4 different concepts combined using the Boolean operator “AND”. Search will be limited to Human, English language, and publication until 2022. Studies will be included if they meet the study inclusion criteria. The quality of the studies will be appraised using the Newcastle-Ottawa quality assessment scale (NOS) for observation-based studies. This systematic review does not require formal ethical approval as data will be extracted from selected published studies. The results will be disseminated through a peer-reviewed publication and relevant conference presentations.(PROSPERO registration CRD42021273813)

Generation of a human iPSC line (CHCMUi002-A) from peripheral blood mononuclear cells from a chronic granulomatous disease patient

Chronic granulomatous disease (CGD) is a rare X-linked recessive primary immunodeficiency disease (PID). Herein, a human induced pluripotent stem cell (iPSC) line was generated from the peripheral blood mononuclear cells (PBMCs) of a CGD patient with a mutation (c.785_786delTT) in the CYBB gene. These iPSCs showed the expression of pluripotency markers, the ability to differentiate into three germ layers. They offer a promising technique for studying the pathogenesis and conducting drug screening for CGD patients.